title: Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index.
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.
authors: Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.|University of Queensland Diamantina Institute, Translation Research Institute, Brisbane, Queensland, Australia.
authors: Jian
authors: http://orcid.org/0000-0003-2001-2474
authors: J
authors: Yang
authors: Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
authors: Andrew
authors: A
authors: Bakshi
authors: Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
authors: Zhihong
authors: Z
authors: Zhu
authors: Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.|Medical Research Council (MRC) Integrative Epidemiology Unit (IEU) at the University of Bristol, School of Social and Community Medicine, Bristol, UK.
authors: Gibran
authors: G
authors: Hemani
authors: Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
authors: Anna A E
authors: AA
authors: Vinkhuyzen
authors: Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.|School of Environmental and Rural Science, University of New England, Armidale, New South Wales, Australia.
authors: Sang Hong
authors: SH
authors: Lee
authors: Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
authors: Matthew R
authors: MR
authors: Robinson
authors: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
authors: John R B
authors: JR
authors: Perry
authors: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors: Ilja M
authors: IM
authors: Nolte
authors: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.|Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors: Jana V
authors: JV
authors: van Vliet-Ostaptchouk
authors: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors: Harold
authors: H
authors: Snieder
authors: Estonian Genome Center, University of Tartu, Tartu, Estonia.|Division of Endocrinology, Boston Children's Hospital, Cambridge, Massachusetts, USA.|Program in Medical and Populational Genetics, Broad Institute, Cambridge, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors: Tonu
authors: http://orcid.org/0000-0003-1982-6569
authors: T
authors: Esko
authors: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors: Lili
authors: L
authors: Milani
authors: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors: Reedik
authors: R
authors: Mägi
authors: Estonian Genome Center, University of Tartu, Tartu, Estonia.|Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors: Andres
authors: A
authors: Metspalu
authors: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors: Anders
authors: A
authors: Hamsten
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Patrik K E
authors: PK
authors: Magnusson
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Nancy L
authors: NL
authors: Pedersen
authors: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.|Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors: Erik
authors: E
authors: Ingelsson
authors: Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK.|Department of Haematology, University of Cambridge, Cambridge, UK.
authors: Nicole
authors: http://orcid.org/0000-0003-1095-3852
authors: N
authors: Soranzo
authors: Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado, USA.|Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA.
authors: Matthew C
authors: MC
authors: Keller
authors: Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
authors: Naomi R
authors: http://orcid.org/0000-0001-7421-3357
authors: NR
authors: Wray
authors: Faculty of Veterinary and Agricultural Science, University of Melbourne, Parkville, Victoria, Australia.|Biosciences Research Division, Department of Economic Development, Jobs, Transport and Resources, Bundoora, Victoria, Australia.
authors: Michael E
authors: ME
authors: Goddard
authors: Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.|University of Queensland Diamantina Institute, Translation Research Institute, Brisbane, Queensland, Australia.
authors: Peter M
authors: http://orcid.org/0000-0002-2143-8760
authors: PM
authors: Visscher
mesh_terms: D001827:Body Height / Q000235:genetics*; D015992:Body Mass Index; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans