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Heritability in the genome-wide association era

Abstract

Heritability, the fraction of phenotypic variation explained by genetic variation, has been estimated for many phenotypes in a range of populations, organisms, and time points. The recent development of efficient genotyping and sequencing technology has led researchers to attempt to identify the genetic variants responsible for the genetic component of phenotype directly via GWAS. The gap between the phenotypic variance explained by GWAS results and those estimated from classical heritability methods has been termed the “missing heritability problem”. In this work, we examine modern methods for estimating heritability, which use the genotype and sequence data directly. We discuss them in the context of classical heritability methods, the missing heritability problem, and describe their implications for understanding the genetic architecture of complex phenotypes.

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References

  1. Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101

  2. Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA, Julier C, Morahan G, Nerup J, Nierras C, Plagnol V, Pociot F, Schuilenburg H, Smyth DJ, Stevens H, Todd JA, Walker NM, Rich SS (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41:703–707

  3. Boehnke M, Moll PP, Lange K, Weidman WH, Kottke BA (1986) Univariate and bivariate analyses of cholesterol and triglyceride levels in pedigrees. Am J Med Genet 23:775–792

  4. Browning SR, Browning BL (2011) Population structure can inflate SNP-based heritability estimates. Am J Hum Genet 89:191–193 (author reply 193–195)

  5. Daetwyler HD, Villanueva B, Woolliams JA (2008) Accuracy of predicting the genetic risk of disease using a genome-wide approach. PLoS One 3:e3395

  6. De los Campos G, Gianola D, Allison DB (2010) Predicting genetic predisposition in humans: the promise of whole-genome markers. Nat Rev Genet 11:880–886

  7. Deary IJ, Yang J, Davies G, Harris SE, Tenesa A, Liewald D, Luciano M, Lopez LM, Gow AJ, Corley J, Redmond P, Fox HC, Rowe SJ, Haggarty P, McNeill G, Goddard ME, Porteous DJ, Whalley LJ, Starr JM, Visscher PM (2012) Genetic contributions to stability and change in intelligence from childhood to old age. Nature 482(7384):212–215. doi:10.1038/nature10781

  8. Dempster E, Lerner I (1949) Heritability of threshold characters. Genetics 35:212–236

  9. Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB (2010) Rare variants create synthetic genome-wide associations. PLoS Biol 8:e1000294

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

  11. Evans DM, Visscher PM, Wray NR (2009) Harnessing the information contained within genome-wide association studies to improve individual prediction of complex disease risk. Hum Mol Genet 18:3525–3531

  12. Falconer DS (1989) Introduction to quantitative genetics, 3rd edn. Wiley, Burnt Mill

  13. Fisher R (1918) The correlation among relatives on the supposition of Mendelian inheritance. Trans Roy Soc Edinburgh 52:399–433

  14. Gibson G (2011) Rare and common variants: twenty arguments. Nat Rev Genet 13:135–145

  15. Harrell F (2001) Regression modeling strategies. Springer, New York

  16. Hastie T, Tibshirani R, Friedman J (2001) The elements of statistical learning. Springer, New York

  17. Hayes BJ, Visscher PM, Goddard ME (2009) Increased accuracy of artificial selection by using the realized relationship matrix. Genet Res (Camb) 91:47–60

  18. Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 106:9362–9367

  19. Ioannidis JP (2007) Non-replication and inconsistency in the genome-wide association setting. Hum Hered 64:203–213

  20. Ioannidis JP (2008) Why most discovered true associations are inflated. Epidemiology 19:640–648

  21. Kang HM, Sul JH, Service SK, Zaitlen NA, Kong SY, Freimer NB, Sabatti C, Eskin E (2010) Variance component model to account for sample structure in genome-wide association studies. Nat Genet 42:348–354

  22. Kraft P (2008) Curses—winner’s and otherwise—in genetic epidemiology. Epidemiology 19:649–651 (discussion 657–658)

  23. Lange K (2002) Mathematical and statistical methods for genetic analysis. Springer, New York

  24. Lange K, Boehnke M (1983) Extensions to pedigree analysis. IV. Covariance components models for multivariate traits. Am J Med Genet 14:513–524

  25. Lango Allen H, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F, Willer CJ, Jackson AU, Vedantam S, Raychaudhuri S, Ferreira T, Wood AR, Weyant RJ, Segre AV, Speliotes EK, Wheeler E, Soranzo N, Park JH, Yang J, Gudbjartsson D, Heard-Costa NL, Randall JC, Qi L, Vernon Smith A, Magi R, Pastinen T, Liang L, Heid IM, Luan J, Thorleifsson G, Winkler TW, Goddard ME, Sin Lo K, Palmer C, Workalemahu T, Aulchenko YS, Johansson A, Zillikens MC, Feitosa MF, Esko T, Johnson T, Ketkar S, Kraft P, Mangino M, Prokopenko I, Absher D, Albrecht E, Ernst F, Glazer NL, Hayward C, Hottenga JJ, Jacobs KB, Knowles JW, Kutalik Z, Monda KL, Polasek O, Preuss M, Rayner NW, Robertson NR, Steinthorsdottir V, Tyrer JP, Voight BF, Wiklund F, Xu J, Hua Zhao J, Nyholt DR, Pellikka N, Perola M, Perry JR, Surakka I, Tammesoo ML, Altmaier EL, Amin N, Aspelund T, Bhangale T, Boucher G, Chasman DI, Chen C, Coin L, Cooper MN, Dixon AL, Gibson Q, Grundberg E, Hao K, Juhani Junttila M, Kaplan LM, Kettunen J, Konig IR, Kwan T, Lawrence RW, Levinson DF, Lorentzon M, McKnight B, Morris AP, Muller M, Suh Ngwa J, Purcell S, Rafelt S, Salem RM, Salvi E et al (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467:832–838

  26. Lee SH, Wray NR, Goddard ME, Visscher PM (2011) Estimating missing heritability for disease from genome-wide association studies. Am J Hum Genet 88:294–305

  27. Lippert C, Listgarten J, Liu Y, Kadie CM, Davidson RI, Heckerman D (2011) FaST linear mixed models for genome-wide association studies. Nat Methods 8:833–835

  28. Lynch M, Walsh B (1998) Genetics and analysis of quantitative traits. Sinauer, Sunderland

  29. Macgregor S, Cornes BK, Martin NG, Visscher PM (2006) Bias, precision and heritability of self-reported and clinically measured height in Australian twins. Hum Genet 120:571–580

  30. Maher B (2008) Personal genomes: the case of the missing heritability. Nature 456:18–21

  31. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM (2009) Finding the missing heritability of complex diseases. Nature 461:747–753

  32. Park JH, Gail MH, Weinberg CR, Carroll RJ, Chung CC, Wang Z, Chanock SJ, Fraumeni JF Jr, Chatterjee N (2011) Distribution of allele frequencies and effect sizes and their interrelationships for common genetic susceptibility variants. Proc Natl Acad Sci USA 108:18026–18031

  33. Pharoah PD, Antoniou A, Bobrow M, Zimmern RL, Easton DF, Ponder BA (2002) Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31:33–36

  34. Pharoah PD, Antoniou AC, Easton DF, Ponder BA (2008) Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 358:2796–2803

  35. Powell JE, Visscher PM, Goddard ME (2010) Reconciling the analysis of IBD and IBS in complex trait studies. Nat Rev Genet 11(11):800–805

  36. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909

  37. Price AL, Helgason A, Thorleifsson G, McCarroll SA, Kong A, Stefansson K (2011) Single-tissue and cross-tissue heritability of gene expression via identity-by-descent in related or unrelated individuals. PLoS Genet 7:e1001317

  38. Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, Sklar P (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460:748–752

  39. Shaw R (1987) Maximum-likelihood approaches applied to quantitative genetics of natural populations. Evolution 41:812–826

  40. So HC, Gui AH, Cherny SS, Sham PC (2011a) Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases. Genet Epidemiol 35:310–317

  41. So HC, Li M, Sham PC (2011b) Uncovering the total heritability explained by all true susceptibility variants in a genome-wide association study. Genet Epidemiol 35:447–456

  42. Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP, Li Y, Kurreeman FA, Zhernakova A, Hinks A, Guiducci C, Chen R, Alfredsson L, Amos CI, Ardlie KG, Barton A, Bowes J, Brouwer E, Burtt NP, Catanese JJ, Coblyn J, Coenen MJ, Costenbader KH, Criswell LA, Crusius JB, Cui J, de Bakker PI, De Jager PL, Ding B, Emery P, Flynn E, Harrison P, Hocking LJ, Huizinga TW, Kastner DL, Ke X, Lee AT, Liu X, Martin P, Morgan AW, Padyukov L, Posthumus MD, Radstake TR, Reid DM, Seielstad M, Seldin MF, Shadick NA, Steer S, Tak PP, Thomson W, van der Helm-van Mil AH, van der Horst-Bruinsma IE, van der Schoot CE, van Riel PL, Weinblatt ME, Wilson AG, Wolbink GJ, Wordsworth BP, Wijmenga C, Karlson EW, Toes RE, de Vries N, Begovich AB, Worthington J, Siminovitch KA, Gregersen PK, Klareskog L, Plenge RM (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42:508–514

  43. Visscher PM, Medland SE, Ferreira MA, Morley KI, Zhu G, Cornes BK, Montgomery GW, Martin NG (2006) Assumption-free estimation of heritability from genome-wide identity-by-descent sharing between full siblings. PLoS Genet 2:e41

  44. Visscher PM, Macgregor S, Benyamin B, Zhu G, Gordon S, Medland S, Hill WG, Hottenga JJ, Willemsen G, Boomsma DI, Liu YZ, Deng HW, Montgomery GW, Martin NG (2007) Genome partitioning of genetic variation for height from 11,214 sibling pairs. Am J Hum Genet 81:1104–1110

  45. Visscher PM, Hill WG, Wray NR (2008) Heritability in the genomics era—concepts and misconceptions. Nat Rev Genet 9:255–266

  46. Visscher PM, Yang J, Goddard ME (2010) A commentary on ‘common SNPs explain a large proportion of the heritability for human height’ by Yang et al. (2010). Twin Res Hum Genet 13:517–524

  47. Visscher PM, Brown MA, McCarthy MI, Yang J (2012) Five years of GWAS discovery. Am J Hum Genet 90:7–24

  48. Wray NR, Goddard ME (2010) Multi-locus models of genetic risk of disease. Genome Med 2:10

  49. Wray NR, Purcell SM, Visscher PM (2011) Synthetic associations created by rare variants do not explain most GWAS results. PLoS Biol 9:e1000579

  50. Wright S (1921) Systems of mating. Genetics 6:111–178

  51. Yang J, Benyamin B, McEvoy BP, Gordon S, Henders AK, Nyholt DR, Madden PA, Heath AC, Martin NG, Montgomery GW, Goddard ME, Visscher PM (2010) Common SNPs explain a large proportion of the heritability for human height. Nat Genet 42:565–569

  52. Yang J, Lee SH, Goddard ME, Visscher PM (2011a) GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88:76–82

  53. Yang J, Manolio TA, Pasquale LR, Boerwinkle E, Caporaso N, Cunningham JM, de Andrade M, Feenstra B, Feingold E, Hayes MG, Hill WG, Landi MT, Alonso A, Lettre G, Lin P, Ling H, Lowe W, Mathias RA, Melbye M, Pugh E, Cornelis MC, Weir BS, Goddard ME, Visscher PM (2011b) Genome partitioning of genetic variation for complex traits using common SNPs. Nat Genet 43:519–525

  54. Yang J, Weedon MN, Purcell S, Lettre G, Estrada K, Willer CJ, Smith AV, Ingelsson E, O’Connell JR, Mangino M, Magi R, Madden PA, Heath AC, Nyholt DR, Martin NG, Montgomery GW, Frayling TM, Hirschhorn JN, McCarthy MI, Goddard ME, Visscher PM (2011c) Genomic inflation factors under polygenic inheritance. Eur J Hum Genet 19:807–812

  55. Zuk O, Hechter E, Sunyaev SR, Lander ES (2012) The mystery of missing heritability: genetic interactions create phantom heritability. Proc Natl Acad Sci USA 109(4):1193–1198

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Acknowledgments

The authors thank Alkes Price, Eli Stahl and Dan Stram for helpful discussions, and Poorva Mudgal for programming support. NZ was supported by NIH fellowship 5T32ES007142-27, PK by NIH grant R21 DK084529.

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Correspondence to Noah Zaitlen or Peter Kraft.

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Zaitlen, N., Kraft, P. Heritability in the genome-wide association era. Hum Genet 131, 1655–1664 (2012). https://doi.org/10.1007/s00439-012-1199-6

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Keywords

  • Rare Variant
  • Heritability Estimate
  • Epistatic Interaction
  • Causal Variant
  • Related Individual