Genetics Chapter 12 + Paragraphs

What does QT (LQT) syndrome predispose affected people to?

Fatal cardiac arrhythmias caused by either inherited mutations or by exposure to drugs that block potassium channels

recurrence risks and transmission patterns part 2

It is sometimes difficult to differentiate polygenic or multifactorial diseases from single-gene diseases that have reduced penetrance or variable expression. Large data sets and good family history data are necessary to make the distinction. Several criteria are usually used to define multifactorial inheritance . • The recurrence risk is higher if more than one family member is affected. For example, the sibling recurrence risk for a ventricular septal defect (VSD, a type of congenital heart defect) is 3% if one sibling has had a VSD but increases to approximately 10% if two siblings have had VSDs. In contrast, the recurrence risk for single-gene diseases remains the same regardless of the number of affected siblings. This increase does not mean that the family's risk has actually changed. Rather, it means that we now have more information about the family's true risk: because they have had two affected children, they are probably located higher on the liability distribution than a family with only one affected child. In other words, they have more risk factors (genetic and/or environmental) and are more likely to produce an affected child. • If the expression of the disease in the proband is more severe, the recurrence risk is higher. This is again consistent with the liability model, because a more-severe expression indicates that the affected person is at the extreme tail of the liability distribution (see Fig. 12-2). His or her relatives are thus at a higher risk to inherit disease-causing genes. For example, the occurrence of a bilateral (both sides) cleft lip/palate confers a higher recurrence risk on family members than does the occurrence of a unilateral (one side) cleft . • The recurrence risk is higher if the proband is of the less commonly affected sex (see, for example, the previous discussion of pyloric stenosis). This is because an affected individual of the less susceptible sex is usually at a more extreme position on the liability distribution. • The recurrence risk for the disease usually decreases rapidly in more remotely related relatives (Table 12-2). Although the recurrence risk for single-gene diseases decreases by 50% with each degree of relationship (e.g., an autosomal dominant disease has a 50% recurrence risk for offspring of affected persons, 25% for nieces or nephews, 12.5% for first cousins, and so on), it decreases much more quickly for multifactorial diseases. This reflects the fact that many genetic and environmental factors must combine to produce a trait. All of the necessary risk factors are unlikely to be present in less closely related family members. • If the prevalence of the disease in a population is f (which varies between zero and one), the risk for offspring and siblings of probands is approximately f . This does not hold true for single-gene traits, because their recurrence risks are independent of population prevalence. It is not an absolute rule for multifactorial traits either, but many such diseases do tend to conform to this prediction. Examination of the risks given in Table 12-2 shows that these three diseases follow the prediction fairly well. Risks for multifactorial diseases usually increase if more family members are affected, if the disease has more severe expression, and if the affected proband is a member of the less commonly affected sex. Recurrence risks decrease rapidly with moreremote degrees of relationship. In general, the sibling recurrence risk is approximately equal to the square root of the prevalence of the disease in the population

cardiovascular diseases - Heart disease

. Heart disease is the leading cause of death worldwide, and it accounts for approximately 25% of all deaths in the United States. The most common underlying cause of heart disease is coronary artery disease (CAD), which is caused by atherosclerosis (a narrowing of the coronary arteries resulting from the formation of lipid-laden lesions). This narrowing impedes blood flow to the heart and can eventually result in a myocardial infarction (death of heart tissue caused by an inadequate supply of oxygen). When atherosclerosis occurs in arteries that supply blood to the brain, a stroke can result. A number of risk factors for CAD have been identified, including obesity, cigarette smoking, hypertension, elevated cholesterol level, and positive family history (usually defined as having one or more affected firstdegree relatives). Many studies have examined the role of family history in CAD, and they show that a person with a positive family history is at least twice as likely to suffer from CAD than is a person with no family history. Generally, these studies also show that the risk is higher if there are more affected relatives, if the affected relative is female (the less commonly affected sex) rather than male, and if the age of onset in the affected relative is early (before 55 years of age). For example, one study showed that men between the ages of 20 and 39 years had a threefold increase in CAD risk if they had one affected first-degree relative. This risk increased to 13-fold if there were two first-degree relatives affected with CAD before 55 years of age. What part do genes play in the familial clustering of CAD? Because of the key role of lipids in atherosclerosis, many studies have focused on the genetic determination of variation in circulating lipoprotein levels. An important advance was the identification of the gene that encodes the low-density lipoprotein (LDL) receptor. Heterozygosity for a mutation in this gene roughly doubles LDL cholesterol levels and is seen in approximately 1 in 500 persons. (This condition, known as familial hypercholesterolemia, is described further in Clinical Commentary 12-2.) Mutations in the gene encoding apolipoprotein B, which are seen in about 1 in 1000 persons, are another genetic cause of elevated LDL cholesterol. These mutations occur in the portion of the gene that is responsible for binding of apolipoprotein B to the LDL receptor, and they increase circulating LDL cholesterol levels by 50% to 100%. Dozens of other genes involved in lipid metabolism and transport have been identified, including those genes that encode various apolipoproteins (these are the protein components of lipoproteins) (Table 12-5). In addition, several genes whose protein products contribute to inflammation have been associated with CAD, reflecting the critical role of inflammation in generating atherosclerotic plaques. Functional analysis of these genes is leading to increased understanding and more effective treatment of CAD. Environmental factors, many of which are easily modified, are also important causes of CAD. There is abundant epidemiological evidence that cigarette smoking and obesity increase the risk of CAD, whereas exercise and a diet low in saturated fats decrease the risk. Indeed, the approximate 60% reduction in age-adjusted mortality due to CAD and stroke in the United States since 1950 is usually attributed to a decrease in the percentage of adults who smoke cigarettes, decreased consumption of saturated fats, improved medical care, and increased emphasis on healthy lifestyle factors such as exercise. Another form of heart disease is cardiomyopathy, an abnormality of the heart muscle that leads to inadequate cardiac function. Cardiomyopathy is a common cause of heart failure, resulting in approximately 10,000 deaths annually in the United States. Nearly 100 different genes have been linked to cardiomyopathy. Hypertrophic cardiomyopathy, one major form of the disease, is characterized by thickening (hypertrophy) of portions of the left ventricle and is seen in as many as 1 in 500 adults. About half of hypertrophic cardiomyopathy cases are familial and are caused by autosomal dominant mutations in any of the multiple genes that encode various components of the cardiac sarcomere. The most commonly mutated genes are those that encode the β-myosin heavy chain (35% of familial cases), myosin-binding protein C (20% of cases), and troponin T (15% of cases). In contrast to the hypertrophic form of cardiomyopathy, dilated cardiomyopathy, which is seen in about 1 in 2500 persons, consists of increased size and impaired contraction of the ventricles. The end result is impaired pumping of the heart. This disease is familial in about one third of affected persons; although autosomal dominant mutations are most common, mutations can also be X-linked or mitochondrial. The most commonly mutated gene encodes titin, a cytoskeletal protein. Other genes that can cause dilated cardiomyopathy encode other cytoskeletal proteins, including actin, cardiac troponin T, desmin, and components of the dystroglycan-sarcoglycan complex. (Recall from Chapter 5 that abnormalities of the latter proteins can also cause muscular dystrophies.) Mutations have also been identified in more than a dozen genes that cause the long QT (LQT) syndrome. LQT, which is seen in approximately 1 in 2000 persons, describes the characteristically elongated QT interval in the electrocardiogram of affected individuals, indicative of delayed cardiac repolarization. This disorder, which can be caused either by inherited mutations or by exposure to drugs that block potassium channels, predisposes affected persons to potentially fatal cardiac arrhythmia. An autosomal dominant form, known as Romano-Ward syndrome, can be caused by lossof-function mutations in genes that encode potassium channels (such as KCNQ1, KCNH2, KCNE1, KCNE2, or KCNJ2). These mutations delay cardiac repolarization. Gain-of-function mutations in several of these same genes have been shown to produce a shortened QT interval, as might be expected. Romano-Ward syndrome can also be caused by gain-of-function mutations in sodium or calcium channel genes (SCN5A and CACNA1C, respectively), which result in a prolonged depolarizing current. (Other examples of mutations that can cause LQT are given in Table 12-6.) An autosomal recessive form of LQT syndrome, known as Jervell-Lange-Nielsen syndrome, is less common than the Romano-Ward syndrome but is associated with a longer QT interval, a higher incidence of sudden cardiac death, and sensorineural deafness. This syndrome is caused by mutations in either KCNQ1 or KCNE1. Because LQT syndrome can be difficult to diagnose clinically, genetic testing enables more accurate diagnosis of affected persons. In addition, the identification of disease-causing genes and their protein products is now guiding the development of drug therapy to activate the encoded ion channels. Because cardiac arrhythmias account for most of the 300,000 sudden cardiac deaths that occur annually in the United States, a better understanding of the genetic defects underlying arrhythmia is of considerable public health significance. Heart disease aggregates in families. This aggregation is especially strong if there is early age of onset and if there are several affected relatives. Specific genes have been identified for some subsets of families with heart disease, and lifestyle changes (exercise, diet, avoidance of tobacco) can modify heart disease risks appreciably.

Stroke

. Stroke, which refers to brain damage caused by a sudden and sustained loss of blood flow to the brain, can result from arterial obstruction (ischemic stroke, which accounts for 80% of stroke cases) or breakage (hemorrhagic stroke). This disease is the fourth leading cause of mortality in the United States, accounting for approximately 140,000 deaths per year. As with heart disease, strokes cluster in families: One's risk of having a stroke increases by two- to threefold if a parent has had a stroke. The largest twin study conducted to date showed that concordance rates for stroke death in MZ and DZ twins were 10% and 5%, respectively. These figures imply that genes might influence one's susceptibility to this disease. Stroke can be caused by any of more than a dozen singlegene disorders, including sickle cell disease (see Chapter 3), MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke, a mitochondrial disorder discussed in Chapter 5), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, a condition characterized by recurrent strokes and dementia and caused by mutations in the NOTCH3 gene). Because blood clots are a common cause of stroke, it is expected that mutations in genes that encode coagulation factors might affect stroke susceptibility. For example, inherited deficiencies of protein C and protein S, both of which are coagulation inhibitors, are associated with an increased risk of stroke, especially in children. A specific mutation in clotting factor V, the factor V Leiden allele, causes resistance to activated protein C and thus produces an increased susceptibility to clotting. Heterozygosity for this allele, which is seen in approximately 5% of whites, produces a sevenfold increase in the risk of venous thrombosis (clots). In homozygotes, the risk increases to 100-fold. However, the evidence for an association between the factor V Leiden allele and stroke is inconsistent. In addition to family history and specific genes, several factors are known to increase the risk of stroke. These include hypertension, obesity, atherosclerosis, diabetes, and smoking. Stroke, which clusters in families, is associated with several singlegene disorders and with some inherited coagulation disorders

What do Twin studies show about Schizophrenia?

1- A 47% concordance rate for MZ twins, compared with only 12% for DZ twins 2- The concordance rate for MZ twins reared apart, 46%, is about the same as the rate for MZ twins reared together. 3- The risk of developing the disease for offspring of a schizophrenic parent who are adopted by normal parents is about 10%, approximately the same as the risk when the offspring are raised by a schizophrenic biological parent.

What are the characteristics of Type I Alcoholics?

1- Characterized by later onset (after 25 years of age) 2- Occurrence in both males and females, and greater psychological dependency on alcohol 3- Are more likely to be introverted, solitary drinkers 4- Type I is less likely to cluster in families

What is obesity an important risk factor for?

1- Heart disease 2- Stroke 3- Type 2 diabetes 4- Cancers of prostate, breast and colon

What are examples of cancers caused primarily by infectious agents?

1- Human papilloma virus for cervical cancer 2- Hepatits B and C for liver cancer appx 15% of worldwide cancer cases are caused primarily by infectious agents

What are the biases that twin studies are faced with?

1- Most serious: greater degree of environmental sharing among MZ twins 2- Somatic mutations - can affect one twin and not the other plus more

What are the 2 most important risk factors for Type II diabetes?

1- Positive family history 2- Obesity (increases insulin resistance)

Describe the characteristics of Type II alcoholics

1- Predominantly seen in males, typically occurs before 25 years of age (early onset) 2- Tend to be extroverted and thrill seeking 3- Type II is more difficult to treat successfully and tends to cluster more strongly in families

What are the biases in adoption studies?

1- Prenatal environmental influences could have long-lasting effects on an adopted child 2- Children are sometimes adopted after they are several years old, ensuring that some nongenetic influences have been imparted by the natural parents 3- Adoption agencies sometimes try to match the adoptive parents with the natural parents in terms of attributes such as socioeconomic status all of these factors could exaggerate the apparent influence of biological inheritance

What chances of developing Type I diabetes in families?

1- Siblings of persons with type 1 diabetes face a substantial elevation in risk: approximately 6%, as opposed to a risk of about 0.3% to 0.5% in the general population 2- The risk for offspring of diabetic mothers is only 1% to 3%, but it is 4% to 6% for the offspring of diabetic fathers. 3- Twin studies show that the empirical risk for MZ twins of type 1 diabetes patients ranges from 30% to 50%. In contrast, the concordance rate for DZ twins is 5% to 10% 4- If an affected proband and a sibling are both heterozygous for the DR3 and DR4 alleles, the sibling's risk of developing type 1 diabetes is nearly 20%

How are Emperical risks calculated?

1- a large series of families is examined in which one child (the proband) has developed the disease 2- The relatives of each proband are surveyed in order to calculate the percentage who have also developed the disease. 3- For example in North America neural tube defects are seen in about 2% to 3% of the siblings of probands with this condition Thus, the recurrence risk for parents who have had one child with a neural tube defect is 2% to 3% In contrast to most single-gene diseases, recurrence risks for multifactorial diseases can change substantially from one population to another

What is the frequency of twin births?

1/100 births in populations of European ancestry They are slightly more common among African americans nad bit less common among Asians

What is the increased risk of developing CAD if one has 2 first-degree relatives affected with CAD before the age of 55?

13 fold

What chromosome are several dozen of the polymorphisms associated with prostate cancer located on?

8q24 which contains polymorphisms associated with several other cancers as well (colon, pancreas, and esophagus) Although the 8q24 region contains no protein-coding genes, it contains enhancer elements that affect expression of the MYC oncogene, located about 250 kb from 8q24.

