Heritability is a fundamental parameter in genetics. Traditional estimates based on family or twin studies can be biased due to shared environmental or non-additive genetic variance. Alternatively, those based on genotyped or imputed variants typically underestimate narrow-sense heritability contributed by rare or otherwise poorly tagged causal variants. Identical-by-descent (IBD) segments of the genome share all variants between pairs of chromosomes except new mutations that have arisen since the last common ancestor. Therefore, relating phenotypic similarity to degree of IBD sharing among classically unrelated individuals is an appealing approach to estimating the near full additive genetic variance while possibly avoiding biases that can occur when modeling close relatives. We applied an IBD-based approach (GREML-IBD) to estimate heritability in unrelated individuals using phenotypic simulation with thousands of whole-genome sequences across a range of stratification, polygenicity levels, and the minor allele frequencies of causal variants (CVs). In simulations, the IBD-based approach produced unbiased heritability estimates, even when CVs were extremely rare, although precision was low. However, population stratification and non-genetic familial environmental effects shared across generations led to strong biases in IBD-based heritability. We used data on two traits in ~120,000 people from the UK Biobank to demonstrate that, depending on the trait and possible confounding environmental effects, GREML-IBD can be applied to very large genetic datasets to infer the contribution of very rare variants lost using other methods. However, we observed apparent biases in these real data, suggesting that more work may be required to understand and mitigate factors that influence IBD-based heritability estimates.
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This work utilized the Janus supercomputer, which is supported by the National Science Foundation (award number CNS-0821794), the University of Colorado Boulder, the University of Colorado Denver, and the National Center for Atmospheric Research, and is operated by the University of Colorado Boulder. This research has been conducted using the UK Biobank Resource. We thank the participants of the individual HRC cohorts and the UK Biobank. We thank the Keller and Vrieze lab groups, the Institute for Behavioral Genetics, and Sean Caron. This study was funded by NIH R01MH100141 (MCK), NIH R01DA037904 and R01HG008983 (SV), NHMRC grants 1078037 (PMV) and 1113400 (PMV and JY), and Sylvia & Charles Viertel Charitable Foundation Senior Medical Research Fellowship (JY).
Haplotype Reference Consortium:
http://www.haplotype-reference-consortium.org/ Gonçalo Abecasis, David Altshuler, Carl A Anderson, Andrea Angius, Jeffrey C Barrett, Sonja Berndt, Michael Boehnke, Dorrett Boomsma, Kari Branham, Gerome Breen, Chad M Brummett, Fabio Busonero, Harry Campbell, Peter Campbell, Andrew Chan, Sai Chen, Emily Chew, Massimiliano Cocca, Francis S Collins, Laura J Corbin, Francesco Cucca, Petr Danecek, Sayantan Das, Paul I W de Bakker, George Dedoussis, Annelot Dekker, Olivier Delaneau, Marcus Dorr, Richard Durbin, Aliki-Eleni Farmaki, Luigi Ferrucci, Lukas Forer, Ross M Fraser, Timothy Frayling, Christian Fuchsberger, Stacey Gabriel, Ilaria Gandin, Paolo Gasparini, Christopher E Gillies, Arthur Gilly, Leif Groop, Tabitha Harrison, Andrew Hattersley, Oddgeir L Holmen, Kristian Hveem, William Iacono, Amit Joshi, Hyun Min Kang, Hamed Khalili, Charles Kooperberg, Seppo Koskinen, Matthias Kretzler, Warren Kretzschmar, Alan Kwong, James C Lee, Shawn Levy, Yang Luo, Anubha Mahajan, Jonathan Marchini, Steven McCarroll, Mark I McCarthy, Shane McCarthy, Matt McGue, Melvin McInnis, Thomas Meitinger, David Melzer, Massimo Mezzavilla, Josine L Min, Karen L Mohlke, Richard M Myers, Matthias Nauck, Deborah Nickerson, Aarno Palotie, Carlos Pato, Michele Pato, Ulrike Peters, Nicola Pirastu, Wouter Van Rheenen, J Brent Richards, Samuli Ripatti, Cinzia Sala, Veikko Salomaa, Matthew G Sampson, David Schlessinger, Robert E Schoen, Sebastian Schoenherr, Laura J Scott, Kevin Sharp, Carlo Sidore, P Eline Slagboom, Kerrin Small, George Davey Smith, Nicole Soranzo, Timothy Spector, Dwight Stambolian, Anand Swaroop, Morris A Swertz, Alexander Teumer, Nicholas Timpson, Daniela Toniolo, Michela Traglia, Marcus Tuke, Jaakko Tuomilehto, Leonard H Van den Berg, Cornelia M van Duijn, Jan Veldink, John B Vincent, Uwe Volker, Scott Vrieze, Klaudia Walter, Cisca Wijmenga, Cristen Willer, James F Wilson, Andrew R Wood, Eleftheria Zeggini, He Zhang
The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. We thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf
Conflict of interest
The authors declare that they have no conflict of interest.
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