The inheritance of complex traits part 3

Animal models and obesity

*Animal models can be used to study the role of a single gene in obesity.* • The ob gene (mice) or LP gene (humans): encodes the hormone leptin • Leptin is produced in fat cells • Helps to regulate energy balance by inhibiting hunger. Mutations in single genes that cause obesity account for *only about 5%* of all cases of obesity in humans and cannot explain the explosive increase in obesity in developed countries.

Misinterpretation of Heritability

*Assume a heritability of 0.8:* • Incorrect: 80% is genetic, 20% is environmental, e.g. 80% of your height is inherited and 20% due to your environment. • Correct: 80% of the variation in a population is due to different genetic makeup and 20% due to different environment. *What's wrong?* • Heritability can not be used for individuals. • It does not tell us what part of an individual's phenotype can be ascribed to its heredity and what part to its environment. • We can not determine that an individual owes 60 inches of their height to genes and 15 inches to environment.

How do we estimate heritability?

*Keep one parameter constant: either environment or genetics* • Twin studies: compare monozygotic (identical) twins to dizygotic (fraternal) twins Identical twins: share 100% of their genes and same environment Fraternal twins: share 50% of their genes and same environment Also adoption studies: identical twins reared apart (same genes, different environment).

Obesity over time

1998: • 42 states had obesity rates <20% • 7 states had obesity rates ≥ 20% 2010: • All states had obesity rates ≥ 20% • 70% of all adults in the US are overweight • > 35% are obese

Genome-wide association studies (GWAS)

Analyze SNPs (single-nucleotide polymorphism): variation in a single nucleotide that occurs at a specific position in the genome. GWAS studies compare the DNA of individuals with varying phenotypes for a particular trait or disease. If one SNP is more frequent in people with the trait, the variant is said to be association with the trait. The associated SNPs are then considered to mark a region of the human genome that may influence the risk of disease.

Learning Objectives

Define heritability, including what heritability estimates and how to correctly interpret a heritability value. Predict whether a multifactorial trait is highly heritable by analyzing concordance values that result from twin studies. Describe how GWAS and animal models can be useful in identifying genes that contribute to complex traits. Describe what is known about the influence of genetic and environmental factors on the multifactorial traits weight and height.

Heritability

Heritability estimates the genetic contribution to phenotypic *variation* in a *population.* Phenotypic variation in a population results from: - Genetic variance: the phenotypic variation caused by the presence of different genotypes in a population. - Environmental variance: the phenotypic variation in a population that is caused by differences in environment. *Heritability*: the proportion of phenotypic variation in a population that is due to genetic variation. - Heritability uses values between 0 and 1 - H=0 all of the observed variation in the population is environmental. - H=1 all of the observed variation in the population is genetic. Heritability is a population parameter.

Multifactorial trait: Weight

Obesity affects more than 650 million people worldwide. Obesity results from an energy imbalance that occurs when a person consumes more calories than their body burns. Individuals who are obese are at a greatly increased risk for conditions such as high blood pressure, elevated cholesterol, coronary artery disease, etc. In the US, costs for treating obesity and related medical problems exceeds $200 billion per year.

What are some genetic clues to obesity

Obesity has a surprisingly high heritability BUT, increases in the incidence of obesity have taken place over the last 30-40 years thus it is unlikely that large-scale changes in our genetic makeup are responsible for this increase. Heritability estimates are performed at the phenotypic level and cannot tell us about how many genes or which genes control the trait being studied.

Twin studies and concordance values

To evaluate phenotypic differences between twins, traits are scored as present or absent rather than being measured quantitatively. Twins show concordance if both twins share the trait and are discordant if only one twin shows the trait. The concordance rate is the percent of cases in which both members of a pair have a particular attribute. *If trait is exclusively genetic:* • Concordance for identical twins = 100% • Concordance for fraternal twins = close to 50% The greater the *difference* between concordance values of MZ and DZ twins, the greater the heritability.

Interpretation of concordance values

Which trait has the higher heritability?

Results of GWAS (2012)

http://www.ebi.ac.uk/gwas/diagram#diagramtab