Threshold model

A number of diseases do not follow the bell-shaped distribution. Instead, they appear to be either present or absent in individuals. Yet they do not follow the patterns expected of single-gene diseases. A commonly used explanation is that there is an underlying liability distribution for these diseases in a population (Fig. 12-2). Persons who are on the low end of the distribution have little chance of developing the disease in question (i.e., they have few of the alleles or environmental factors that would cause the disease). Those who are closer to the high end of the distribution have more of the diseasecausing alleles and environmental factors and are more likely to develop the disease. For multifactorial diseases that are either present or absent, a threshold of liability must be crossed before the disease is expressed. Below the threshold, the person appears unaffected; above it, he or she is affected by the disease A disease that is thought to correspond to this threshold model is pyloric stenosis, a disorder that manifests shortly after birth and is caused by a narrowing or obstruction of the pylorus, the area between the stomach and intestine. Chronic vomiting, constipation, weight loss, and electrolyte imbalance result from the condition, which can be corrected by surgery or sometimes resolves spontaneously. The prevalence of pyloric stenosis among whites is about 3/1000 live births. It is much more common in males than in females, affecting 1/200 males and 1/1000 females. It is thought that this difference in prevalence reflects two thresholds in the liability distribution; a lower one in males and a higher one in females (see Fig. 12-2). A lower male threshold implies that fewer disease-causing factors are required to generate the disorder in males. The liability threshold concept can explain the pattern of sibling recurrence risks for pyloric stenosis, shown in Table 12-1. Notice that males, having a lower threshold, always have a higher risk than females. However, the recurrence risk also depends on the sex of the proband. It is higher when the proband is female than when the proband is male. This reflects the concept that females, having a higher liability threshold, must be exposed to more disease-causing factors than males in order to develop the disease. Thus, a family with an affected female must have more genetic and environmental risk factors, producing a higher recurrence risk for pyloric stenosis in future offspring. In such a situation, we would expect that the highest risk category would be male relatives of female probands; Table 12-1 shows that this is indeed the case. A number of other congenital malformations are thought to correspond to this model. They include isolated* cleft lip and/or cleft palate, neural tube defects (anencephaly and spina bifida), club foot (talipes), and some forms of congenital heart disease The threshold model applies to many multifactorial diseases. It assumes that there is an underlying liability distribution in a population and that a threshold on this distribution must be passed before a disease is expressed

What genes affect Schizophrenia? What do major drugs used to treat schizophrenia block?

A number of the genes in these regions encode components of the glutamatergic and dopaminergic neuronal signaling pathways Dopamine receptors

What is Schizophrenia?

A severe emotional disorder characterized by delusions, hallucinations, retreat from reality and bizarre, withdrawn or inappropriate behavior The lifetime recurrence risk for schizophrenia among the offspring of one affected parent is approximately 8% to 10%, which is about 10 times higher than the risk in the general population. a person with an affected sibling and an affected parent has a risk of about 15% to 20%, and a person with two affected parents has a risk of 40% to 50%.

People with the presence of what allele are much less likely to become alcoholics?

ALDH2*2 allele of the ALDH2 gene (ALDH2*2) results in excessive accumulation of acetaldehyde and thus in facial flushing, nausea, palpitations, and lightheadedness.

A small percentages of mutations are caused by what gene located on Chromosome 21?

APP gene encodes APP itself mutations in this gene lead to accumulation of the longer protein product It is interesting that this gene is present in three copies in persons with trisomy 21, where the extra gene copy leads to amyloid deposition and the frequent occurrence of earlyonset AD in Down syndrome patients

What is cardiomyopathy? What is it a common cause of?

Abnormality of the heart muscle that leads to inadequate cardiac muscle Heart failure - results in appx 10,000 deaths annually in the US nearly 100 different genes have been linked to cardiomyopathy

What is hypertrophic cardiomyopathy caused by?

About half of hypertrophic cardiomyopathy cases are familial and are caused by autosomal dominant mutations in any of the multiple genes that encode various components of the cardiac sarcomere

Alzheimer's Disease

Alzheimer disease (AD), which is responsible for 60% to 70% of cases of progressive cognitive impairment among the elderly, affects approximately 10% of the population older than 65 years and 40% of the population older than 85 years. Because of the aging of the population, the number of Americans with AD, which is currently about 5 million, continues to increase. Alzheimer disease is characterized by progressive dementia and memory loss and by the formation of amyloid plaques and neurofibrillary tangles in the brain, particularly in the cerebral cortex and hippocampus. The plaques and tangles lead to progressive neuronal loss, and death usually occurs within 7 to 10 years after the first appearance of symptoms. n affected first-degree relative. Although most cases do not appear to be caused by single genes, approximately 10% follow an autosomal dominant mode of transmission. About 3% to 5% of AD cases occur before age 65 years and are considered early onset; these are much more likely to be inherited in autosomal dominant fashion Alzheimer disease is a genetically heterogeneous disorder. Approximately half of early-onset cases can be attributed to mutations in any of three genes, all of which affect amyloid-β deposition. Two of the genes, presenilin 1 (PS1) and presenilin 2 (PS2), are very similar to each other, and their protein products are involved in cleavage of the amyloid-β precursor protein (APP) by γ-secretase (posttranslational modification; see Chapter 2). Gain-of-function mutations in PS1 or PS2 affect the cleavage of APP such that amyloid-producing forms of it accumulate excessively and are deposited in the brain (Fig. 12-9). This is thought to be a primary cause of AD. Mutations in PS1 typically result in especially early onset of AD, with the first occurrence of symptoms in the fifth decade of life A small percentage of cases of early-onset AD are caused by mutations of the gene (APP) that encodes APP itself, which is located on chromosome 21. These mutations disrupt normal secretase cleavage sites in APP (see Fig. 12-9), again leading to the accumulation of the longer protein product. It is interesting that this gene is present in three copies in persons with trisomy 21, where the extra gene copy leads to amyloid deposition and the frequent occurrence of earlyonset AD in Down syndrome patients (see Chapter 6). Highthroughput DNA sequencing studies have revealed an allele in APP that is protective against Alzheimer disease and may help to prevent cognitive decline An important risk factor for the more common late-onset form of AD is allelic variation in the apolipoprotein E (APOE) locus, which has three major alleles: ε2, ε3, and ε4. Studies conducted in diverse populations have shown that persons who have one copy of the ε4 allele are 2 to 5 times more likely to develop AD, and those with two copies of this allele are 5 to 10 times more likely to develop AD. The risk varies somewhat by population, with higher ε4-associated risks in whites and Japanese and relatively lower risks in Latin Americans and African Americans. Despite the strong association between ε4 and AD, approximately half of persons who develop late-onset AD do not have a copy of the ε4 allele, and many who are homozygous for ε4 remain free of AD even at advanced age. The apolipoprotein E protein product is not involved in cleavage of APP but instead appears to be associated with clearance of amyloid from the brain. Genome-wide association studies, based on microarrays and high-throughput sequencing, indicate that there are many additional genes associated with late-onset AD. Diseaseassociated variants that are relatively common in populations tend to confer only a modest increase in risk, as is the case with most multifactorial conditions. Less common diseaseassociated variants, revealed by high-throughput sequencing, confer a higher relative risk of AD but are generally rare in populations. AD has several features that have made it somewhat refractory to genetic analysis. Its genetic heterogeneity has already been described. In addition, because a definitive diagnosis can be obtained only by a brain autopsy, it is often difficult to diagnose AD in living family members (although clinical features and brain imaging studies can provide strong evidence that a person is affected with AD). Finally, because onset of the disease can occur very late in life, persons carrying an AD-predisposing mutation could die from another cause before developing the disease. They would then be misidentified as noncarriers. These types of difficulties arise not only with AD but with many other common adult diseases as well. Despite these obstacles, multiple AD-associated genes have now been identified, leading to a better understanding of the disorder and to the possibility of more effective AD treatment. Approximately 10% of AD cases are caused by autosomal dominant genes. Earlyonset cases cluster more strongly in families and are more likely to follow an autosomal dominant inheritance pattern. This disease is genetically heterogeneous, and many AD susceptibility genes have been identified. Three genes (encoding presenilin 1, presenilin 2, and amyloidβ precursor protein) cause earlyonset AD and affect the cleavage and processing of the amyloid precursor protein. The most significant gene associated with lateage onset AD encodes the apolipoprotein E protein

What disease is responsible for 60-70% of cases of progressive cognitive impairment among the eldery?

Alzheimer's disease affects appx 10% of the population older than 65 years and 40% of the population older than 85 years old

congenital malformations

Approximately 2% of newborns present with a congenital malformation (i.e., one that is present at birth); most of these conditions are considered to be multifactorial in etiology. Some of the more common congenital malformations are listed in Table 12-4. In general, sibling recurrence risks for most of these disorders range from 1% to 5%. Some congenital malformations, such as cleft lip/palate and pyloric stenosis, are relatively easy to repair and thus do not cause lasting problems. Others, such as neural tube defects, usually have more severe consequences. Although some cases of congenital malformations can occur in the absence of any other problems, it is quite common for them to be associated with other disorders. For example, cleft lip/ palate is often seen in babies with trisomy 13, and congenital heart defects are seen in many syndromes, including trisomy of chromosomes 13, 18, and 21. Considerable progress is now being made in isolating single genes that can cause congenital malformations. Many of these, including the HOX, PAX, and TBX families of genes, were discussed in Chapter 10. Another example is the RET proto-oncogene, which is responsible for some cases of Hirschsprung disease. However, the causes of many cases of this disorder remain undiscovered. Indeed, most of the genetic factors that contribute to important congenital malformations (e.g., neural tube defects, common congenital heart defects, cleft lip/palate) are as yet unidentified. Environmental factors have also been shown to cause some congenital malformations. An example is thalidomide, a sedative used during pregnancy in the early 1960s (and recently reintroduced for the treatment of dermatological conditions such as leprosy). When ingested during early pregnancy, this drug often can cause phocomelia (severely shortened limbs) in babies. Maternal exposure to retinoic acid, which is used to treat acne, can cause congenital defects of the heart, ear, and central nervous system. Maternal rubella infection can cause congenital heart defects. Other environmental factors that can cause congenital malformations are discussed in Chapter 15. Congenital malformations are seen in roughly 1 of every 50 live births. Most of them are considered to be multifactorial disorders. Specific genes and environmental causes have been detected for some congenital malformations, but the causes of most congenital malformations remain largely unknown.

Epidemiology of alcoholism

At some point in their lives, alcoholism (alcohol dependence) is diagnosed in approximately 10% of men and 3% to 5% of women in the United States. More than 100 studies have shown that this disease clusters in families: the risk of developing alcoholism among persons with one affected parent is three to five times higher than for those with unaffected parents. Most twin studies have yielded concordance rates for DZ twins of less than 30% and for MZ twins in excess of 60%, with an estimated heritability of approximately 50%. Adoption studies have shown that the offspring of an alcoholic parent, even when raised by nonalcoholic parents, have a fourfold increased risk of developing the disorder.

alcoholism

At some point in their lives, alcoholism (alcohol dependence) is diagnosed in approximately 10% of men and 3% to 5% of women in the United States. More than 100 studies have shown that this disease clusters in families: the risk of developing alcoholism among persons with one affected parent is three to five times higher than for those with unaffected parents. Most twin studies have yielded concordance rates for DZ twins of less than 30% and for MZ twins in excess of 60%, with an estimated heritability of approximately 50%. Adoption studies have shown that the offspring of an alcoholic parent, even when raised by nonalcoholic parents, have a fourfold increased risk of developing the disorder. To control for possible prenatal effects from an alcoholic mother, some studies have included the offspring of alcoholic fathers only. The results have remained the same. These data argue that there may be genes that predispose some people to alcoholism. Alcohol dependence can be divided into different subtypes, and some researchers distinguish two major types of alcoholism. Type I is characterized by a later age of onset (after 25 years of age), occurrence in both males and females, and greater psychological dependency on alcohol. Type I alcoholics are more likely to be introverted, solitary drinkers. This form of alcoholism is less likely to cluster in families (one study yielded a heritability estimate of 0.21), has a lesssevere course, and is more easily treated. Type II alcoholism is seen predominantly in males, typically occurs before 25 years of age, and tends to involve persons who are extroverted and thrill-seeking. This form is more difficult to treat successfully and tends to cluster more strongly in families, with heritability estimates ranging from 0.55 to more than 0.80. It has long been known that an individual's physiological response to alcohol can be influenced by variation in the key enzymes responsible for alcohol metabolism: alcohol dehydrogenase (ADH), which converts ethanol to acetaldehyde, and aldehyde dehydrogenase (ALDH), which converts acetaldehyde to acetate. In particular, an allele of the ALDH2 gene (ALDH2*2) results in excessive accumulation of acetaldehyde and thus in facial flushing, nausea, palpitations, and lightheadedness. Because of these unpleasant effects, persons who have the ALDH2*2 allele are much less likely to become alcoholics. This protective allele is common in some East Asian populations, with a frequency of approximately 40%, but is rare in most other populations. A number of genome scans have been undertaken in large cohorts of alcoholics and controls. One of the most consistent findings is that variants in genes that encode components of gamma-aminobutyric acid (GABA) receptors are associated with addiction to alcohol. This finding is biologically plausible, because the GABA neurotransmitter system inhibits excitatory signals in neurons, exerting a calming effect. Alcohol has been shown to increase GABA release, and allelic variation in GABA receptor genes might modulate this effect. It should be underscored that we refer to genes that might increase one's susceptibility to alcoholism. This is obviously a disease that requires an environmental component, regardless of one's genetic constitution. Twin and adoption studies show that alcoholism clusters quite strongly in families, reflecting a genetic contribution to this disease. Familial clustering is particularly strong for type II alcoholism (earlyonset form primarily affecting males).

autism spectrum disorder

Autism spectrum disorder (ASD) is characterized by impairments in social interaction and communication, as well as restricted, repetitive, and stereotyped behaviors and activities. The definition of ASD has been broadened considerably in the past decade or so (e.g., it now includes Asperger syndrome), resulting in a much higher current prevalence estimate (approximately 1% worldwide). ASD is 3-4 times more common in males than in females and is usually diagnosed during the first three years of life. As predicted by the multifactorial threshold model, the empirical recurrence risk is substantially higher in the siblings of females with ASD. Genetic factors play a large role in the etiology of ASD, with twin studies suggesting a heritability of approximately 70%. Many large, well-controlled studies have investigated the relationship between ASD and vaccination (in particular for measles, mumps, and rubella), and no relationship has been found. Approximately 10% of ASD cases have a known mendelian condition or genetic syndrome, most of which have been discussed in previous chapters. These include Fragile X syndrome (1-2% of cases), Rett syndrome (0.5%), tuberous sclerosis (1%), and neurofibromatosis type 1 (<1%). The most frequent cytogenetic abnormality seen in persons with ASD (1-3%) is a maternally transmitted duplication of chromosome 15q11-q13, the region that is deleted in Prader-Willi and Angelman syndromes (see Chapter 5). A 600 kb duplication or deletion of 16p11.2 is seen in about 1% of ASD cases Numerous GWAS and sequencing studies have been carried out to identify additional loci associated with ASD, and more than 100 susceptibility loci (each with small effect) have been identified. An increased number of de novo mutations are seen in children with ASD, most of which are inherited paternally (these are detected by comparing the DNA sequences of affected cases with those of their unaffected parents). This may help to explain the increased risk of autism among the offspring of older fathers. In addition, an increase in the number of copy number variants (CNVs) is seen in persons with autism Psychiatric disorders, such as schizophrenia, bipolar disorder, and ASD, present a number of challenges for genetic analysis. These diseases are undoubtedly heterogeneous, reflecting the influence of numerous genetic and environmental factors (the same is true of other psychiatric diseases, such as attention hyperactivity deficit disorder, which are not discussed here). This genetic heterogeneity is to be expected, in part because at least one-third of human genes are expressed in the brain. Also, the definition of a psychiatric phenotype is not always straightforward, and it can change through time. Several measures are being taken to improve the likelihood of finding genes underlying these conditions. Phenotypes are being defined in standardized and rigorous fashion. Larger sample sizes of affected persons (often tens of thousands), with more rigorous phenotype definition, are being collected in efforts to increase the power to detect linkage and association. Heterogeneity can be decreased by studying clinically defined subtypes of these diseases and by carrying out studies in genetically homogeneous populations. Marked familial aggregation, as well as familial cooccurrence, has been observed for schizophrenia, bipolar disorder, and autism spectrum disorder. Casecontrol and family studies have revealed evidence that these conditions are caused by brainexpressed genes that encode neurotransmitters, receptors, ion channels, and neurotransmitterrelated enzymes.

Clinical commentary- familial hypercholesterolemia

Autosomal dominant familial hypercholesterolemia (FH) is an important cause of heart disease, accounting for approximately 5% of myocardial infarctions (MIs) in persons younger than 60 years. FH is one of the most common autosomal dominant disorders: in most populations surveyed to date, about 1 in 500 persons is a heterozygote. Plasma cholesterol levels are approximately twice as high as normal (i.e., about 300-400 mg/ dL), resulting in substantially accelerated atherosclerosis and the occurrence of distinctive cholesterol deposits in skin and tendons, called xanthomas (Fig. 12-6). Data compiled from multiple studies showed that approximately 75% of men with FH developed coronary artery disease, and 50% had a fatal MI, by age 60 years. The corresponding percentages for women were lower (45% and 15%, respectively), because women generally develop heart disease at a later age than men Consistent with Hardy-Weinberg predictions (see Chapter 4), about 1/1,000,000 births is homozygous for the FH gene. Homozygotes are severely affected, with cholesterol levels ranging from 600 to 1200 mg/dL. Most homozygotes experience MIs before 20 years of age, and an MI at 18 months of age has been reported. Without treatment, most FH homozygotes die before the age of 30 years All cells require cholesterol as a component of their plasma membrane. They can either synthesize their own cholesterol, or preferentially they obtain it from the extracellular environment, where it is carried primarily by low-density lipoprotein (LDL). In a process known as endocytosis, LDL-bound cholesterol is taken into the cell via LDL receptors on the cell's surface. FH is caused by a reduction in the number of functional LDL receptors on cell surfaces. Cellular cholesterol uptake is reduced, and circulating cholesterol levels increase Much of what we know about endocytosis has been learned through the study of LDL receptors. The process of endocytosis and the processing of LDL in the cell is described in detail in Figure 12-7. These processes result in a fine-tuned regulation of cholesterol levels within cells, and they influence the level of circulating cholesterol as well. The identification of the LDL receptor gene (LDLR) in 1984 was a critical step in understanding exactly how LDL receptor defects cause FH. More than a thousand different mutations, two thirds of which are missense and nonsense substitutions, have been identified. Most of the remaining mutations are insertions and deletions, many of which arise from unequal crossovers (see Chapters 5 and 6) that occur between Alu repeat sequences (see Chapter 2) scattered throughout the gene. The LDLR mutations can be grouped into five broad classes, according to their effects on the activity of the receptor: • Class I mutations in LDLR result in no detectable protein product. Thus, heterozygotes would produce only half the normal number of LDL receptors. • Class II mutations result in production of the LDL receptor, but it is altered to the extent that it cannot leave the endoplasmic reticulum. It is eventually degraded . • Class III mutations produce an LDL receptor that is capable of migrating to the cell surface but is incapable of normal binding to LDL . • Class IV mutations, which are comparatively rare, produce receptors that are normal except that they do not migrate specifically to coated pits and thus cannot carry LDL into the cell. • Class V mutations produce an LDL receptor that cannot disassociate from the LDL particle after entry into the cell. The receptor cannot return to the cell surface and is degraded Each class of mutations reduces the number of effective LDL receptors, resulting in decreased LDL uptake and hence elevated levels of circulating cholesterol. The number of effective receptors is reduced by about half in FH heterozygotes, and homozygotes have virtually no functional LDL receptors. Understanding the defects that lead to FH has helped in the development of effective therapies for the disorder. Dietary reduction of cholesterol (primarily through the reduced intake of saturated fats) has only modest effects on cholesterol levels in FH heterozygotes. Because cholesterol is reabsorbed into the gut and then recycled through the liver (where most cholesterol synthesis takes place), serum cholesterol levels can be reduced by the administration of bile-acid absorbing resins, such as cholestyramine. The absorbed cholesterol is excreted. It is interesting that reduced recirculation from the gut causes the liver cells to form additional LDL receptors, lowering circulating cholesterol levels. However, the decrease in intracellular cholesterol also stimulates cholesterol synthesis by liver cells, so the overall reduction in plasma LDL is only about 15% to 20%. This treatment is much more effective when combined with one of the statin drugs (e.g., lovastatin, pravastatin), which reduce cholesterol synthesis by inhibiting 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase. Decreased synthesis leads to further production of LDL receptors. When these therapies are used in combination, serum cholesterol levels in FH heterozygotes can often be reduced to approximately normal levels. The picture is less encouraging for FH homozygotes. The therapies mentioned can enhance cholesterol elimination and reduce its synthesis, but they are largely ineffective in homozygotes because these persons have few or no LDL receptors. Liver transplants, which provide hepatocytes that have normal LDL receptors, have been successful in some cases, but this option is often limited by a lack of donors. Plasma exchange, carried out every 1 to 2 weeks, in combination with drug therapy, can reduce cholesterol levels by about 50%. However, this therapy is difficult to continue for long periods. Somatic cell gene therapy, in which hepatocytes carrying normal LDL receptor genes are introduced into the portal circulation, is now being tested (see Chapter 13). It might eventually prove to be an effective treatment for FH homozygotes. As discussed in the main text, FH can also be caused by inherited mutations in the gene that encodes apolipoprotein B. In addition, a small number of FH cases are caused by mutations in the gene that encodes PCSK9 (proprotein convertase subtilisin/kexin type 9), an enzyme that plays a key role in degrading LDL receptors. Gain-of-function mutations in the PCSK9 gene reduce the number of LDL receptors, causing FH. Loss-of-function mutations in this gene can increase the number of LDL receptors, resulting in exceptionally low circulating LDL levels. These findings have led to the development of drugs that inhibit PCSK9 activity, thus lowering LDL cholesterol levels. These drugs, which are in late-stage clinical trials, can reduce LDL cholesterol levels by approximately 50% in the general population of persons with hypercholesterolemia and produce significant effects even in those who are using statin drugs. The FH story illustrates how medical genetics research has made important contributions to both the understanding of basic cell biology and advancements in clinical therapy. The process of receptor-mediated endocytosis, elucidated largely by research on the LDL receptor defects, is of fundamental significance for cellular processes throughout the body. Equally, this research, by clarifying how cholesterol synthesis and uptake can be modified, has led to significant improvements in therapy for this important cause of heart disease. The discovery of rare mutations in PCSK9 has led to PCSK9 inhibitor drugs that may benefit millions of persons with high cholesterol levels.

What are 2 genes involved in DNA repair that predispose women to breast cancer if mutated?

BRCA1 and BRCA2

What is blood pressure regulated by?

Blood pressure regulation is a highly complex process that is influenced by many physiological systems, including various aspects of kidney function, cellular ion transport, vascular tone, and heart function

bipolar disorder

Bipolar disorder, also known as manic- depressive disorder, is characterized by extreme mood swings and emotional instability. The prevalence of the disorder in the general population is approximately 0.5% to 1%, but it rises to 5% to 10% among those with an affected first-degree relative. A study based on the Danish twin registry yielded concordance rates of 79% and 24% for MZ and DZ twins, respectively, yielding a heritability estimate of approximately 72% (other studies have yielded even higher heritability estimates—up to 90%). The corresponding concordance rates for major depressive disorder (sometimes termed unipolar depression) were 54% and 19%. Thus, it appears that bipolar disorder is more strongly influenced by genetic factors than is major depressive disorder. As with schizophrenia, many linkage and genome-wide association studies have been carried out to identify genes contributing to bipolar disorder. These studies have implicated many chromosome regions in multiple population samples. Some of the best-replicated results are for genes that encode voltage-gated calcium channels. Ion-channel modulating drugs are frequently used as mood stabilizers, giving these results functional plausibility. Many of the genes associated with bipolar disorder are also associated with schizophrenia

What does a stroke refer to? What can it result from>

Brain damage caused by a sudden and sustained loss of blood flow to the brain can result from arterial obstruction (ischemic stroke accounts for upto 80% of stroke cases) Is the 4th leading cause of mortality in the US- appx 140,000 deaths per year One's risk of having a stroke increases by two- to threefold if a parent has had a stroke.

What is the secondly most diagnosed cancer (after skin cancer) in women?

Breast cancer affects appx 12% of american women who live to age 85 Invasive breast cancer was diagnosed in approximately 230,000 American women in 2014

Breast cancer

Breast cancer is the second most commonly diagnosed cancer (after skin cancer) among women, affecting approximately 12% of American women who live to age 85 years or older. Invasive breast cancer was diagnosed in approximately 230,000 American women in 2014. Although the breast cancer mortality rate has been declining for 25 years, about 40,000 women in the United States die from this disease each year. Breast cancer was formerly the leading cause of cancer death among women, but it has been surpassed by lung cancer. Breast cancer can also occur in men, with a lifetime prevalence that is roughly 100 times lower than that of women (2400 cases diagnosed in 2014). The familial aggregation of breast cancer has been recognized for centuries, having been described by physicians in ancient Rome. If a woman has one affected first-degree relative, her risk of developing breast cancer doubles. The risk increases further with additional affected relatives, and it increases if those relatives developed cancer at a relatively early age (before 50 years of age). Several genes are now known to predispose women to developing hereditary breast cancer. Most important among these are BRCA1 and BRCA2, two genes involved in DNA repair (see Chapter 11). Germline mutations in the TP53 and CHK2 genes can cause Li-Fraumeni syndrome, which also predisposes to breast cancer. Cowden disease, a rare autosomal dominant condition that includes multiple hamartomas and breast cancer, is caused by mutations in the PTEN tumor suppressor gene (see Chapter 11). Ataxia-telangiectasia, an autosomal recessive disorder caused by defective DNA repair, includes breast cancer in its presentation. Mutations in the MSH2 and MLH1 DNA repair genes, which lead to hereditary nonpolyposis colorectal cancer (HNPCC), also confer an increased risk of breast cancer. Despite the significance of these genes, it should be emphasized that more than 90% of breast cancer cases are not inherited as mendelian diseases A number of environmental factors are known to increase the risk of developing breast cancer. These include nulliparity (never bearing children), bearing the first child after 30 years of age, a high-fat diet, alcohol use, and estrogen replacement therapy.

Alleles of what gene is strongly associated with Type I diabetes?

CTLA4 (cyotoxic lymphocyte associated-4 gene) encodes an inhibitory T-cell receptor associated with other autoimmune diseases, such as rheumatoid arthritis and celiac disease. Another gene associated with type 1 diabetes susceptibility,

What are some of the causes of stroke?

Can be caused by more than a dozen single gene disorders: 1- Sickle cell disease 2- MELAS (mitochondrial myopathy, encephelopathy, lacitc acidosis, and stroke) 3- Cerebral autosomal dominant Arteriopathy with subcortical infarcts and leukoencephelopathy (CADASIL)- characterized by recurrent strokes and dementia caused by mutations in NOTCH3 gene

What is the second leading cause of death in the United States?

Cancer It is well established that many major types of cancer (e.g., breast, colon, prostate, ovarian) cluster strongly in families. This is due both to shared genes and shared environmental factors environmental factors such as Tobacco use accounts for 1/3 of all cancer - most known cause of cancer Diet (i.e., carcinogenic substances and the lack of "anticancer" components such as fiber, fruits, and vegetables) is another leading cause of cancer and may also account for as much as one third of cancer cases

Cancer

Cancer is the second leading cause of death in the United States, although it is estimated that it might soon surpass heart disease as the leading cause of death. It is well established that many major types of cancer (e.g., breast, colon, prostate, ovarian) cluster strongly in families. This is due both to shared genes and shared environmental factors. Although numerous cancer genes have been isolated, environmental factors also play an important role in causing cancer by inducing somatic mutations. In particular, tobacco use is estimated to account for one third of all cancer cases in developed countries, making it the most important known cause of cancer. Diet (i.e., carcinogenic substances and the lack of "anticancer" components such as fiber, fruits, and vegetables) is another leading cause of cancer and may also account for as much as one third of cancer cases. It is estimated that approximately 15% of worldwide cancer cases are caused primarily by infectious agents (e.g., human papilloma virus for cervical cancer, hepatitis B and C for liver cancer). Because cancer genetics was the subject of Chapter 11, we confine our attention here to genetic and environmental factors that influence susceptibility to some of the most common cancers.

What is QT (LQT) syndrome characterized by? What is it indicative of?

Characteristically elongated QT interval in the electrocardiogram of affected individuals Delayed cardiac repolarization

What are the symptoms that occur as a result of Pyloric stenosis? How can it be treated?

Chronic vomiting, constipation, weight loss and electrolyte imbalance Can be corrected by surgery or sometimes resolves spontaneously

What 2 factors is there abundant evidence for that they increase the risk of CAD? With 2 factors decrease the risk for CAD?

Cigarette smoking and Obesity Exercise and a diet low in saturated fats The approximate 60% reduction in age-adjusted mortality due to CAD and stroke in the United States since 1950 is usually attributed to a decrease in the percentage of adults who smoke cigarettes, decreased consumption of saturated fats, improved medical care, and increased emphasis on healthy lifestyle factors such as exercise.

