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Nat Genet. 2015 Oct;47(10):1114-20. doi: 10.1038/ng.3390. Epub 2015 Aug 31.

Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index.

Author information

1
Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
2
University of Queensland Diamantina Institute, Translation Research Institute, Brisbane, Queensland, Australia.
3
Medical Research Council (MRC) Integrative Epidemiology Unit (IEU) at the University of Bristol, School of Social and Community Medicine, Bristol, UK.
4
School of Environmental and Rural Science, University of New England, Armidale, New South Wales, Australia.
5
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
6
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
7
Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
8
Estonian Genome Center, University of Tartu, Tartu, Estonia.
9
Division of Endocrinology, Boston Children's Hospital, Cambridge, Massachusetts, USA.
10
Program in Medical and Populational Genetics, Broad Institute, Cambridge, Massachusetts, USA.
11
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
12
Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
13
Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
14
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
15
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
16
Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
17
Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK.
18
Department of Haematology, University of Cambridge, Cambridge, UK.
19
Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA.
20
Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA.
21
Faculty of Veterinary and Agricultural Science, University of Melbourne, Parkville, Victoria, Australia.
22
Biosciences Research Division, Department of Economic Development, Jobs, Transport and Resources, Bundoora, Victoria, Australia.

Abstract

We propose a method (GREML-LDMS) to estimate heritability for human complex traits in unrelated individuals using whole-genome sequencing data. We demonstrate using simulations based on whole-genome sequencing data that ∼97% and ∼68% of variation at common and rare variants, respectively, can be captured by imputation. Using the GREML-LDMS method, we estimate from 44,126 unrelated individuals that all ∼17 million imputed variants explain 56% (standard error (s.e.) = 2.3%) of variance for height and 27% (s.e. = 2.5%) of variance for body mass index (BMI), and we find evidence that height- and BMI-associated variants have been under natural selection. Considering the imperfect tagging of imputation and potential overestimation of heritability from previous family-based studies, heritability is likely to be 60-70% for height and 30-40% for BMI. Therefore, the missing heritability is small for both traits. For further discovery of genes associated with complex traits, a study design with SNP arrays followed by imputation is more cost-effective than whole-genome sequencing at current prices.

PMID:
26323059
PMCID:
PMC4589513
DOI:
10.1038/ng.3390
[Indexed for MEDLINE]
Free PMC Article

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