The Impact of Population Demography and Selection on the Genetic Architecture of Complex Traits

Abstract

Population genetic studies have found evidence for dramatic population growth in recent human history. It is unclear how this recent population growth, combined with the effects of negative natural selection, has affected patterns of deleterious variation, as well as the number, frequency, and effect sizes of mutations that contribute risk to complex traits. Because researchers are performing exome sequencing studies aimed at uncovering the role of low-frequency variants in the risk of complex traits, this topic is of critical importance. Here I use simulations under population genetic models where a proportion of the heritability of the trait is accounted for by mutations in a subset of the exome. I show that recent population growth increases the proportion of nonsynonymous variants segregating in the population, but does not affect the genetic load relative to a population that did not expand. Under a model where a mutation's effect on a trait is correlated with its effect on fitness, rare variants explain a greater portion of the additive genetic variance of the trait in a population that has recently expanded than in a population that did not recently expand. Further, when using a single-marker test, for a given false-positive rate and sample size, recent population growth decreases the expected number of significant associations with the trait relative to the number detected in a population that did not expand. However, in a model where there is no correlation between a mutation's effect on fitness and the effect on the trait, common variants account for much of the additive genetic variance, regardless of demography. Moreover, here demography does not affect the number of significant associations detected. These findings suggest recent population history may be an important factor influencing the power of association tests and in accounting for the missing heritability of certain complex traits.

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References 96

1. 1.

   Altshuler D, Daly MJ, Lander ES (2008 ) Genetic mapping in human disease. Science 322: 881–888.

   Not in our library10.1126/science.1156409

2. 2.

   Stranger BE, Stahl EA, Raj T (2011 ) Progress and promise of genome-wide association studies for human complex trait genetics. Genetics 187: 367–383.

   Not in our library10.1534/genetics.110.120907

3. 3.

   Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, et al (2009 ) Finding the missing heritability of complex diseases. Nature 461: 747–753.

   Not in our library10.1038/nature08494

4. 4.

   Gibson G (2012 ) Rare and common variants: Twenty arguments. Nat Rev Genet 13: 135–145.

   Not in our library10.1038/nrg3118

5. 5.

   EE, Flint J, Gibson G, Kong A, Leal SM, et al (2010 ) Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 11: 446–450.

   Not in our library10.1038/nrg2809

6. 6.

   Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, et al (2009 ) Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461: 272–276.

   Not in our library10.1038/nature08250

7. 7.

   Shendure J, Ji H (2008 ) Next-generation DNA sequencing. Nat Biotechnol 26: 1135–1145.

   Not in our library10.1038/nbt1486

8. 8.

   Wu MC, Lee S, Cai T, Li Y, Boehnke M, et al (2011 ) Rare-variant association testing for sequencing data with the sequence kernel association test. Am J Hum Genet 89: 82–93.

   Not in our library10.1016/j.ajhg.2011.05.029

9. 9.
   A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic · 2009

   No notice
10. 10.

    B, Leal SM (2008 ) Methods for detecting associations with rare variants for common diseases: Application to analysis of sequence data. Am J Hum Genet 83: 311–321.

    Not in our library10.1016/j.ajhg.2008.06.024

11. 11.
    Discovery of rare variants via sequencing: implications for the design of complex trait association studies. · 2009

    Not checked
12. 12.

    Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, et al (2011 ) Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 12: 745–755.

    Not in our library10.1038/nrg3031

13. 13.

    Bamshad MJ, Shendure JA, Valle D, Hamosh A, Lupski JR, et al (2012 ) The centers for Mendelian genomics: A new large-scale initiative to identify the genes underlying rare Mendelian conditions. Am J Med Genet A 158A: 1523–1525.

    Not in our library10.1002/ajmg.a.35470

14. 14.

    Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, et al (2010 ) Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet 42: 790–793.

    Not in our library10.1038/ng.646

15. 15.

    Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, et al (2010 ) Exome sequencing identifies the cause of a Mendelian disorder. Nat Genet 42: 30–35.

    Not in our library10.1038/ng.499

16. 16.

    Ng SB, Nickerson DA, Bamshad MJ, Shendure J (2010 ) Massively parallel sequencing and rare disease. Hum Mol Genet 19: R119–24.

    Not in our library10.1093/hmg/ddq390

17. 17.

    1000 Genomes Project Consortium, Durbin RM, Abecasis GR, Altshuler DL, Auton A, et al (2010 ) A map of human genome variation from population-scale sequencing. Nature 467: 1061–1073.

    Not in our library10.1038/nature09534

18. 18.

    1000 Genomes Project Consortium, Abecasis GR, Auton A, Brooks LD, DePristo MA, et al (2012 ) An integrated map of genetic variation from 1,092 human genomes. Nature 491: 56–65.

    Not in our library10.1038/nature11632

19. 19.

    Cirulli ET, Goldstein DB (2010 ) Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet 11: 415–425.