Studies for the genetic determinants of Coronary artery disease have been focused on what?

Circulating lipoprotein levels

What are babies born with Trisomy 13 often suffer from?

Cleft lip/palate it is quite common for congential malformations to be associated with other disorders

What do adoption studies consist of?

Comparing disease rates among the adopted offspring of affected parents with the rates among adopted offspring of unaffected parents

What type of condition is often seen with trisomy 13,18 and 21?

Congenital heart defects

What occurs in Dilated Cardiomyopathy? What is the end result?

Consists of increased size and impaired contraction of ventricles Impaired pumping of the heart occurs in 1/2500 people is familial in about 1/3 of affected persons, although autosomal dominant mutations are most common, mutations can also be X-linked or mitochondrial

What is the most common underlying cause of heart disease? What is it caused by?

Coronary artery disease (CAD) Atherosclerosis- narrowing of the coronary arteries resulting from the formation of lipid-laden lesions this narrowing impedes blood flow to the heart and can eventually result in a myocardial infarction (death of heart tissue caused by inadequate supply of oxygen)

Recurrence risks for First, second and third degree relatives of probands

DISEASE PREVALENCE IN GENERAL POPULATION DEGREE OF RELATION FIRST DEGREE SECOND DEGREE THIRD DEGREE Cleft lip/palate 0.001 0.04 0.007 0.003 Club foot 0.001 0.025 0.005 0.002 Congenital hip dislocation 0.002 0.005 0.006 0.004

Prevalent Rates of Common congenital malformations in persons of European descent

DISORDER APPROXIMATE PREVALENCE PER 1000 BIRTHS Cleft lip/palate 1.0 Club foot 1.0 Congenital heart defects 4.0-8.0 Hydrocephaly 0.5-2.5 Isolated cleft palate 0.4 Neural tube defects 1.0-3.0 Pyloric stenosis 3.0

What is special about of DZ twin studies?

DZ twins provide a convient comparision: their environmental differences should be similar to those of MZ twins but their genetic differences are as great as those between siblings

What occurs in liability distriubtion?

Diseases do not follow bell shaped distribution, they appear to be either present or absent in individuals A commonly used explanation is an underlying liability distribution in which people on the low end of the distribution have little chance of developing the disease (ie: they have few of the alleles or environmental factors that would cause the disease) Those who are closer to the high end of the distribution have more of the diseases causing alleles and environmental factors and are more likely to develop the disease

What are Congenital malformations?

Diseases that are present at birth appx 2% of newborns present with them- 1/50 live births sibling recurrence risks for most of these disorders range from 1-5%

What is a women's risk for cancer if she has affected first-degree relatives?

Doubles The risk increases further with additional affected relatives, and it increases if those relatives developed cancer at a relatively early age (before 50 years of age).

For most multifactorial diseases what type of risks have been derived?

Empirical risks ie: risks based on direct observation of data since risk estimation for multifactorial is more complex bc the number of genes contributing to the disease is usually not known

Since monozygotic twins are genetically identical any differences among them should be only due to?

Environmental effects

What is Bipolar disorder characterized by?

Extreme mood swings and emotional instability AKA manic-depressive disorder The prevalence of the disorder in the general population is approximately 0.5% to 1%, but it rises to 5% to 10% among those with an affected first-degree relative.

Comparison of the major features of Type I and Type II diabetes Mellitus

FEATURE TYPE 1 DIABETES TYPE 2 DIABETES Age of onset Usually <40 yr Usually >40 yr Insulin production None Partial Insulin resistance No Yes Autoimmunity Yes No Obesity Not common Common MZ twin concordance 0.35-0.50 0.90 Sibling recurrence risk 1-6% 15-40

Receptor Mediated Endocytosis

FIG 12-7 The process of receptor-mediated endocytosis. 1, The low-density lipoprotein (LDL) receptors, which are glycoproteins, are synthesized in the endoplasmic reticulum of the cell. 2, They pass through the Golgi apparatus to the cell surface, where part of the receptor protrudes outside the cell. 3, The circulating LDL particle is bound by the LDL receptor and localized in cell-surface depressions called coated pits (so named because they are coated with a protein called clathrin). 4, The coated pit invaginates, bringing the LDL particle inside the cell. 5, Once inside the cell, the LDL particle is separated from the receptor, taken into a lysosome, and broken down into its constituents by lysosomal enzymes. 6, The LDL receptor is recirculated to the cell surface to bind another LDL particle. Each LDL receptor goes through this cycle approximately once every 10 minutes, even if it is not occupied by an LDL particle. 7, Free cholesterol is released from the lysosome for incorporation into cell membranes or metabolism into bile acids or steroids. Excess cholesterol can be stored in the cell as a cholesterol ester or removed from the cell by association with high-density lipoprotein (HDL). 8, As cholesterol levels in the cell rise, cellular cholesterol synthesis is reduced by inhibition of the rate-limiting enzyme, HMG-CoA reductase. 9, Rising cholesterol levels also increase the activity of acyl-coenzyme A:cholesterol acyltransferase (ACAT), an enzyme that modifies cholesterol for storage as cholesterol esters. 10, In addition, the number of LDL receptors is decreased by lowering the transcription rate of the LDL receptor gene itself. This decreases cholesterol uptake.

nature and nurture- disentangling the effects of genes and environment

Family members share genes and a common environment. Family resemblance in traits such as blood pressure therefore reflects both genetic and environmental commonality ("nature" and "nurture," respectively). For centuries, people have debated the relative importance of these two types of factors. It is a mistake, of course, to view them as mutually exclusive. Few traits are influenced only by genes or only by environment. Most are influenced by both. Determining the relative influence of genetic and environmental factors can lead to a better understanding of disease etiology. It can also help in the planning of public health strategies. A disease in which hereditary influence is relatively small, such as lung cancer, may be prevented most effectively through emphasis on lifestyle changes (avoidance of tobacco). When a disease has a relatively larger hereditary component, as in breast cancer, examination of family history should be emphasized in addition to lifestyle modification. In the following sections, we review two research strategies that are often used to estimate the relative influence of genes and environment: twin studies and adoption studies. We then discuss methods that aim to delineate the individual genes responsible for multifactorial diseases

Is the risk for Pyloric stenosis higher when the proband is male or female?

Female this reflects the concept that females, having a higher liability threshold, must be exposed to more disease-causing factors than males in order to develop the disease Thus, a family with an affected female must have more genetic and environmental risk factors, producing a higher recurrence risk for pyloric stenosis in future offspring

Variants in what genes are associated with addiction to alcohol?

GABA (gamma-aminobutyric acid) receptors alcohol is shown to increase GABA(inhibitory Neutotransmitter- thus brings calming effect) release and allelic variation in GABA receptor genes might modulate this affect

Lipoprotein genes known to contribute to coronary heart disease risk

GENE CHROMOSOME LOCATION FUNCTION OF PROTEIN PRODUCT Apolipoprotein A-I 11q HDL component; LCAT cofactor Apolipoprotein A-IV 11q Component of chylomicrons and HDL; may influence HDL metabolism Apolipoprotein C-III 11q Allelic variation associated with hypertriglyceridemia Apolipoprotein B 2p Ligand for LDL receptor; involved in formation of VLDL, LDL, IDL, and chylomicrons Apolipoprotein D 2p HDL component Apolipoprotein C-I 19q LCAT activation Apolipoprotein C-II 19q Lipoprotein lipase activation Apolipoprotein E 19q Ligand for LDL receptor Apolipoprotein A-II 1p HDL component LDL receptor 19p Uptake of circulating LDL particles Lipoprotein(a) 6q Cholesterol transport Lipoprotein lipase 8p Hydrolysis of lipoprotein lipids Hepatic triglyceride lipase 15q Hydrolysis of lipoprotein lipids LCAT 16q Cholesterol esterification Cholesterol ester transfer protein 16q Facilitates transfer of cholesterol esters and phospholipids between lipoproteins

What 3 genes can half of early onset Alzheimer's disease be attributed to?

Genes that affect: 1- Beta-amyloid deposition 2- Presenilin 1 (PS1) 3- Presenilin 2 (PS2) Gain-of-function mutations in PS1 or PS2 affect the cleavage of APP such that amyloid-producing forms of it accumulate excessively and are deposited in the brain This is thought to be a primary cause of AD. Mutations in PS1 typically result in especially early onset of AD, with the first occurrence of symptoms in the fifth decade of life.

What chromosome regions/genes are associated with bipolar disorder? What drugs are used to treat it?

Genes that encode voltage gated calcium channels Ion-channel modulating drugs are frequently used as mood stabilizers

What are the most commonly mutated genes that lead to hypertrophic cardiomyopathy?

Genes that encode: 1- Beta- myosin heavy chain (35% of familial cases) 2- Myosin binding protein C (20% of cases) 3- Troponin T (15% of cases)

What loci accounts for about 40-50% of the genetic susceptibility to Type I diabetes?

HLA Loci Approximately 95% of whites with type 1 diabetes have the HLA DR3 and/or DR4 alleles, whereas only about 50% of the general white population has either of these alleles

the genetics of common diseases

Having discussed the principles of multifactorial inheritance, we turn next to a discussion of the common multifactorial disorders themselves. Some of these disorders, the congenital malformations, are by definition present at birth. Others, including heart disease, cancer, diabetes, and most psychiatric disorders, are seen primarily in adolescents and adults. Because of their complexity, unraveling the genetics of these disorders is a daunting task. Nonetheless, significant progress is now being made

What disease is the leading cause of death worldwide?

Heart disease it accounts for appx 25% of all deaths in the United States

What does comparisons of correlations and concordance rates in MZ and DZ twins allow the estimation of?

Heritability a measure of the percentage of population variation in a disease that can be attributed to genes

What can be used to measure correlations and concordance rates in MZ and DZ twins?

Heritability of multifactorial traits heritability is the percentage of population variation in a trait that is due to genes (statistically, it is the proportion of the total variance of a trait that is caused by genes/ formula for estimating heritability (h) from twin correlations or concordance is as follows: h= Cmz- Cdz/ 1- Cdz cMZ is the concordance rate (or intraclass correlation) for MZ twins and cDZ is the concordance rate (or intraclass correlation) for DZ twins

What is seen in people Heterozygote for Factor V Leiden? Homozygosity?

Heterozygosity for this allele, which is seen in approximately 5% of whites, produces a sevenfold increase in the risk of venous thrombosis (clots). In homozygotes, the risk increases to 100-fold. However, the evidence for an association between the factor V Leiden allele and stroke is inconsistent.

In addition to family history and specific genes what factors are known to increase the risk of stroke?

Hypertension, Obesity, atherosclerosis, diabetes and smoking

What is a major form of Cardiomyopathy? What is it characterized by?

Hypertrophic cardiomyopathy thickening (hypertrophy) of portions of the left ventricle seen in as many as 1/500 adults

What is Autism spectrium disorder characterized by?

Impairments in social interaction and communication as well as restricted, repetitive and stereotyped behaviors and activities ASD is 3-4 times more common in males than in females and is usually diagnosed during the first three years of life Genetic factors play a large role in the etiology of ASD, with twin studies suggesting a heritability of approximately 70%.

What do lower leptin levels lead to?

Increased apetite

What effect do increased fat stores have?

Increased fat stores lead to elevated leptin levels which produces satiety and a loss of apetite

What does a mutation in clotting factor V- Factor V Leiden allele cause?

Increased resistance to activated protein C and thus produces an increased susceptibility to clotting

What are the most important environmental risk factors for hypertension?

Increased sodium intake, decreased physical activity, psychosocial stress and obesity

What is used to estimate quantitative traits like blood pressure or height?

Intraclass correlation coefficient This statistic varies bw -1.0 and +1.0 and measures the degree of homogeneity of a trait in a sample of individuals

What is the epidemiology of Colorectal cancer?

It is estimated that 1 in 20 Americans will develop colorectal cancer, and roughly one third of those with this cancer will die from it. With approximately 135,000 new cases and 50,000 deaths in the United States each year, colorectal cancer is second only to lung cancer in the total number of annual cancer deaths. The risk of colorectal cancer in people with one affected first-degree relative is two to three times higher than that of the general population. As with breast cancer, most colorectal cancer cases (>90%) are not inherited as mendelian conditions and are likely to be caused by a complex interaction of inherited and somatic genetic alterations and environmental factors. The latter risk factors include a lack of physical activity and a high-fat, lowfiber diet.

colorectal cancer

It is estimated that 1 in 20 Americans will develop colorectal cancer, and roughly one third of those with this cancer will die from it. With approximately 135,000 new cases and 50,000 deaths in the United States each year, colorectal cancer is second only to lung cancer in the total number of annual cancer deaths. Like breast cancer, it clusters in families; familial clustering of this form of cancer was reported in the medical literature as early as 1881. The risk of colorectal cancer in people with one affected first-degree relative is two to three times higher than that of the general population As discussed in Chapter 11, familial colorectal cancer can be the result of mutations in the APC tumor suppressor gene or in one of several DNA mismatch-repair genes (HNPCC). Another, less common, inherited cause of colorectal cancer is the autosomal dominant Peutz-Jeghers syndrome. About half of Peutz-Jeghers cases are caused by mutations in the STK11 tumor suppressor gene, which encodes a protein kinase. Juvenile intestinal polyposis, an autosomal dominant disease defined by the presence of 10 or more polyps before adulthood, can be caused by mutations in SMAD4 (see Chapter 11), in BMPRA1 (a receptor serine-threonine kinase gene), or, in rare cases, in PTEN. As with breast cancer, most colorectal cancer cases (>90%) are not inherited as mendelian conditions and are likely to be caused by a complex interaction of inherited and somatic genetic alterations and environmental factors. The latter risk factors include a lack of physical activity and a high-fat, lowfiber diet.

multifactorial versus single gene inheritance

It is important to clarify the difference between a multifactorial disease and a single-gene disease in which there is locus heterogeneity. In the former case, a disease is caused by the simultaneous influence of multiple genetic and environmental factors, each of which has a relatively small effect. In contrast, a disease with locus heterogeneity, such as osteogenesis imperfecta, requires only a single mutation to cause it. Because of locus heterogeneity, a single mutation at either of two or more loci can cause disease; some affected persons have one mutation while others have the other mutation In some cases, a trait may be influenced by the combination of both a single gene with large effects and a multifactorial background in which additional genes and environmental factors have small individual effects (Fig. 12-4). Imagine that variation in height, for example, is caused by a single locus (termed a major gene) and a multifactorial component. Individuals with the AA genotype tend to be taller, those with the aa genotype tend to be shorter, and those with Aa tend to be intermediate. But additional variation is caused by other factors (the multifactorial component). Thus, those with the aa genotype vary in height from 130 cm to about 170 cm, those with the Aa genotype vary from 150 cm to 190 cm, and those with the AA genotype vary from 170 to 210 cm. There is substantial overlap among the three major genotypes because of the influence of the multifactorial background. The total distribution of height, which is bell-shaped, is caused by the superposition of the three distributions about each genotype. Many of the diseases to be discussed later can be caused by a major gene and/or multifactorial inheritance. That is, there are subsets of the population in which diseases such as colon cancer, breast cancer, or heart disease are inherited as single-gene disorders (with additional variation in disease susceptibility contributed by other genetic and environmental factors). These subsets usually account for only a small percentage of the total number of disease cases. It is nevertheless important to identify the responsible major genes, because their function can provide important clues to the pathophysiology and treatment of the disease. Multifactorial diseases can be distinguished from singlegene disorders caused by mutations at different loci (locus heterogeneity). Sometimes a disease has both singlegene and multifactorial components.

