Despite recent progress on estimating the heritability explained by genotyped SNPs (h2g), a large gap between h2g and estimates of total narrow-sense heritability (h2) remains. Explanations for this gap include rare variants or upward bias in family-based estimates of h2 due to shared environment or epistasis. We estimate h2 from unrelated individuals in admixed populations by first estimating the heritability explained by local ancestry (h2γ). We show that h2γ = 2FSTCθ(1 − θ)h2, where FSTC measures frequency differences between populations at causal loci and θ is the genome-wide ancestry proportion. Our approach is not susceptible to biases caused by epistasis or shared environment. We applied this approach to the analysis of 13 phenotypes in 21,497 African-American individuals from 3 cohorts. For height and body mass index (BMI), we obtained h2 estimates of 0.55 ± 0.09 and 0.23 ± 0.06, respectively, which are larger than estimates of h2g in these and other data but smaller than family-based estimates of h2.
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Wray, N.R. et al. Pitfalls of predicting complex traits from SNPs. Nat. Rev. Genet. 14, 507–515 (2013).
Eichler, E.E. et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nat. Rev. Genet. 11, 446–450 (2010).
Zaitlen, N. & Kraft, P. Heritability in the genome-wide association era. Hum. Genet. 131, 1655–1664 (2012).
Manolio, T.A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).
Visscher, P.M., Brown, M.A., McCarthy, M.I. & Yang, J. Five years of GWAS discovery. Am. J. Hum. Genet. 90, 7–24 (2012).
Chatterjee, N. et al. Projecting the performance of risk prediction based on polygenic analyses of genome-wide association studies. Nat. Genet. 45, 400–405 (2013).
Visscher, P.M., Hill, W.G. & Wray, N.R. Heritability in the genomics era—concepts and misconceptions. Nat. Rev. Genet. 9, 255–266 (2008).
Hindorff, L.A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl. Acad. Sci. USA 106, 9362–9367 (2009).
Gibson, G. Rare and common variants: twenty arguments. Nat. Rev. Genet. 13, 135–145 (2011).
Yang, J. et al. Common SNPs explain a large proportion of the heritability for human height. Nat. Genet. 42, 565–569 (2010).
Zaitlen, N. et al. Using extended genealogy to estimate components of heritability for 23 quantitative and dichotomous traits. PLoS Genet. 9, e1003520 (2013).
Zuk, O., Hechter, E., Sunyaev, S.R. & Lander, E.S. The mystery of missing heritability: genetic interactions create phantom heritability. Proc. Natl. Acad. Sci. USA 109, 1193–1198 (2012).
Lynch, M. & Walsh, B. Genetics and Analysis of Quantitative Traits (Sinauer, Sunderland, Massachusetts, 1998).
Alexander, D.H., Novembre, J. & Lange, K. Fast model-based estimation of ancestry in unrelated individuals. Genome Res. 19, 1655–1664 (2009).
Bhatia, G. et al. Genome-wide comparison of African-ancestry populations from CARe and other cohorts reveals signals of natural selection. Am. J. Hum. Genet. 89, 368–381 (2011).
Sham, P.C. & Purcell, S. Equivalence between Haseman-Elston and variance-components linkage analyses for sib pairs. Am. J. Hum. Genet. 68, 1527–1532 (2001).
Yang, J., Lee, S.H., Goddard, M.E. & Visscher, P.M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011).
Lee, S.H., Wray, N.R., Goddard, M.E. & Visscher, P.M. Estimating missing heritability for disease from genome-wide association studies. Am. J. Hum. Genet. 88, 294–305 (2011).
Yang, J., Zaitlen, N.A., Goddard, M.E., Visscher, P.M. & Price, A.L. Advantages and pitfalls in the application of mixed-model association methods. Nat. Genet. 46, 100–106 (2014).
Golan, D. & Rosset, S. Narrowing the gap on heritability of common disease by direct estimation in case-control GWAS. http://arxiv.org/abs/1305.5363 (2013).
Pasaniuc, B. et al. Analysis of Latino populations from GALA and MEC studies reveals genomic loci with biased local ancestry estimation. Bioinformatics 29, 1407–1415 (2013).
Price, A.L. et al. Sensitive detection of chromosomal segments of distinct ancestry in admixed populations. PLoS Genet. 5, e1000519 (2009).
Johnson, N.A. et al. Ancestral components of admixed genomes in a Mexican cohort. PLoS Genet. 7, e1002410 (2011).
Maples, B.K., Gravel, S., Kenny, E.E. & Bustamante, C.D. RFMix: a discriminative modeling approach for rapid and robust local-ancestry inference. Am. J. Hum. Genet. 93, 278–288 (2013).
Simons, Y.B., Turchin, M.C., Pritchard, J.K. & Sella, G. The deleterious mutation load is insensitive to recent population history. Nat. Genet. 46, 220–224 (2014).
