title: Dominance genetic variation contributes little to the missing heritability for human complex traits.
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 (hSNP(2) and δSNP(2)) in unrelated individuals based on an orthogonal model where the estimate of hSNP(2) is independent of that of δSNP(2). With this method, we analyzed 79 quantitative traits in 6,715 unrelated European Americans. The estimate of δSNP(2) averaged across all the 79 quantitative traits was 0.03, approximately a fifth of that for additive variation (average hSNP(2) = 0.15). There were a few traits that showed substantial estimates of δSNP(2), 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.
authors: Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Zhihong
authors: Z
authors: Zhu
authors: Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Andrew
authors: A
authors: Bakshi
authors: Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Anna A E
authors: AA
authors: Vinkhuyzen
authors: Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, School of Social and Community Medicine, Bristol BS8 1TH, UK.
authors: Gibran
authors: G
authors: Hemani
authors: Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Sang Hong
authors: SH
authors: Lee
authors: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands.
authors: Ilja M
authors: IM
authors: Nolte
authors: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands; Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands.
authors: Jana V
authors: JV
authors: van Vliet-Ostaptchouk
authors: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands.
authors: Harold
authors: H
authors: Snieder
authors: Estonian Genome Centre, University of Tartu, Tartu 51006, Estonia; Division of Endocrinology, Boston Children's Hospital, Cambridge, MA 02141, USA; Program in Medical and Populational Genetics, Broad Institute, Cambridge, MA 02242, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors: Tonu
authors: T
authors: Esko
authors: Estonian Genome Centre, University of Tartu, Tartu 51006, Estonia.
authors: Lili
authors: L
authors: Milani
authors: Estonian Genome Centre, University of Tartu, Tartu 51006, Estonia.
authors: Reedik
authors: R
authors: Mägi
authors: Estonian Genome Centre, University of Tartu, Tartu 51006, Estonia; Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia.
authors: Andres
authors: A
authors: Metspalu
authors: Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, UK.
authors: William G
authors: WG
authors: Hill
authors: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors: Bruce S
authors: BS
authors: Weir
authors: Department of Food and Agricultural Systems, University of Melbourne, Parkville, VIC 3010, Australia; Biosciences Research Division, Department of Primary Industries, Bundoora, VIC 3083, Australia.
authors: Michael E
authors: ME
authors: Goddard
authors: Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; The University of Queensland Diamantina Institute, The Translation Research Institute, Brisbane, QLD 4102, Australia.
authors: Peter M
authors: PM
authors: Visscher
authors: Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; The University of Queensland Diamantina Institute, The Translation Research Institute, Brisbane, QLD 4102, Australia. Electronic address: jian.yang@uq.edu.au.
authors: Jian
authors: J
authors: Yang
mesh_terms: D015331:Cohort Studies; D005069:Evaluation Studies as Topic; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D016014:Linear Models; D008297:Male; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D044465:White People / Q000235:genetics