What is the autosomal recessive form of LQT syndrome known as? What is it associated with?

Jervell -lange- Nielsen syndrome Longer QT interval, a higher incidence of sudden cardiac death and sensorineural defects

What is Jervell- Lange- Nielsen syndrome caused by mutations in?

KCNQI or KCNE1 genetic testing enables more accurate diagnosis

What is diabetes the leading cause of?

Leading cause of adult blindness, kidney failure, and lower-limb amputation and a major cause of heart disease and stroke

diabetes mellitus

Like the other disorders discussed in this chapter, the etiology of diabetes mellitus is complex and not fully understood. Nevertheless, progress is being made in understanding the genetic basis of this disorder, which is the leading cause of adult blindness, kidney failure, and lower-limb amputation and a major cause of heart disease and stroke. An important advance has been the recognition that diabetes mellitus is actually a heterogeneous group of disorders, all characterized by elevated blood sugar. We focus here on the three major types of diabetes, type 1 (formerly termed insulin-dependent diabetes mellitus, or IDDM), type 2 (formerly termed non- insulin-dependent diabetes mellitus, or NIDDM), and maturity-onset diabetes of the young (MODY).

Genes that encode what play a significant role in human obesity?

Leptin and its receptor Leptin hormone is secreted by adipocytes(fat storage cells) and binds to receptors in the hypothalamus, the site of the body's appetite control center

What is Peutz-Jeghers syndrome? Mutation in what causes it?

Less common inherited cause of colorectal cancer Is an autosomal dominant mutation STK11 tumor suppressor gene - encodes a protein kinase

What does germline mutations in TP53 and CHK2 cause? What does it predispose to?

Li-Fraumeni syndrome Breast cancer

Examples of Mendelian subtypes of Complex disorders

MENDELIAN SUBTYPE PROTEIN (GENE) CONSEQUENCE OF MUTATION Heart Disease Familial hypercholesterolemia LDL receptor (LDLR) Elevated LDL level Apolipoprotein B (APOB) Elevated LDL level Proprotein convertase subtilisin/kexin type 9 (PCSK9) Gain-of-function mutations elevate LDL; loss-of-function mutations reduce LDL Tangier disease ATP-binding cassette 1 (ABC1) Reduced HDL level Familial dilated cardiomyopathy Cardiac troponin T (TNNT2) Reduced force generation by sarcomere Titin (TTN) Destabilized sarcomere Cardiac β-myosin heavy chain (MYH7) Reduced force generation by sarcomere β-Sarcoglycan (SGCB) Destabilized sarcolemma and signal transduction δ-Sarcoglycan (SGCD) Destabilized sarcolemma and signal transduction Dystrophin Destabilized sarcolemma in cardiac myocytes Familial hypertrophic cardiomyopathy Cardiac β-myosin heavy chain (MYH7) Reduced force generation by sarcomere Cardiac troponin T (TNNT2) Reduced force generation by sarcomere Myosin-binding protein C (MYBPC) Sarcomere damage Long QT syndrome Cardiac potassium channel α subunit (LQT1, KCNQ1) Prolonged QT interval on electrocardiogram, arrhythmia Cardiac potassium channel α subunit (LQT2, KCNH2) Prolonged QT interval on electrocardiogram, arrhythmia Cardiac sodium channel (LQT3, SCN5A) Prolonged QT interval on electrocardiogram, arrhythmia Ankyrin B anchoring protein (LQT4, ANK2) Prolonged QT interval on electrocardiogram, arrhythmia Cardiac potassium channel β subunit (LQT5, KCNE1) Prolonged QT interval on electrocardiogram, arrhythmia Cardiac potassium channel subunit (LQT6, KCNE2) Prolonged QT interval on electrocardiogram, arrhythmia Hypertension Liddle syndrome Renal epithelial sodium channel subunits (SCNN1B, SCNN1G) Severe hypertension, low renin and suppressed aldosterone Gordon syndrome WNK1 or WNK4 kinase genes High serum potassium level and increased renal salt reabsorption Glucocorticoid-remediable aldosteronism Fusion of genes that encode aldosterone synthase and steroid 11β-hydroxylase Early-onset hypertension with suppressed plasma renin and normal or elevated aldosterone levels Syndrome of apparent mineralocorticoid excess 11 β-Hydroxysteroid dehydrogenase (11β-HSD2) Early-onset hypertension, low potassium and renin levels, low aldosterone Diabetes MODY1 Hepatocyte nuclear factor-4α (HNF4A) Decreased insulin secretion MODY2 Glucokinase (GCK) Impaired glucose metabolism, leading to mild nonprogressive hyperglycemia MODY3 Hepatocyte nuclear factor-1α (HNF1α) Decreased insulin secretion MODY4 Insulin promoter factor-1 (IPF1) Decreased transcription of insulin gene MODY5 Hepatocyte nuclear factor-1β (HNF1β) β-cell dysfunction leads to decreased insulin secretion MODY6 NeuroD transcription factor (NEUROD1) Decreased insulin secretion Alzheimer Disease Familial Alzheimer disease Amyloid-β precursor protein (APP) Alteration of cleavage sites in amyloid-β precursor protein, producing longer amyloid fragments Presenilin 1 (PS1) Altered cleavage of amyloid-β precursor protein, producing larger proportion of long amyloid fragments Presenilin 2 (PS2) Altered cleavage of amyloid-β precursor protein, producing larger proportion of long amyloid fragments

Examples of Mendelian subtypes of Complex disorders- cont'd

MENDELIAN SUBTYPE PROTEIN (GENE) CONSEQUENCE OF MUTATION Parkinson Disease Familial Parkinson disease (autosomal dominant) α-Synuclein (PARK1, SNCA) Formation of α-synuclein aggregates Familial Parkinson disease (autosomal recessive) Parkin: E3 ubiquityl ligase, thought to ubiquinate α-synuclein (PARK2) Compromised degradation of α-synuclein Familial Parkinson disease (autosomal dominant) Ubiquitin C-hydrolase-L1 (PARK5) Accumulation of α-synuclein Amyotrophic Lateral Sclerosis Familial amyotrophic lateral sclerosis Superoxide dismutase 1 (SOD1) Neurotoxic gain of function Familial amyotrophic lateral sclerosis C9ORF72 Expanded repeat mutation Juvenile amyotrophic lateral sclerosis (autosomal recessive) Alsin (ALS2) Presumed loss of function Epilepsy Benign neonatal epilepsy, types 1 and 2 Voltage-gated potassium channels (KCNQ2 and KCNQ3, respectively) Reduced M current increases neuronal excitability Generalized epilepsy with febrile seizures plus type 1 Sodium channel β1 subunit (SCN1B) Sodium current persistence leading to neuronal hyperexcitability Autosomal dominant nocturnal frontal lobe epilepsy Neuronal nicotinic acetylcholine receptor subunits (CHRNA4 and CHRNB2) Increased neuronal excitability in response to cholinergic stimulation Generalized epilepsy with febrile seizures plus type 3 GABAA receptor (GABRG2) Loss of synaptic inhibition leading to neuronal excitability

mature onset diabetes of the young

MODY, which accounts for 1% to 5% of all diabetes cases, typically occurs before 25 years of age and follows an autosomal dominant mode of inheritance. In contrast to type 2 diabetes, it is not associated with obesity. Studies of MODY pedigrees have shown that about 50% of cases are caused by mutations in the gene that encodes glucokinase, a rate-limiting enzyme in the conversion of glucose to glucose-6-phosphate in the pancreas. Another 40% of MODY cases are caused by mutations in any of five genes that encode transcription factors involved in pancreatic development or insulin regulation: hepatocyte nuclear factor-1α (HNF1α), hepatocyte nuclear factor-1β (HNF1β), hepatocyte nuclear factor-4α (HNF4α), insulin promoter factor-1 (IPF1), and neurogenic differentiation 1 (NEUROD1). Mutations in these genes, all of which are expressed in pancreatic beta cells, lead to beta cell abnormalities and thus to diabetes. Type 1 (insulindependent) and type 2 (non- insulindependent) diabetes both cluster in families, with stronger familial clustering observed for type 2 diabetes. Type 1 has an earlier average age of onset, is HLAassociated, and is an autoimmune disease. Type 2 is not an autoimmune disorder and is more likely to be seen in obese persons. Several genes have been identified that increase susceptibility to type 1 or type 2 diabetes. Most cases of autosomal dominant MODY are caused by mutations in any of six specific genes.

Mutations in what genes can lead to Hereditary nonpolyposis colorectal cancer (HNPCC)? What does this disease also confer?

MSH2 and MLH1 Increased risk of breast cancer Despite the significance of these genes, it should be emphasized that more than 90% of breast cancer cases are not inherited as mendelian disease

What is the Concordance rates for stroke death in MZ and DZ twins respectively?

MZ- 10% DZ- 5%

What is the most frequent cytogenetic abnormality seen in persons with Autism spectrum disorder?

Maternally transmitted duplication of chromosome 15q11-q13- the region that is deleted in Prader-Willi and Angelman syndromes A 600 kb duplication or deletion of 16p11.2 is seen in about 1% of ASD cases.

Twin studies usually consist of comparisons between?

Monozygotic and Dizygotic twins if both members of a twin pair share a trait (eg: cleft lip) they are said to be concordant if they do not share the trait, they are discordant for traits determined completely by genes, MZ twins should always be concordant, and DZ twins should be concordant less often

What are the outcome of mouse studies with leptin?

Mice with loss-of-function mutations in the leptin gene have uncontrolled appetites and become obese When injected with leptin, these mice lose weight. leptin participates in important interactions with other components of appetite control, such as neuropeptide Y, as well as α-melanocyte-stimulating hormone and its receptor, the melanocortin-4 receptor (MC4R). Several genomewide association studies have demonstrated an association between an intronic variant in the brain-expressed FTO gene and obesity in whites. Homozygosity for this variant, which is seen in about 16% of whites, confers increased

What type of trait is blood pressure?

Multifactorial trait There is a correlation between parents' blood pressures (systolic and diastolic) and those of their children, and there is good evidence that this correlation is due in part to genes. But blood pressure is also influenced by environmental factors, such as diet and stress

What causes familial Colorectal cancer?

Mutations in APC tumor suppressor gene or Mutations in one of several DNA mismatch repair genes (HNPCC)

What is the major cause of MODY?

Mutations in gene that encodes Glucokinase - rate limiting enzyme in the conversion of glucose to glucose-6-phosphate in the pancreas Another 40% of MODY cases are caused by mutations in any of five genes that encode transcription factors involved in pancreatic development or insulin regulation: hepatocyte nuclear factor-1α (HNF1α), hepatocyte nuclear factor-1β (HNF1β), hepatocyte nuclear factor-4α (HNF4α), insulin promoter factor-1 (IPF1), and neurogenic differentiation 1 (NEUROD1)

clinical commentary - neural tube defects

Neural tube defects (NTDs) include anencephaly, spina bifida, and encephalocele, as well as several other less-common forms (Fig. 12-3). They are one of the most important classes of birth defects, with a newborn prevalence of approximately 1 per 1000. There is considerable variation in the prevalence of NTDs among populations, with an especially high rate among some northern Chinese populations (as high as 6 per 1000 births). The prevalence of NTDs has been decreasing in many parts of the United States and Europe during the past three decades Normally the neural tube closes at about the fourth week of gestation. A defect in closure or a subsequent reopening of the neural tube results in an NTD. Spina bifida is the most commonly observed NTD and consists of a protrusion of spinal tissue through the vertebral column (the tissue usually includes meninges, spinal cord, and nerve roots). About 75% of spina bifida patients have secondary hydrocephalus, which sometimes in turn produces intellectual disability. Paralysis or muscle weakness, lack of sphincter control, and club feet are often observed. A study conducted in British Columbia showed that survival rates for spina bifida patients have improved dramatically over the past several decades. Less than 30% of such children born between 1952 and 1969 survived to 10 years of age, but 65% of those born between 1970 and 1986 survived to this age. Anencephaly is characterized by partial or complete absence of the cranial vault and calvarium and partial or complete absence of the cerebral hemispheres. At least two thirds of anencephalics are stillborn; term deliveries do not survive more than a few hours or days. Encephalocele consists of a protrusion of the brain into an enclosed sac. It is seldom compatible with survival NTDs are thought to arise from a combination of genetic and environmental factors. In most populations surveyed thus far, empirical recurrence risks for siblings of affected individuals range from 2% to 5%. Consistent with a multifactorial model, the recurrence risk increases with additional affected siblings. A Hungarian study showed that the overall prevalence of NTDs in that country was 1/300 births and that the sibling recurrence risks were 3%, 12%, and 25% after one, two, and three affected offspring, respectively. Recurrence risks tend to be slightly lower in populations with lower NTD prevalence rates, as predicted by the multifactorial model. Recurrence risk data support the idea that the major forms of NTDs are caused by shared or similar factors. An anencephalic conception increases the recurrence risk for subsequent spina bifida conceptions, and vice versa. NTDs can usually be diagnosed prenatally, sometimes by ultrasound and usually by an elevation in α-fetoprotein (AFP) in the maternal serum or amniotic fluid (see Chapter 13). A spina bifida lesion can be either open or closed (i.e., covered with a layer of skin). Open spina bifida is more likely to be detected by an AFP assay A major epidemiological finding is that mothers who supplement their diet with folic acid at the time of conception are less likely to produce children with NTDs. This result has been replicated in several different populations and is thus well confirmed. It has been estimated that approximately 50% to 70% of NTDs can be avoided simply by dietary folic acid supplementation. (Traditional prenatal vitamin supplements would not have an effect because administration does not usually begin until well after the time that the neural tube closes.) Since mothers would be likely to ingest similar amounts of folic acid from one pregnancy to the next, folic acid deficiency could well account for at least part of the elevated sibling recurrence risk for NTDs. Dietary folic acid is an important example of a nongenetic factor that contributes to familial clustering of a disease However, it is likely that there is genetic variation in response to folic acid, which helps to explain why most mothers with folic acid deficiency do not bear children with NTDs and why some who ingest adequate amounts of folic acid nonetheless bear children with NTDs. To address this issue, researchers are testing for associations between NTDs and variants in several genes whose products (e.g., methylene tetrahydrofolate reductase) are involved in folic acid metabolism (see Clinical Commentary 15-6 in Chapter 15 for further information on dietary folic acid supplementation and NTD prevention).

