Unit 6- Multifactorial Inheritance

multifactorial

-polygenic traits in which ENVIRONMENTAL factors are also believed to cause variation in the trait

If heritability is 0.6-0.8 in type 1 DM and 0.9-1.0 in type 2 DM which one has a stronger genetic component?

-type 2

for quick reference the day of the exam: use tables on slide 13 and 14

nice and concise

threshold model -liability

*in order to be affected by a multifactorial disease, a person must exceed a certain threshold of liability -liability is composed of contribution from BOTH genetic and environmental factors -individuals will have more or less liability toward the trait, depending on how many of the predisposing genes they have inherited and the degree to which they are exposed to the relevant environmental factors -up until the threshold they are asymptomatic, but if threshold of liability is crossed, the trait appears

concordance

-Cmz and Cdz represent the concordance values -if both members of a twin pair share a trait, they are said to be concordant -if both members do not share a trait: discordant

Threshold model -types of traits it describes

-QUALITATIVE traits -ie. the genetic disease is present or absent, one has the disease or not -all-or-nothing traits that do not follow the bell curve

additive polygenic model assumes...

-SIMPLEST model assumes the action of multiple genes (polygenic inheritance) but NOT environmental factors

threshold model -assumption

-assumes there is a "liability" toward development of a disorder that is normally distributed in the general population *in order to be affected by a multifactorial disease, a person must exceed a certain threshold of liability

underestimation of environmental contribution in twin studies

-assuming environment is similar for MZ and DZ twins, but in many cases MZ twins are treated more similarly than DZ twins -more similar environment makes MZ twins more concordant, inflating the apparent genetic influence -typically, heritability varies between 0.0 and 1.0; in some cases, heritability value above 1.0 is possible (indicative of an overestimation of genetic contribution)

occurrence risk of multifactorial diseases

-calculation of occurrence risk is not even attempted -it is very complex since very little is known about the genes or the environmental influence that lead to the diseased phenotype -typically, the number of genes involved is unknown and the allelic constitution of the parents is unknown -the influence of the environment is unclear, and can vary substantially, even within a family

bottom line of adoption and twin studies

-caution must be used when evaluating both types of studies -they do NOT provide definitive measures for the role of genes in multifactorial diseases, but a PRELIMINARY indication of the extent of genetic influence on multifactorial diseases

what are twin studies based on?

-comparison between monozygotic (MZ) twins and dizygotic (DZ) twins

adoption studies ex. schizophrenia

-consist of comparing rates among the adopted offspring of affected parents with rates among adopted offspring of unaffected parents -ie. large adoption study revealed that 8-10% of children born into, but adopted out of schizophrenic familes will develop schizophrenia -however, only 1% of adopted children of normal parents become schizophrenic *provides evidence that genes may be involved, because the adopted children do not share the environment with their affected natural parents, and still show higher chances of manifesting the disorder

common adult diseases classified as multifactorial diseases

-coronary artery disease -obesity -alcoholism -diabetes -infantile autism -schizophrenia

pyloric stenosis (in general)

-due to hyperplasia of the muscles at the pylorus of the stomach, causes obstruction to gastric emptying -infants present in the early weeks with recurrent vomiting, dehydration, and electrolyte imbalance due to loss of HCl from the stomach, excretion of K ions and retention of H ions in the kidney -surgical incision is curative

recurrent risk for multifactorial diseases

-for most, an empirical risk (aka empirical recurrence risk or recurrence risk) is determined base on direct observation of data -although not great, represents the best possible guess available -based upon the best available data obtained

monozygotic (MZ) or identical twins

-genetically identical -originate when the developing embryo divides to form two separate but identical embryos -example of natural clones -because they are genetically identical, any differences between them should be due exclusively to environmental effects

additive polygenic model: -hypothetical genetic system involved in determining inheritance of human height

-if two loci A and B with two alleles each (A, a, B, b) contributed in a similar way to determine height, then 9 genotypes are possible -individual might have 0,1,2,3, or 4 of the "tall" alleles (A and B) and thus there are five distinct phenotypes -majority will be the average having two dominant alleles, 1/16 will be tallest, and 1/16 will be shortest *according to this model, it is the number of dominant alleles that determines the height, NOT the specific combination -height distribution approaches a bell-shaped curve

list of 6 diseases that follow the threshold model -also an example of a multifactorial disease that does not follow the model

-infantile autism -neural tube defects -some forms of congential heart disease -isolated cleft lip/palate -club foot -HTN *does NOT fit all multifactorial disease (ie. DM type 1 is an exception)

two necessary components to be able to distinguish between multifactorial vs. single-gene inheritance

