Hidden heritability due to heterogeneity across seven populations

Felix C. Tropf (), S. Hong Lee, Renske M. Verweij, Gert Stulp, Peter J. van der Most, Ronald de Vlaming, Andrew Bakshi, Daniel A. Briley, Charles Rahal, Robert Hellpap, Anastasia N. Iliadou, Tõnu Esko, Andres Metspalu, Sarah E. Medland, Nicholas G. Martin, Nicola Barban, Harold Snieder, Matthew R. Robinson and Melinda C. Mills
Additional contact information
Felix C. Tropf: University of Oxford
S. Hong Lee: University of New England
Renske M. Verweij: University of Groningen
Gert Stulp: University of Groningen
Peter J. van der Most: University Medical Center Groningen, University of Groningen
Ronald de Vlaming: Erasmus School of Economics
Andrew Bakshi: The University of Queensland
Daniel A. Briley: University of Illinois at Urbana-Champaign
Charles Rahal: University of Oxford
Robert Hellpap: University of Oxford
Anastasia N. Iliadou: Karolinska Institutet
Tõnu Esko: University of Tartu
Andres Metspalu: University of Tartu
Sarah E. Medland: Queensland Institute of Medical Research Berghofer Medical Research Institute
Nicholas G. Martin: Queensland Institute of Medical Research Berghofer Medical Research Institute
Nicola Barban: University of Oxford
Harold Snieder: University Medical Center Groningen, University of Groningen
Matthew R. Robinson: The University of Queensland
Melinda C. Mills: University of Oxford

Nature Human Behaviour, 2017, vol. 1, issue 10, 757-765

Abstract: Abstract Meta-analyses of genome-wide association studies, which dominate genetic discovery, are based on data from diverse historical time periods and populations. Genetic scores derived from genome-wide association studies explain only a fraction of the heritability estimates obtained from whole-genome studies on single populations, known as the ‘hidden heritability’ puzzle. Using seven sampling populations (n = 35,062), we test whether hidden heritability is attributed to heterogeneity across sampling populations and time, showing that estimates are substantially smaller across populations compared with within populations. We show that the hidden heritability varies substantially: from zero for height to 20% for body mass index, 37% for education, 40% for age at first birth and up to 75% for number of children. Simulations demonstrate that our results are more likely to reflect heterogeneity in phenotypic measurement or gene–environment interactions than genetic heterogeneity. These findings have substantial implications for genetic discovery, suggesting that large homogenous datasets are required for behavioural phenotypes and that gene–environment interaction may be a central challenge for genetic discovery.

Date: 2017
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DOI: 10.1038/s41562-017-0195-1

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