What do non-genetic risk factors for prostate cancer include?

Nongenetic risk factors for prostate cancer may include a high-fat diet. Because prostate cancer usually progresses slowly and because it can be detected by digital examination and by the prostate-specific antigen (PSA) test, fatal metastasis can usually be prevented

What type of distribution is displayed by polygenic/multifactorial traits?

Normal or Bell shaped distribution

What are risk factors for Coronary artery disease (CAD)?

Obesity, cigarette smoking, hypertension, elevated cholesterol level, and positive family history (more than one affected first degree relative) a person with family history for CAD is twice (2X) as likely to suffer from CAD

What gene associated T cell regulation is associated with Type I diabetes?

PTPN22 is also associated with other autoimmune disorders, including rheumatoid arthritis and systemic lupus erythematosus.

What differentiates Type II diabetes from Type I?

Persons with type 2 diabetes usually have some degree of endogenous insulin production, at least in earlier stages of the disease, and they can sometimes be treated successfully with dietary modification, oral drugs, or both patients with type 2 diabetes have insulin resistance (i.e., their cells have difficulty using insulin) and are more likely to be obese No HLA associations nor autoantibodies are seen commonly in this form of diabetes

What type of a trait is height?

Polygenic multifactorial trait the loci underlying variation in a quantitative trait such as height are termed quantitative trait loci

What is Juvenile intestinal polyposis defined by? What is it caused by?

Presence of 10 or more polyps before adulthood Mutations in SMAD4, BMPRA1 ( a receptor serine-threonine kinase gene) or in rare cases- PTEN

What is the prevalence of Pyloric stenosis? More common in males or females?

Prevalence among whites is about 3/1000 live births. It is much more common in males than females, affecting 1/200 males and 1/1000 females It is thought that this difference in prevalence reflects two thresholds in the liability distribution; a lower one in males and a higher one in females (see Fig. 12-2). A lower male threshold implies that fewer disease-causing factors are required to generate the disorder in males.

The recurrence risk is higher if the expression of the disease in the ..... is more severe?

Proband eg: the occurrence of a bilateral (both sides) cleft lip/palate confers a higher recurrence risk on family members than does the occurrence of a unilateral (one side) cleft

What is Alzheimer's disease characterized by?

Progressive dementia and memory loss and by the formation of amyloid plaques and neurofibrillary tangles in the brain, particularly in the cerebral cortex and hippocampus The plaques and tangles lead to progressive neuronal loss, and death usually occurs within 7 to 10 years after the first appearance of symptoms. The risk of developing AD doubles in persons who have an affected first-degree relative

What is the second most commonly diagnosed cancer in men (after skin cancer)?

Prostate Cancer Prostate cancer is second only to lung cancer as a cause of cancer death in men, causing more than 27,000 deaths each year. Having an affected first-degree relative increases the risk of developing prostate cancer by a factor of two to three, and the heritability of prostate cancer is estimated to be approximately 40%. The relatively late age of onset of most prostate cancer cases (median age, 72 years) makes genetic analysis especially difficult

prostate cancer

Prostate cancer is the second most commonly diagnosed cancer in men (after skin cancer), with approximately 220,000 new cases annually in the United States. Prostate cancer is second only to lung cancer as a cause of cancer death in men, causing more than 27,000 deaths each year. Having an affected first-degree relative increases the risk of developing prostate cancer by a factor of two to three, and the heritability of prostate cancer is estimated to be approximately 40%. The relatively late age of onset of most prostate cancer cases (median age, 72 years) makes genetic analysis especially difficult. However, loss of heterozygosity (see Chapter 11) has been observed in a number of genomic regions in prostate tumor cells, possibly indicating the presence of genetic alterations in these regions. In addition, genome scans (GWAS) have identified several dozen polymorphisms associated with prostate cancer risk. Several of these are located in chromosome 8q24, which contains polymorphisms associated with several other cancers as well (colon, pancreas, and esophagus). Although the 8q24 region contains no protein-coding genes, it contains enhancer elements that affect expression of the MYC oncogene, located about 250 kb from 8q24. Nongenetic risk factors for prostate cancer may include a high-fat diet. Because prostate cancer usually progresses slowly and because it can be detected by digital examination and by the prostate-specific antigen (PSA) test, fatal metastasis can usually be prevented. Most common cancers have genetic components. Recurrence risks tend to be higher if there are several affected relatives and if those relatives developed cancer at an early age. Specific genes have been discovered that cause inherited colon, breast, and prostate cancer in some families.

What is an example of a disease that corresponds to threshold model and presents shortly after birth? What is it caused by?

Pyloric stenosis Narrowing or obstruction of the pylorus, the area between the stomach and the intestine

Recurrence Risks for Relatives of Schizophrenic Probands, Based on Multiple Studies of Western European Population

RELATIONSHIP TO PROBAND RECURRENCE RISK (%) Monozygotic twin 44.3 Dizygotic twin 12.1 Offspring 9.4 Sibling 7.3 Niece or nephew 2.7 Grandchild 2.8 First cousin 1.6 Spouse 1.0

Recurrence risks (%) for Pyloric stenosis, subdivided by gender of affected probands and relatives

RELATIVES MALE PROBANDS FEMALE PROBANDS LONDON BELFAST LONDON BELFAST Brothers 3.8 9.6 9.2 12.5 Sisters 2.7 3.0 3.8 3.8

What is Cowden disease? What is it caused by?

Rare autosomal dominant condition that includes multiple hamartomas and breast cancer Mutations in the PTEN tumor supressor gene

What is higher if more than one family member is affected?

Recurrence risk eg: the sibling recurrence risk for a ventricular septal defect (VSD, a type of congenital heart defect) is 3% if one sibling has had a VSD but increases to appx 10% if two siblings have had VSDs

What is lower if the proband is of the less commonly affected sex?

Recurrence risk This is because an affected individual of the less susceptible sex is usually at a more extreme position on the liability distribution.

The recurrence risk for the disease usually decreases rapidly for more ........ related relatives?

Remotely

What the autosomal dominant form of QT (LQT) syndrome known as? What is it caused by?

Roman-Ward syndrome loss of-function mutations in genes that encode potassium channels (such as KCNQ1, KCNH2, KCNE1, KCNE2, or KCNJ2). These mutations delay cardiac repolarization. Romano-Ward syndrome can also be caused by gain-of-function mutations in sodium or calcium channel genes (SCN5A and CACNA1C, respectively), which result in a prolonged depolarizing current

schizophrenia

Schizophrenia is a severe emotional disorder characterized by delusions, hallucinations, retreat from reality, and bizarre, withdrawn, or inappropriate behavior (contrary to popular belief, schizophrenia is not a "split personality" disorder). The lifetime recurrence risk for schizophrenia among the offspring of one affected parent is approximately 8% to 10%, which is about 10 times higher than the risk in the general population. The empirical risks increase when more relatives are affected. For example, a person with an affected sibling and an affected parent has a risk of about 15% to 20%, and a person with two affected parents has a risk of 40% to 50%. The risks decrease when the affected family member is a second- or third-degree relative. Details are given in Table 12-8. On inspection of this table, it may seem puzzling that the proportion of schizophrenic probands who have a schizophrenic parent is only about 5%, which is substantially lower than the risk for other first-degree relatives (e.g., siblings, affected parents, and their offspring). This can be explained by the fact that schizophrenics are less likely to marry and produce children than are other persons. There is thus substantial selection against schizophrenia in the population. Twin and adoption studies indicate that genetic factors are likely to be involved in schizophrenia. Data pooled from multiple twin studies show a 47% concordance rate for MZ twins, compared with only 12% for DZ twins. The concordance rate for MZ twins reared apart, 46%, is about the same as the rate for MZ twins reared together. The risk of developing the disease for offspring of a schizophrenic parent who are adopted by normal parents is about 10%, approximately the same as the risk when the offspring are raised by a schizophrenic biological parent. Dozens of genome scans have been performed in an effort to locate schizophrenia genes. The techniques discussed in Chapter 8 (GWAS, exome sequencing) have identified significant associations between schizophrenia and polymorphisms in more than 100 genomic regions. A number of the genes in these regions encode components of the glutamatergic and dopaminergic neuronal signaling pathways. These findings are biologically plausible because the major drugs used to treat schizophrenia block dopamine receptors

What is Liddle syndrome? What is it characterized by?

Single gene disorder that causes hypertension Low plasma aldosterone and hypertension caused by mutations that alter the ENaC epithelial sodium channel

What is Gordon Syndrome? What is it characterized by?

Single gene disorder that causes hypertension hypertension, high serum potassium level and increased renal salt reabsorption caused by mutations in the WNK1 or WNK4 kinase genes

What is required to cause a disease with locus heterogeneity? example?

Single mutation Osteogenesis imperfecta

some general principals and conclusions

Some general principles can be deduced from the results obtained thus far regarding the genetics of complex disorders. First, the more strongly inherited forms of complex disorders generally have an earlier age of onset (examples include breast cancer, Alzheimer disease, and heart disease). Often, these include subsets of cases in which there is single-gene inheritance. Second, when there is laterality, bilateral forms sometimes cluster more strongly in families (e.g., cleft lip/palate or breast cancer). Third, while the sex-specific threshold model fits some of the complex disorders (e.g., pyloric stenosis, cleft lip/palate, autism, heart disease), it fails to fit others (e.g., type 1 diabetes). There is a tendency, particularly among the lay public, to assume that the presence of a genetic component means that the course of a disease cannot be altered ("If it's genetic, you can't change it"). This is incorrect. Most of the diseases discussed in this chapter have both genetic and environmental components. Thus, environmental modification (e.g., diet, exercise, stress reduction) can often reduce risk significantly. Such modifications may be especially important for persons who have a family history of a disease, because they are likely to develop the disease earlier in life. Those with a family history of heart disease, for example, can often add many years of productive living with relatively minor lifestyle alterations. By targeting those who can benefit most from intervention, genetics helps to serve the goal of preventive medicine In addition, the identification of a specific genetic alteration can lead to more effective prevention and treatment of the disease. Identification of mutations causing familial colorectal cancer can allow early screening and prevention of metastasis. Pinpointing a gene responsible for a neurotransmitter defect in a psychiatric disorder such as schizophrenia could lead to the development of more effective drug treatments. In some cases, such as familial hypercholesterolemia, gene therapy may be useful. It is important for health-care practitioners to make their patients aware of these facts. Although the genetics of common disorders is complex and sometimes confusing, the public health impact of these diseases and the evidence for hereditary factors in their etiology demand that genetic studies be pursued. Substantial progress is already being made. The next decade will undoubtedly witness many advancements in our understanding and treatment of these disorders.

What can occur if atherosclerosis develops in arteries that supplies the brain?

Stroke

Inherited deficiences in Protein C and Protein S (both of which are Coagulation inhibitors) are increased with increased risk of what ?

Stroke Because blood clots are a common cause of stroke, it is expected that mutations in genes that encode coagulation factors might affect stroke susceptibility especially in children

adoption studies

Studies of adopted children are also used to estimate the genetic contribution to a multifactorial trait. Offspring who were born to parents who have a disease but who were adopted by parents lacking the disease can be studied to find out whether the offspring develop the disease. In some cases, these adopted persons develop the disease more often than do children in a comparative control population (i.e., adopted children who were born to parents who do not have the disease). This provides evidence that genes may be involved in causing the disease, because the adopted children do not share an environment with their affected natural parents. For example, schizophrenia is seen in 8% to 10% of adopted children whose natural parent had schizophrenia, whereas it is seen in only 1% of adopted children of unaffected parents. As with twin studies, several precautions must be exercised in interpreting the results of adoption studies. First, prenatal environmental influences could have long-lasting effects on an adopted child. Second, children are sometimes adopted after they are several years old, ensuring that some nongenetic influences have been imparted by the natural parents. Finally, adoption agencies sometimes try to match the adoptive parents with the natural parents in terms of attributes such as socioeconomic status. All of these factors could exaggerate the apparent influence of biological inheritance. Adoption studies provide a second means of estimating the influence of genes on multifactorial diseases. They consist of comparing disease rates among the adopted offspring of affected parents with the rates among adopted offspring of unaffected parents. As with the twin method, several biases can influence these studies These reservations, as well as those summarized for twin studies, underscore the need for caution in basing conclusions on twin and adoption studies. These approaches do not provide definitive measures of the role of genes in multifactorial disease, nor can they identify specific genes responsible for disease. Instead, they provide a preliminary indication of the extent to which a multifactorial disease may be influenced by genetic factors. Methods for the direct detection of genes underlying multifactorial traits are summarized in Box 12-1.

What is the absence of Aspartic acid at position 57 of the DQ polypeptide strongly associated with?

Susceptibility to type 1 diabetes in fact, those who do not have this amino acid at position 57 (and instead are homozygous for a different amino acid) are 100 times more likely to develop type 1 diabetes

What is a key risk factor for heart disease, stroke and kidney disease?