-large data sets and good family history

how is empirical risk calculated

-large number of families are examined, where an affected individual is noted (proband) -the relatives of each proband are evaluated in order to calculate the percentage who have also developed the disease -important to assign a family to the proper population to provide a realistic risk assessment -empirical risks are specific for each multifactorial disease

pyloric stenosis (genetics)

-more prevalent in males (4x greater) -tends to cluster in families with increased risk among siblings or offspring of affected individuals -no specific gene has been discovered yet that contributes to pathogenesis -inheritance is MULTIFACTORIAL --females have a higher threshold of liability

dizygotic (DZ) or fraternal twins

-only as genetically similar (50%) as any other two siblings -originate from a double ovulation followed by the fertilization of each egg by a different sperm cell -used as a control, since environmental differences should be similar to the MZ twins but genetically they are as different as typical brother and sister -thus, the influence of the environment can be subtracted, leaving just the genetic aspect (in theory)

heretability

-represents the proportion of the population variation in a disease trait that can be attributed to genes --the higher the heritability value, the greater the genetic influence on a trait --not universal, specific for a given population in a given environment h=2(Cmz-Cdz) *high concordance does not affect the heritability **estimate of genetic component only comes from comparing concordance values and thus eliminating the environmental differences in the process

limitations of adoption studies

-studies are informative but several environmental influences unknown to the observer may be significant to the disease phenotype 1. prenatal environmental influences 2. adopted children may have been raised for a short time with their biological parents 3. adoption agency finds adoptive parents with similar socioeconomic status to the natural parents

additive polygenic model: -how traits are represented with regards to distribution in a population

-traits display a gradient of phenotypes (ie. there is continuous variation between one extreme nad the other) -can be represented with a BELL-SHAPED CURVE -this is because of the additive effects of many genes -the greater the number of genes that are considered to influence a trait, the more the trait will follow a normal distribution in a population

polygenic/multigenic genes

-traits in which variation is thought to be caused by the combined effects of multiple genes ie. researchers have identified 127 genes that play a role in determining BMI *each individual gene follows mendelian principles of inheritance, but many of them act together to influence a trait

additive polygenic model -used for

-used to explain QUANTITATIVE traits: --measurable traits such as height, bp, serum cholesterol concentration or BMI

2 models of multifactorial inheritance

1. additive polygenic model 2. threshold model

four criteria used to define multifactorial inheritance

1. recurrence risk increases with more than one family member affected 2. recurrence risk is higher if the proband is of the less commonly affected sex 3. more severe phenotype in the proband increases the recurrence risk 4. recurrence risk decreases rapidly in more remotely related relatives

distinctive characteristics that can differentiate a multifactorial disease from clear-cut Mendelian, sex-linked, or mitochondrial inheritance (4)

1. the disease can occur in isolation, with affected children born to unaffected parents, but familial aggregation is also common (ie. multiple cases in the same family) NO CLEAR MENDELIAN PATTERN OF INHERITANCE 2. ENVIRONMENTAL INFLUENCES an increase or decrease risk of disease 3. some occur more commonly in one gender but is NOT a sex-linked trait 4. Some multifactorial diseases occur more frequently in a specific ethnic group

three factors that can be used as predictors of the recurrence risk

1. the more individuals affected in the family, the higher the recurrence risk 2. the less the degree of relationship with the proband, the less the recurrence risk 3. the risk to relatives varies with the severity of the condition in the proband; individuals with more severe cases tend to transmit greater number of risk genes

two prominaent methods used to evaluate the relative influence of genes and environment

1. twin studies 2. adoption studies

limitations to remember in twin studies (3)

1. underestimation of environmental contribution 2. uterine environments for different pairs of MZ twins can be more or less similar 3. somatic mutations after birth may affect only one of the MZ twins

true or false: the threshold of liability changes within a specific population

FALSE -the threshold of liability does NOT change within a specific population *however, the threshold of liability can be different in DIFFERENT populations (ie. threshould can be different between the two sexes)

congenital malformations and some common ones that are classified as multifactorial diseases

Malformations present at birth -cleft lip/palate -pyloric stenosis -club foot -spina bifida

Question: Bob was the 1st child in his family with pyloric stenosis (male proband), Martha was the first child in her family with pyloric stenosis (female proband). Which family has higher recurrence risk?

Martha's -since females have higher thresholds she must be exposed to more environmental factors, meaning her family is more at risk *a male relative of a female proband is most at risk for recurrence

degree of relationship with the proband and recurrence risk in single-gene disorders vs. multifactorial diseases

Single gene disorders: recurrence risk decreases by 50% with each degree of relationship Multifactorial disease: recurrence risks decrease much more rapidly -a rather unique set of factors are necessary to exceed the liability threshold -ALL factors necessary to reproduce the disease are unlikely to be present in a more distant family member