    Not in our library10.1038/nrg2779

20. 20.

    Gorlov IP, Gorlova OY, Sunyaev SR, Spitz MR, Amos CI (2008 ) Shifting paradigm of association studies: Value of rare single-nucleotide polymorphisms. Am J Hum Genet 82: 100–112.

    Not in our library10.1016/j.ajhg.2007.09.006

21. 21.

    Schork NJ, Murray SS, Frazer KA, Topol EJ (2009 ) Common vs. rare allele hypotheses for complex diseases. Curr Opin Genet Dev 19: 212–219.

    Not in our library10.1016/j.gde.2009.04.010

22. 22.

    Kiezun A, Garimella K, Do R, Stitziel NO, Neale BM, et al (2012 ) Exome sequencing and the genetic basis of complex traits. Nat Genet 44: 623–630.

    Not in our library10.1038/ng.2303

23. 23.

    Helgason H, Sulem P, Duvvari MR, Luo H, Thorleifsson G, et al (2013 ) A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration. Nat Genet 45: 1371–1374.

    Not in our library10.1038/ng.2740

24. 24.

    Seddon JM, Yu Y, Miller EC, Reynolds R, Tan PL, et al (2013 ) Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat Genet 45: 1366–1370.

    Not in our library10.1038/ng.2741

25. 25.

    Zhan X, Larson DE, Wang C, Koboldt DC, Sergeev YV, et al (2013 ) Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. Nat Genet 45: 1375–1379.

    Not in our library10.1038/ng.2758

26. 26.

    Heinzen EL, Depondt C, Cavalleri GL, Ruzzo EK, Walley NM, et al (2012 ) Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy. Am J Hum Genet 91: 293–302.

    Not in our library10.1016/j.ajhg.2012.06.016

27. 27.

    Need AC, McEvoy JP, Gennarelli M, Heinzen EL, Ge D, et al (2012 ) Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. Am J Hum Genet 91: 303–312.

    Not in our library10.1016/j.ajhg.2012.06.018

28. 28.

    Hunt KA, Mistry V, Bockett NA, Ahmad T, Ban M, et al (2013 ) Negligible impact of rare autoimmune-locus coding-region variants on missing heritability. Nature 498: 232–235.

    Not in our library10.1038/nature12170

29. 29.

    Liu L, Sabo A, Neale BM, Nagaswamy U, Stevens C, et al (2013 ) Analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls. PLoS Genet 9: e1003443.

    Not in our library10.1371/journal.pgen.1003443

30. 30.

    Lohmueller KE, Sparso T, Li Q, Andersson E, Korneliussen T, et al (2013 ) Whole-exome sequencing of 2,000 Danish individuals and the role of rare coding variants in type 2 diabetes. Am J Hum Genet 93: 1072–1086.

    Not in our library10.1016/j.ajhg.2013.11.005

31. 31.

    Tennessen JA, Bigham AW, O'Connor TD, Fu W, Kenny EE, et al (2012 ) Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 337: 64–69.

    Not in our library10.1126/science.1219240

32. 32.

    Nelson MR, Wegmann D, Ehm MG, Kessner D, St Jean P, et al (2012 ) An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people. Science 337: 100–104.

    Not in our library10.1126/science.1217876

33. 33.

    Fu W, O'Connor TD, Jun G, Kang HM, Abecasis G, et al (2013 ) Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature 493: 216–220.

    Not in our library10.1038/nature11690

34. 34.
    The functional spectrum of low-frequency coding variation · 2011

    No notice
35. 35.

    Coventry A, Bull-Otterson LM, Liu X, Clark AG, Maxwell TJ, et al (2010 ) Deep resequencing reveals excess rare recent variants consistent with explosive population growth. Nat Commun 1: 131.

    Not in our library10.1038/ncomms1130

36. 36.

    Keinan A, Clark AG (2012 ) Recent explosive human population growth has resulted in an excess of rare genetic variants. Science 336: 740–743.

    Not in our library10.1126/science.1217283

37. 37.

    Kryukov GV, Shpunt A, Stamatoyannopoulos JA, Sunyaev SR (2009 ) Power of deep, all-exon resequencing for discovery of human trait genes. Proc Natl Acad Sci U S A 106: 3871–3876.

    Not in our library10.1073/pnas.0812824106

38. 38.

    Simons YB, Turchin MC, Pritchard JK, Sella G (2014 ) The deleterious mutation load is insensitive to recent population history. Nat Genet 46: 220–224.

    Not in our library10.1038/ng.2896

39. 39.

    Wright AF, Carothers AD, Pirastu M (1999 ) Population choice in mapping genes for complex diseases. Nat Genet 23: 397–404.

    Not in our library10.1038/70501

40. 40.

    Pritchard JK, Przeworski M (2001 ) Linkage disequilibrium in humans: Models and data. Am J Hum Genet 69: 1–14.

    Not in our library10.1086/321275

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