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; LifeLines Cohort Study; Tonu Esko; Lili Milani; Reedik Mägi; Andres Metspalu; William G Hill; Bruce S Weir; Michael E Goddard; Peter M Visscher; Jian Yang

doi:10.1016/j.ajhg.2015.01.001

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

Am J Hum Genet. 2015 Mar 5;96(3):377-85. doi: 10.1016/j.ajhg.2015.01.001. Epub 2015 Feb 12.

Authors

Zhihong Zhu¹, Andrew Bakshi¹, Anna A E Vinkhuyzen¹, Gibran Hemani², Sang Hong Lee¹, Ilja M Nolte³, Jana V van Vliet-Ostaptchouk⁴, Harold Snieder³; LifeLines Cohort Study; Tonu Esko⁵, Lili Milani⁶, Reedik Mägi⁶, Andres Metspalu⁷, William G Hill⁸, Bruce S Weir⁹, Michael E Goddard¹⁰, Peter M Visscher¹¹, Jian Yang¹²

Affiliations

¹ Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
² 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.
³ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands.
⁴ 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.
⁵ 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.
⁶ Estonian Genome Centre, University of Tartu, Tartu 51006, Estonia.
⁷ Estonian Genome Centre, University of Tartu, Tartu 51006, Estonia; Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia.
⁸ Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, UK.
⁹ Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
¹⁰ Department of Food and Agricultural Systems, University of Melbourne, Parkville, VIC 3010, Australia; Biosciences Research Division, Department of Primary Industries, Bundoora, VIC 3083, Australia.
¹¹ 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.
¹² 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cohort Studies
Evaluation Studies as Topic
Female
Genome-Wide Association Study / methods*
Humans
Linear Models
Male
Models, Genetic
Phenotype*
Polymorphism, Single Nucleotide*
Quantitative Trait, Heritable*
White People / genetics

Abstract

Publication types

MeSH terms

Grants and funding