A Population Genetic Model of Disease Susceptibility and Other Quantitative Traits

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Uses Fisher's geometric model with Gaussian stabilizing fitness, infinite-sites mutation and diffusion approximations to derive closed-form allele dynamics and a tight normal population distribution around the optimum. Predicts an emergent underdominance (q=1/2 unstable) and links effect size to selection by selection coefficient ~ a^2/(2w^2). Fits simulations to GWAS simulations showing height GWAS (≈180k samples, ~180 loci) explains ~10% heritability and that pleiotropy and the distribution of selection strengths control how sample size converts into discovered variance.

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1. 0:00A population genetic model of disease susceptibility and other quantitative traits
2. 0:54Phenotypic variation in the population is often normally distributed
3. 1:11A substantial portion of this variation is heritable
4. 2:01An additive model explains these observations
5. 3:19An example: height
6. 4:52The heritability for most traits is substantial (0.1-0.9)
7. 5:43Genome Wide Association Studies
8. 7:03More than 180 SNPs associated with height
9. 8:14Missing heritability
10. 8:42Genetic architecture The number of ALL the variants and their joint distribution of frequencies and effect sizes
11. 12:56The distribution of selection effects and pleiotropy are key determinants of architecture
12. 14:53Some requirements from a model for genetic architecture
13. 20:10The steady state distribution of phenotypes in the population is simple
14. 22:18The dynamic of a segregating variant follows (the first two moments)
15. 23:50Two notes on the first moment
16. 27:46The relationship between selection coefficients and effect sizes
17. 28:59The effects of pleiotropy and selection on genetic architecture (2N53)
18. 30:08Simulated GWAS: Study size 10K & explained variance is 20%
19. 30:57The effects of pleiotropy and selection on genetic architecture (2N5-3): density of variance
20. 36:28Inference: a likelihood approach
21. 37:00Summary and future directions
22. 41:32Polygenic adaptation
23. 48:03The effects of pleiatropy and selection on genetic architecture (2N5-3): density of variance