Morrison, A.C. et al. Whole-genome sequence-based analysis of high-density lipoprotein cholesterol. Nat. Genet. 45, 899–901 (2013).
Hamblin, M.T. & Di Rienzo, A. Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus. Am. J. Hum. Genet. 66, 1669–1679 (2000).
Reich, D. et al. Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. PLoS Genet. 5, e1000360 (2009).
Hernandez, R.D. et al. Classic selective sweeps were rare in recent human evolution. Science 331, 920–924 (2011).
Freedman, M.L. et al. Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc. Natl. Acad. Sci. USA 103, 14068–14073 (2006).
Yang, J. et al. Genome partitioning of genetic variation for complex traits using common SNPs. Nat. Genet. 43, 519–525 (2011).
Lee, S.H. et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45, 984–994 (2013).
Lee, S.H. et al. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat. Genet. 44, 247–250 (2012).
Visscher, P.M. et al. Genome partitioning of genetic variation for height from 11,214 sibling pairs. Am. J. Hum. Genet. 81, 1104–1110 (2007).
Hemani, G. et al. Inference of the genetic architecture underlying BMI and height with the use of 20,240 sibling pairs. Am. J. Hum. Genet. 93, 865–875 (2013).
Price, A.L. et al. A genomewide admixture map for Latino populations. Am. J. Hum. Genet. 80, 1024–1036 (2007).
Nalls, M.A. et al. Admixture mapping of white cell count: genetic locus responsible for lower white blood cell count in the Health ABC and Jackson Heart studies. Am. J. Hum. Genet. 82, 81–87 (2008).
Vattikuti, S., Guo, J. & Chow, C.C. Heritability and genetic correlations explained by common SNPs for metabolic syndrome traits. PLoS Genet. 8, e1002637 (2012).
Wilson, J.G. et al. Study design for genetic analysis in the Jackson Heart Study. Ethn. Dis. 15, S6-30–S6-37 (2005).
Reiner, A.P. et al. Genome-wide association study of white blood cell count in 16,388 African Americans: the continental origins and genetic epidemiology network (COGENT). PLoS Genet. 7, e1002108 (2011).
Freedman, B.I. et al. Genome-wide scans for heritability of fasting serum insulin and glucose concentrations in hypertensive families. Diabetologia 48, 661–668 (2005).
Akylbekova, E.L. et al. Clinical correlates and heritability of QT interval duration in blacks: the Jackson Heart Study. Circ Arrhythm Electrophysiol 2, 427–432 (2009).
Fox, E.R. et al. Epidemiology, heritability, and genetic linkage of C-reactive protein in African Americans (from the Jackson Heart Study). Am. J. Cardiol. 102, 835–841 (2008).
Hjelmborg, J.B. et al. The heritability of prostate cancer in the Nordic Twin Study of Cancer. Cancer Epidemiol. Biomarkers Prev. 10.1158/1055-9965.EPI-13-0568 (8 May 2014).
Patterson, N., Price, A.L. & Reich, D. Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).
Pennisi, E. Genomics. 1000 Genomes Project gives new map of genetic diversity. Science 330, 574–575 (2010).
Bhatia, G., Patterson, N., Sankararaman, S. & Price, A.L. Estimating and interpreting FST: the impact of rare variants. Genome Res. 23, 1514–1521 (2013).
Speed, D., Hemani, G., Johnson, M.R. & Balding, D.J. Improved heritability estimation from genome-wide SNPs. Am. J. Hum. Genet. 91, 1011–1021 (2012).
Abecasis, G.R. et al. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).
Lettre, G. et al. Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans: the NHLBI CARe Project. PLoS Genet. 7, e1001300 (2011).
Pasaniuc, B. et al. Enhanced statistical tests for GWAS in admixed populations: assessment using African Americans from CARe and a Breast Cancer Consortium. PLoS Genet. 7, e1001371 (2011).
Franceschini, N. et al. Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations. Am. J. Hum. Genet. 93, 545–554 (2013).
Kolonel, L.N. et al. A multiethnic cohort in Hawaii and Los Angeles: baseline characteristics. Am. J. Epidemiol. 151, 346–357 (2000).
Haiman, C.A. et al. Characterizing genetic risk at known prostate cancer susceptibility loci in African Americans. PLoS Genet. 7, e1001387 (2011).
Olama, A.A. et al. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat. Genet. 46, 1101–1109 (2014).
This research was supported by US National Institutes of Health grants R01 HG006399, R01 GM073059, 1K25HL121295-01A1 and R21 ES020754. The WHI program is funded by the National Heart, Lung, and Blood Institute, US National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C.
The authors declare no competing financial interests.
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Zaitlen, N., Pasaniuc, B., Sankararaman, S. et al. Leveraging population admixture to characterize the heritability of complex traits. Nat Genet 46, 1356–1362 (2014). https://doi.org/10.1038/ng.3139
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