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Finding the missing heritability of complex diseases

Abstract

Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, ‘missing’ heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

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Figure 1: Feasibility of identifying genetic variants by risk allele frequency and strength of genetic effect (odds ratio).

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Acknowledgements

This paper is inspired by the deliberations of an expert working group convened by the National Human Genome Research Institute (NHGRI) on 2–3 February 2009, to address the heritability unexplained in GWAS. The authors acknowledge the participation of J. C. Cohen, M. Daly and A. P. Feinberg in the workshop.

Author Contributions T.A.M., F.S.C., N.J.C., D.B.G., L.A.H., D.J.H., M.I.M. and E.M.R. planned and participated in the workshop; L.R.C., A.C., J.H.C., A.E.G., A.K., L.K., E.M., C.N.R., M.S., D.V., A.S.W., M.B., A.G.C., E.E.E., G.G., J.L.H., T.F.C.M., S.A.M. and P.M.V. participated in the workshop; T.A.M., P.M.V., G.G., M.I.M., E.E.E., T.F.C.M. and S.A.M. drafted the manuscript; F.S.C., N.J.C., D.B.G., L.A.H., D.J.H., E.M.R., L.R.C., A.C., J.H.C., A.P.R., A.E.G., A.K., L.K., E.M., C.N.R., M.S., D.V., A.S.W., M.B., A.G.C. and J.L.H. critically reviewed and revised the manuscript for content.

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Correspondence to Teri A. Manolio.

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[COMPETING INTERESTS: L.R.C. is employed by a pharmaceutical company; A.K. is an employee of decode Genetics, a commercial company that participates in gene discoveries and the development of diagnostic tests. He also owns stocks of the company. E.E.E. is a Pacific Biosciences SAB member. A.C. is a member of the Affymetrix SAB, a potential conflict of interest overseen by Johns Hopkins University policies.]

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Manolio, T., Collins, F., Cox, N. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009). https://doi.org/10.1038/nature08494

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