Systemic hypertension it is estimated that hypertension is responsible for appx half of all cardiovascular mortality

Hypertension

Systemic hypertension is a key risk factor for heart disease, stroke, and kidney disease. It is estimated that hypertension is responsible for approximately half of all cardiovascular mortality. Studies of blood pressure correlations within families yield heritability estimates of approximately 30% to 50% for both systolic and diastolic blood pressure. Heritability estimates based on twin studies tend to be higher (about 60%) and may be inflated because of greater similarities in the environments of MZ compared with DZ twins. The fact that the heritability estimates are substantially less than 100% indicates that environmental factors must also be significant causes of blood pressure variation. The most important environmental risk factors for hypertension are increased sodium intake, decreased physical activity, psychosocial stress, and obesity (as discussed later, the latter factor is itself influenced both by genes and environment). Blood pressure regulation is a highly complex process that is influenced by many physiological systems, including various aspects of kidney function, cellular ion transport, vascular tone, and heart function. Because of this complexity, much research is now focused on specific components that might influence blood pressure variation, such as the renin- angiotensin system (Fig. 12-8) (involved in sodium reabsorption and vasoconstriction); vasodilators such as nitric oxide and the kallikrein-kinin system; and ion transport systems such as adducin and sodium-lithium countertransport. These individual factors are more likely to be under the control of smaller numbers of genes than is blood pressure itself, simplifying the task of identifying these genes and their role in regulating blood pressure. For example, linkage and association studies have implicated several genes involved in the renin-angiotensin system (e.g., the genes that encode angiotensinogen, angiotensin-converting enzyme type 1, and angiotensin II type 1 receptor) in causing hypertension A small percentage of hypertension cases are the result of rare single-gene disorders, such as Liddle syndrome (low plasma aldosterone and hypertension caused by mutations that alter the ENaC epithelial sodium channel) and Gordon syndrome (hypertension, high serum potassium level, and increased renal salt reabsorption caused by mutations in the WNK1 or WNK4 kinase genes); see Table 12-6 for additional examples. More than 20 genes have been identified that can lead to rare inherited forms of hypertension, and many of them affect the reabsorption of water and salt by the kidney, which in turn affects blood volume and blood pressure. It is hoped that isolation and study of these genes, and the pathways in which they act, will lead to the identification of genetic factors underlying essential hypertension.‡ Large-scale genome scans, undertaken in more than 100,000 humans and in experimental animals such as mice and rats, have sought to identify additional loci (see Box 12-1) that might underlie essential hypertension. These studies have identified dozens of genes that influence susceptibility to hypertension. Although the individual effects of each of these genes is small (as expected for a multifactorial trait), they collectively explain a significant proportion of the genetic risk for hypertension. Heritability estimates for systolic and diastolic blood pressure range from 30% to 50%. A number of genes responsible for rare hypertension syndromes have been identified, and genome scans have implicated regions that might contain genes that underlie susceptibility to essential hypertension. Other risk factors for hypertension include increased sodium intake, lack of exercise, psychosocial stress, and obesity.

What is Type I diabetes characterized by? How is treated?

T-cell infiltration of the pancreas and destruction of the insulin-producing beta cells, usually (though not always) manifests before 40 years of age Patients with type 1 diabetes must receive exogenous insulin to survive. In addition to T-cell infiltration of the pancreas, autoantibodies are formed against pancreatic cells, insulin, and enzymes such as glutamic acid decarboxylase These findings, along with a strong association between type 1 diabetes and the presence of several human leukocyte antigen (HLA) class II alleles, indicate that this is an autoimmune disease

What is the most significant gene identified to be linked to Type II diabetes?

TCF7L2 encodes a transcription factor involved in secreting insulin A significant association has also been observed between type 2 diabetes and a common allele of the gene that encodes peroxisome proliferator-activated receptor-γ (PPAR-γ)- This receptor is the target of thiazolidinediones [TZDs], a class of drugs commonly used to increase insulin sensitivity in those with type 2 diabetes. Variation in KCNJ11, which encodes a potassium channel necessary for glucose-stimulated insulin secretion, confers an additional 20% increase in type 2 diabetes susceptibility

What is an example of an environmental factor causing a congenital malformation?

Thalidomide When ingested during early pregnancy it can cause phocomelia (severely short limbs) in babies Maternal exposure to retinoic acid, which is used to treat acne, can cause congenital defects of the heart, ear, and central nervous system Maternal rubella infection can cause congenital heart defects.

other complex disorders

The disorders discussed in this chapter represent some of the most common multifactorial disorders and those for which significant progress has been made in identifying genes. Many other multifactorial disorders are being studied as well, and in some cases specific susceptibility genes have been identified. These include, for example, Parkinson disease, hearing loss, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, asthma, inflammatory bowel disease, and some forms of blindness (see Table 12-6 and Table 8-2 in Chapter 8).

What are adoption studies used to estimate?

The genetic contribution to a multifactorial trait provide a second means of estimating the influence of genes on multifactorial diseases

Relationship of Insulin gene and Type I diabetes

The insulin gene, which is located on the short arm of chromosome 11, is another logical candidate for type 1 diabetes susceptibility. Polymorphisms within and near this gene have been tested for association with type 1 diabetes. Intriguingly, a strong risk association is seen with allelic variation in a VNTR polymorphism located just 5′ of the insulin gene Differences in the number of VNTR repeat units might affect transcription of the insulin gene (possibly by altering chromatin structure), which would result in variation in susceptibility

psychiatric disorders

The major psychiatric diseases, including schizophrenia, bipolar disorder, and autism spectrum disorder, have been the subjects of numerous genetic studies. Twin, adoption, and family studies have shown that these disorders aggregate in families. Moreover, schizophrenia, biopolar disorder, and autism tend to occur together in the same families. In part, this reflects the fact that some of the same genes influence susceptibility to each of these conditions

Figure 12.8-

The renin-angiotensin-aldosterone system. ↑, Increased; ↓, decreased; AT1, angiotensin type II receptor 1. (Modified from King RA, Rotter JI, Motulsky AG, eds. The Genetic Basis of Common Diseases. New York: Oxford University Press; 1992

For multifactorial diseases that are either present or absent what has to be crossed before the disease is expressed?

Threshold of liability before the threshold, the person appears unaffected, above it, he or she is affected by the disease

obesity

The worldwide prevalence of obesity is increasing rapidly among adults and children. Approximately 70% of American adults and 60% of British adults are overweight (body mass index [BMI] >25),§ and about half of these overweight persons are obese (BMI >30). Although obesity itself is not a disease, it is an important risk factor for several common diseases, including heart disease, stroke, type 2 diabetes, and cancers of the prostate, breast, and colon As one might expect, there is a strong correlation between obesity in parents and obesity in their children. This could easily be ascribed to common environmental effects: parents and children usually share similar diet and exercise habits. However, there is good evidence for genetic components as well. Four adoption studies each showed that the body weights of adopted persons correlated significantly with their natural parents' body weights but not with those of their adoptive parents. Twin studies also provide evidence for a genetic effect on body weight, with most studies yielding heritability estimates between 0.60 and 0.80. The heritability of "fatness" (measured, for example, by skinfold thickness) is approximately 0.50 Research, aided substantially by mouse models, has shown that several genes likely play a role in human obesity. Important among these are the genes that encode leptin (Greek, "thin") and its receptor. The leptin hormone is secreted by adipocytes (fat storage cells) and binds to receptors in the hypothalamus, the site of the body's appetite control center. Increased fat stores lead to an elevated leptin level, which produces satiety and a loss of appetite. Lower leptin levels lead to increased appetite. Mice with loss-of-function mutations in the leptin gene have uncontrolled appetites and become obese. When injected with leptin, these mice lose weight. Mice with mutations in the leptin receptor gene cannot respond to increased leptin levels and also develop obesity. Identification of the leptin gene and its receptor in mice led to their identification in humans, which in turn prompted optimistic predictions that leptin could be a key to weight loss in humans (without the perceived unpleasantness of dieting and exercise). However, most obese humans have high levels of leptin, indicating that the leptin gene is functioning normally. Leptin receptor defects were then suspected, but these are also uncommon in humans. Although mutations in the human leptin gene and its receptor have now been identified in a few humans with severe obesity (BMI >40), they both appear to be extremely rare. Unfortunately, studying these genes will not solve the problem of human obesity. However, clinical trials using recombinant leptin have demonstrated moderate weight loss in a subset of obese individuals In addition, leptin participates in important interactions with other components of appetite control, such as neuropeptide Y, as well as α-melanocyte-stimulating hormone and its receptor, the melanocortin-4 receptor (MC4R). Mutations in the gene that encodes MC4R have been found in 3% to 5% of severely obese individuals. Several genomewide association studies have demonstrated an association between an intronic variant in the brain-expressed FTO gene and obesity in whites. Homozygosity for this variant, which is seen in about 16% of whites, confers increased risks of overweight and obesity of 40% and 70%, respectively. Recent evidence shows that the FTO variant is part of an enhancer that binds to the IRX gene, which is located 2 Mb away from FTO and is involved in regulation of fat mass. Identification of these and other obesity-predisposing genes is leading to a better understanding of appetite control in humans and could eventually lead to effective treatments for some cases of obesity. Multifactorial Inheritance and Common Diseases Adoption and twin studies indicate that at least half of the population variation in obesity may be caused by genes. Specific genes and gene products involved in appetite control and susceptibility to obesity, including leptin and its receptor, MC4R, and FTO, are now being studied

What does the most commonly mutated gene in Dilated cardiomyopathy encode?

Titin a cytoskeletal protein other genes that can cause dilated cardiomyopathy encode cytoskeletal proteins including Troponin T, desmin and components of the dystroglycan-sacroglycan complex

What are polygenic traits?

Traits in which variation is thought to be caused by the combined effects of multiple genes When environmental factors are also believed to cause variation in the trait, which is usually the case, the term multifactorial is used

principals of multifactorial inheritance- multifactorial model

Traits in which variation is thought to be caused by the combined effects of multiple genes are called polygenic ("many genes"). When environmental factors are also believed to cause variation in the trait, which is usually the case, the term multifactorial is used. Many quantitative traits (those, such as blood pressure, that are measured on a continuous numerical scale) are multifactorial. Because they are caused by the additive effects of many genetic and environmental factors, these traits tend to follow a normal, or bell-shaped, distribution in populations. Let us use an example to illustrate this concept. To begin with the simplest case, suppose (unrealistically) that height is determined by a single gene with two alleles, A and a. Allele A tends to make people tall, and allele a tends to make them short. If there is no dominance at this locus, then the three possible genotypes, AA, Aa, and aa, will produce three phenotypes: tall, intermediate, and short. Assume that the allele frequencies of A and a are each 0.50. If we assemble a population of individuals, we will observe the height distribution depicted in Figure 12-1A. Now suppose, a bit more realistically, that height is determined by two loci instead of one. The second locus also has two alleles, B (tall) and b (short), and they affect height in exactly the same way as alleles A and a do. There are now nine possible genotypes in our population: aabb, aaBb, aaBB, Aabb, AaBb, AaBB, AAbb, AABb, and AABB. Because an individual might have zero, one, two, three, or four "tall" alleles, there are now five distinct phenotypes (see Fig. 12-1B). Although the height distribution in our population is not yet normal, it approaches a normal distribution more closely than in the single-gene case We now extend our example so that many genes and environmental factors influence height, each having a small effect. Then there are many possible phenotypes, each differing slightly, and the height distribution approaches the bellshaped curve shown in Figure 12-1C. Genome-wide association studies (GWAS, see Chapter 8) have identified more than 200 loci associated with human height, affirming that this is indeed a polygenic, multifactorial trait. The loci underlying variation in a quantitative trait such as height are termed quantitative trait loci. It should be emphasized that the individual genes underlying a multifactorial trait such as height follow the mendelian principles of segregation and independent assortment, just like any other genes. The only difference is that many of them act together to influence the trait. Blood pressure is another example of a multifactorial trait. There is a correlation between parents' blood pressures (systolic and diastolic) and those of their children, and there is good evidence that this correlation is due in part to genes. But blood pressure is also influenced by environmental factors, such as diet and stress. One of the goals of genetic research is identification of the genes responsible for multifactorial traits such as blood pressure and of the interactions of those genes with environmental factors. Many traits are thought to be influenced by multiple genes as well as by environmental factors. These traits are said to be multifactorial. When they can be measured on a continuous scale, they often follow a normal distribution.

T or F There is a strong correlation between obesity in parents and obesity in their children

True can be ascribed to environmental factors- children often share similar diet and exercise levels as parents Four adoption studies each showed that the body weights of adopted persons correlated significantly with their natural parents' body weights but not with those of their adoptive parents Twin studies also provide evidence for a genetic effect on body weight, with most studies yielding heritability estimates between 0.60 and 0.80

