Dominance genetic variation contributes little to the missing heritability for human complex traits

Zhihong Zhu, Andrew Bakshi, Anna A.E. Vinkhuyzen, Gibran Hemani, Sang Hong Lee, Ilja M. Nolte, Jana V. Van Vliet-Ostaptchouk, Harold Snieder, Tonu Esko, Lili Milani, Reedik Mägi, Andres Metspalu, William G. Hill, Bruce S. Weir, Michael E. Goddard, Peter M. Visscher, Jian Yang

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113 Citations (Scopus)

Abstract

For human complex traits, non-additive genetic variation has been invoked to explain "missing heritability," but its discovery is often neglected in genome-wide association studies. Here we propose a method of using SNP data to partition and estimate the proportion of phenotypic variance attributed to additive and dominance genetic variation at all SNPs (hSNP2 and δSNP2) in unrelated individuals based on an orthogonal model where the estimate of hSNP2 is independent of that of δSNP2. With this method, we analyzed 79 quantitative traits in 6,715 unrelated European Americans. The estimate of δSNP2 averaged across all the 79 quantitative traits was 0.03, approximately a fifth of that for additive variation (average hSNP2 = 0.15). There were a few traits that showed substantial estimates of δSNP2, none of which were replicated in a larger sample of 11,965 individuals. We further performed genome-wide association analyses of the 79 quantitative traits and detected SNPs with genome-wide significant dominance effects only at the ABO locus for factor VIII and von Willebrand factor. All these results suggest that dominance variation at common SNPs explains only a small fraction of phenotypic variation for human complex traits and contributes little to the missing narrow-sense heritability problem.

Original languageEnglish
Pages (from-to)377-385
Number of pages9
JournalAmerican Journal of Human Genetics
Volume96
Issue number3
DOIs
Publication statusPublished or Issued - 5 Mar 2015
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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