Twin studies

Twins occur with a frequency of about 1/100 births in populations of European ancestry. They are slightly more common among Africans and a bit less common among Asians. Monozygotic (MZ, or identical) twins originate when the developing embryo divides to form two separate but genetically identical embryos. Because they are genetically identical, MZ twins are an example of natural clones. Their physical appearances can be strikingly similar (Fig. 12-5). Dizygotic (DZ, or fraternal) twins are the result of a double ovulation followed by the fertilization of each egg by a different sperm.† Thus, DZ twins are genetically no more similar than siblings. Because two different sperm cells are required to fertilize the two eggs, it is possible for each DZ twin to have a different father. Because MZ twins are genetically identical, any differences between them should be due only to environmental effects. MZ twins should thus resemble each other very closely for traits that are strongly influenced by genes. DZ twins provide a convenient comparison: their environmental differences should be similar to those of MZ twins, but their genetic differences are as great as those between siblings. Twin studies thus usually consist of comparisons between MZ and DZ twins. If both members of a twin pair share a trait (e.g., cleft lip), they are said to be concordant. If they do not share the trait, they are discordant. For a trait determined completely by genes, MZ twins should always be concordant, and DZ twins should be concordant less often. Like siblings, DZ twins share only 50% of their DNA because each parent transmits half of his or her DNA to each offspring. Concordance rates can differ between opposite-sex DZ twin pairs and same-sex DZ pairs for some traits, such as those that have different frequencies in males and females. For such traits, only samesex DZ twin pairs should be used when comparing MZ and DZ concordance rates. A concordance estimate would not be appropriate for quantitative traits, such as blood pressure or height. Here the intraclass correlation coefficient is used. This statistic varies between −1.0 and +1.0 and measures the degree of homogeneity of a trait in a sample of individuals. For example, we may wish to assess the degree of similarity between twins for a trait such as height. The measurements are made in a collection of twins, and correlation coefficients are estimated separately for the MZ sample and the DZ sample. If a trait were determined entirely by genes, we would expect the correlation coefficient for MZ pairs to be 1.0 (i.e., each pair of twins would have exactly the same height). A correlation coefficient of 0.0 would mean that the similarity between MZ twins for the trait in question is no greater than chance. Because DZ twins share half of their DNA, we would expect a DZ correlation coefficient of 0.50 for a trait determined entirely by genes. Monozygotic (identical) twins are the result of an early cleavage of the embryo, whereas dizygotic (fraternal) twins are caused by the fertilization of two eggs by two sperm cells. Comparisons of concordance rates and correlations in MZ and DZ twins help to estimate the extent to which a trait is influenced by genes Concordance rates and correlation coefficients for a number of traits are given in Table 12-3. The concordance rates for contagious diseases like measles are quite similar in MZ and DZ twins. This is expected, because most contagious diseases are unlikely to be influenced markedly by genes. On the other hand, the concordance rates for schizophrenia are quite dissimilar between MZ and DZ twins, indicating a sizable genetic component for this disease. The MZ correlation for dermatoglyphics (fingerprints), a series of traits determined almost entirely by genes, is close to 1.0 Correlations and concordance rates in MZ and DZ twins can be used to measure the heritability of multifactorial traits. Essentially, heritability is the percentage of population variation in a trait that is due to genes (statistically, it is the proportion of the total variance of a trait that is caused by genes). A simple formula for estimating heritability (h) from twin correlations or concordance rates is as follows: where cMZ is the concordance rate (or intraclass correlation) for MZ twins and cDZ is the concordance rate (or intraclass correlation) for DZ twins. As this formula illustrates, traits that are largely determined by genes result in a heritability estimate that approaches 1.0 (i.e., cmz approaches 1.0, and cDZ approaches 0.5). As the difference between MZ and DZ concordance rates becomes smaller, heritability approaches zero. Correlations and concordance rates in other types of relatives (e.g., between parents and offspring) can also be used to measure heritability. Like recurrence risks, heritability values are specific for the population in which they are estimated. However, there is usually agreement from one population to another regarding the general range of heritability estimates of most traits (e.g., the heritability of height is almost always high, and the heritability of contagious diseases is almost always low). The same is true of empirical recurrence risks. Comparisons of correlations and concordance rates in MZ and DZ twins allow the estimation of heritability, a measure of the percentage of population variation in a disease that can be attributed to genes. At one time, twins were thought to provide a perfect "natural laboratory" in which to determine the relative influences of genetics and environment. But several difficulties arise. One of the most important is the assumption that the environments of MZ and DZ twins are equally similar. MZ twins are often treated more similarly than DZ twins. A greater similarity in environment can make MZ twins more concordant for a trait, inflating the apparent influence of genes. In addition, MZ twins may be more likely to seek the same type of environment, further reinforcing environmental similarity. On the other hand, it has been suggested that some MZ twins tend to develop personality differences in an attempt to assert their individuality. Another difficulty is that the uterine environments of different pairs of MZ twins can be more or less similar, depending on whether there are two amnions and two chorions, two amnions and one shared chorion, or one shared amnion and one shared chorion. In addition, somatic mutations can occur during mitotic divisions of the cells of MZ twin embryos after cleavage occurs. Thus, the MZ twins might not be quite "identical," especially if a mutation occurred early in the development of one of the twins. Finally, methylation patterns, which can influence the transcription of specific genes, become more dissimilar in MZ twin pairs as they age. This dissimilarity is greater when the twins adopt markedly different habits and lifestyles (e.g., when one twin smokes cigarettes and the other does not). Of the various problems with the twin method, the greater degree of environmental sharing among MZ twins is perhaps the most serious. One way to circumvent this problem, at least in part, is to study MZ twins who were raised in separate environments. Concordance among these twin pairs should be caused by genetic, rather than environmental, similarities. As one might expect, it is not easy to find such twin pairs. A major effort to do so has been undertaken by researchers at the University of Minnesota, whose studies have shown a remarkable congruence among MZ twins reared apart, even for many behavioral traits. However, these studies must be viewed with caution, because the sample sizes are relatively small and because many of the twin pairs had at least some contact with each other before they were studied. Although twin studies provide valuable information, they are also affected by certain biases. The most serious is greater environmental similarity between MZ twins than between DZ twins. Other biases include somatic mutations that might affect only one MZ twin and differences in the uterine environments of twins

What are Dizygotic twins?

Twins that are the result of a double sperm ovulation followed by the fertilization of each egg by a different sperm thus, DZ twins are genetically no more similar than siblings it is possible for fraternal twins to have 2 different fathers

What are Monozygotic twins?

Twins that originate when the developing embryo divides to form two separate but genetically identical embryos AKA identical twins MZ twins are an example of natural clones and are strikingly similar in appearance

type I diabetes

Type 1 diabetes, which is characterized by T-cell infiltration of the pancreas and destruction of the insulin-producing beta cells, usually (though not always) manifests before 40 years of age. Patients with type 1 diabetes must receive exogenous insulin to survive. In addition to T-cell infiltration of the pancreas, autoantibodies are formed against pancreatic cells, insulin, and enzymes such as glutamic acid decarboxylase; these autoantibodies can be observed long before clinical symptoms occur. These findings, along with a strong association between type 1 diabetes and the presence of several human leukocyte antigen (HLA) class II alleles, indicate that this is an autoimmune disease. Over the past few decades, the incidence of type 1 diabetes has increased substantially Siblings of persons with type 1 diabetes face a substantial elevation in risk: approximately 6%, as opposed to a risk of about 0.3% to 0.5% in the general population. The recurrence risk is also elevated when there is a diabetic parent, although this risk varies with the sex of the affected parent. The risk for offspring of diabetic mothers is only 1% to 3%, but it is 4% to 6% for the offspring of diabetic fathers. (Because type 1 diabetes affects males and females in roughly equal proportions in the general population, this risk difference is inconsistent with the sex-specific threshold model for multifactorial traits.) Twin studies show that the empirical risk for MZ twins of type 1 diabetes patients ranges from 30% to 50%. In contrast, the concordance rate for DZ twins is 5% to 10%. The fact that type 1 diabetes is not 100% concordant among identical twins indicates that genetic factors are not solely responsible for the disorder. There is evidence that specific viral infections contribute to the cause of type 1 diabetes in at least some persons, possibly by activating an autoimmune response. The association of specific HLA class II alleles and type 1 diabetes has been studied extensively, and it is estimated that the HLA loci account for about 40% to 50% of the genetic susceptibility to type 1 diabetes. Approximately 95% of whites with type 1 diabetes have the HLA DR3 and/or DR4 alleles, whereas only about 50% of the general white population has either of these alleles. If an affected proband and a sibling are both heterozygous for the DR3 and DR4 alleles, the sibling's risk of developing type 1 diabetes is nearly 20% (i.e., about 40 times higher than the risk in the general population). This association may in part reflect linkage disequilibrium between alleles of the DR locus and those of the HLA-DQ locus. The absence of aspartic acid at position 57 of the DQ polypeptide is strongly associated with susceptibility to type 1 diabetes; in fact, those who do not have this amino acid at position 57 (and instead are homozygous for a different amino acid) are 100 times more likely to develop type 1 diabetes. The aspartic acid substitution alters the shape of the HLA class II molecule and thus its ability to bind and present peptides to T cells (see Chapter 9). Altered T-cell recognition might help to protect persons with the aspartic acid substitution from an autoimmune episode. The insulin gene, which is located on the short arm of chromosome 11, is another logical candidate for type 1 diabetes susceptibility. Polymorphisms within and near this gene have been tested for association with type 1 diabetes. Intriguingly, a strong risk association is seen with allelic variation in a VNTR polymorphism (see Chapter 3) located just 5′ of the insulin gene. Differences in the number of VNTR repeat units might affect transcription of the insulin gene (possibly by altering chromatin structure), which would result in variation in susceptibility. It is estimated that inherited genetic variation in the insulin region accounts for approximately 10% of the familial clustering of type 1 diabetes. ve been used extensively to map additional genes that can cause type 1 diabetes. In addition, an animal model, the nonobese diabetic (NOD) mouse, has been used to identify diabetes susceptibility genes that could have similar roles in humans (see Box 12-1). These studies have identified dozens of additional genes associated with type 1 diabetes susceptibility. One of these is the CTLA4 (cytotoxic lymphocyte associated-4) gene, which encodes an inhibitory T-cell receptor. Several studies have demonstrated that alleles of CTLA4 are associated with an increased risk of type 1 diabetes. There is growing evidence that variation in CTLA4 is also associated with other autoimmune diseases, such as rheumatoid arthritis and celiac disease. Another gene associated with type 1 diabetes susceptibility, PTPN22, is involved in T-cell regulation and is also associated with other autoimmune disorders, including rheumatoid arthritis and systemic lupus erythematosus.

type II diabetes

Type 2 diabetes accounts for more than 90% of all diabetes cases, and its incidence is rising rapidly in populations with access to high-calorie diets. It currently affects approximately 10% to 20% of the adult populations of many developed countries. One study estimates that because of the rapid rate of increase of this disease, one third of Americans born in 2000 will eventually develop type 2 diabetes. A number of features distinguish type 2 diabetes from type 1 diabetes. Persons with type 2 diabetes usually have some degree of endogenous insulin production, at least in earlier stages of the disease, and they can sometimes be treated successfully with dietary modification, oral drugs, or both. In contrast to those with type 1 diabetes, patients with type 2 diabetes have insulin resistance (i.e., their cells have difficulty using insulin) and are more likely to be obese. This form of diabetes has traditionally been seen primarily in patients older than 40 years, but because of increasing obesity among adolescents and young adults, it is now increasing rapidly in this segment of the population. Neither HLA associations nor autoantibodies are seen commonly in this form of diabetes. MZ twin concordance rates are substantially higher than in type 1 diabetes, often exceeding 90% (because of age dependence, the concordance rate increases if older subjects are studied). The empirical recurrence risks for first-degree relatives of patients with type 2 diabetes are higher than those for type 1 patients, generally ranging from 15% to 40%. The differences between type 1 and type 2 diabetes are summarized in Table 12-7. The two most important risk factors for type 2 diabetes are a positive family history and obesity; the latter increases insulin resistance. The disease tends to rise in prevalence when populations adopt a diet and exercise pattern typical of United States and European populations. Increases have been seen, for example, among Japanese immigrants to the United States and among some native populations of the South Pacific, Australia, and the Americas. Several studies, conducted on both male and female subjects, have shown that regular exercise can substantially lower one's risk of developing type 2 diabetes, even among persons with a family history of the disease. This is partly because exercise reduces obesity. However, even in the absence of weight loss, exercise increases insulin sensitivity and improves glucose tolerance. Extensive linkage and genome-wide association analyses have identified more than 70 genes that contribute to type 2 diabetes susceptibility. The most significant gene identified thus far is TCF7L2, which encodes a transcription factor involved in secreting insulin. A variant of TCF7L2 is associated with a 50% increased risk of developing type 2 diabetes. A significant association has also been observed between type 2 diabetes and a common allele of the gene that encodes peroxisome proliferator-activated receptor-γ (PPAR-γ), a nuclear receptor that is involved in adipocyte differentiation and glucose metabolism. This receptor is the target of thiazolidinediones [TZDs], a class of drugs commonly used to increase insulin sensitivity in those with type 2 diabetes. Although the common PPARG allele confers only a 25% increase in the risk of developing type 2 diabetes, it is found in more than 75% of persons of European descent and thus helps to account for a significant fraction of type 2 diabetes cases. Variation in KCNJ11, which encodes a potassium channel necessary for glucose-stimulated insulin secretion, confers an additional 20% increase in type 2 diabetes susceptibility. The associations between diabetes susceptibility and each of these genes have been widely replicated in numerous populations. Many rare susceptibility alleles in each of these diabetes-associated genes are now being discovered through high-throughput DNA sequencing studies.

What type of diabetes accounts for more than 90% of all diabetes cases?

Type II diabetes It currently affects approximately 10% to 20% of the adult populations of many developed countries. MZ twin concordance rates are substantially higher than in type 1 diabetes, often exceeding 90% (because of age dependence, the concordance rate increases if older subjects are studied). The empirical recurrence risks for first-degree relatives of patients with type 2 diabetes are higher than those for type 1 patients, generally ranging from 15% to 40%.

multifactorial disorders in the adult population

Until recently, very little was known about specific genes responsible for common adult diseases. With more powerful laboratory and analytical techniques, this situation is changing. We next review recent progress in understanding the genetics of the major common adult diseases

recurrence risks and transmission patterns

Whereas recurrence risks can be given with confidence for single-gene diseases (50% for a completely penetrant autosomal dominant disease, 25% for autosomal recessive diseases, and so on), risk estimation is more complex for multifactorial diseases. This is because the number of genes contributing to the disease is usually not known, the precise allelic constitution of the parents is not known, and the extent of environmental effects can vary substantially. For most multifactorial diseases, empirical risks (i.e., risks based on direct observation of data) have been derived. To estimate empirical risks, a large series of families is examined in which one child (the proband) has developed the disease. The relatives of each proband are surveyed in order to calculate the percentage who have also developed the disease. For example, in North America neural tube defects are seen in about 2% to 3% of the siblings of probands with this condition (Clinical Commentary 12-1). Thus, the recurrence risk for parents who have had one child with a neural tube defect is 2% to 3%. For conditions that are not lethal or severely debilitating, such as cleft lip and cleft palate, recurrence risks can also be estimated for the offspring of affected parents. Because risk factors vary among diseases, empirical recurrence risks are specific for each multifactorial disease. In contrast to most single-gene diseases, recurrence risks for multifactorial diseases can change substantially from one population to another (notice the differences between the London and Belfast populations in Table 12-1). This is because allele frequencies as well as environmental factors can differ among populations. Empirical recurrence risks for multifactorial diseases are based on studies of large collections of families. These risks are specific to a given population

Are the rates of contagious diseases similar in MZ and DZ twins?

Yes because most contagious diseases are unlikely to be influenced markedly by genes on the other hand, the concordance rates for Schizophrenia are quite dissimilar between MZ and DZ twins , indicating a sizeable genetic component for this disease The MZ correlation for dermatoglyphics (fingerprints), a series of traits determined almost entirely by genes, is close to 1.0.

What is Ataxia-telangiectasia? What is caused by?

an autosomal recessive disorder that includes breast cancer in its presentation caused by defective DNA repair

What is an important risk factor for the more common late-onset Alzheimer's disease?

apolipoprotein E (APOE) locus has three major alleles: ε2, ε3, and ε4 persons who have one copy of the ε4 allele are 2 to 5 times more likely to develop AD, and those with two copies of this allele are 5 to 10 times more likely to develop AD

What do Twin studies show about Bipolar disorder?

concordance rates of 79% and 24% for MZ and DZ twins, respectively, yielding a heritability estimate of approximately 72%

What conditions are associated with about 10% of Autism patients?

include Fragile X syndrome (1-2% of cases), Rett syndrome (0.5%), tuberous sclerosis (1%), and neurofibromatosis type 1 (<1%).

If the prevalence of a disease in a population if f (which varies between zero and one), appx what is the risk for offspring and siblings of probands?

sq root of f This does not hold true for single-gene traits, because their recurrence risks are independent of population prevalence. It is not an absolute rule for multifactorial traits either, but many such diseases do tend to conform to this prediction. Examination of the risks given in Table 12-2 shows that these three diseases follow the prediction fairly well.

What occurs in MODY (maturity onset diabetes of the young)?

typically occurs before 25 years of age and follows an autosomal dominant mode of inheritance. In contrast to type 2 diabetes, it is not associated with obesity accounts for 1% to 5% of all diabetes cases