@article{1a2b7be311a646389fb2208d9c30c1e9,
title = "Genetic analyses identify widespread sex-differential participation bias",
abstract = "Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of participation bias is challenging since it requires the genotypes of unseen individuals. Here we demonstrate that it is possible to estimate comparative biases by performing a genome-wide association study contrasting one subgroup versus another. For example, we showed that sex exhibits artifactual autosomal heritability in the presence of sex-differential participation bias. By performing a genome-wide association study of sex in approximately 3.3 million males and females, we identified over 158 autosomal loci spuriously associated with sex and highlighted complex traits underpinning differences in study participation between the sexes. For example, the body mass index-increasing allele at FTO was observed at higher frequency in males compared to females (odds ratio = 1.02, P = 4.4 × 10-36). Finally, we demonstrated how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.",
author = "Nicola Pirastu and Mattia Cordioli and Priyanka Nandakumar and Gianmarco Mignogna and Abdel Abdellaoui and Benjamin Hollis and Masahiro Kanai and Rajagopal, {Veera M.} and Parolo, {Pietro Della Briotta} and Nikolas Baya and Carey, {Caitlin E.} and Juha Karjalainen and Als, {Thomas D.} and {van der Zee}, {Matthijs D.} and Day, {Felix R.} and Ong, {Ken K.} and Takayuki Morisaki and {de Geus}, Eco and Rino Bellocco and {FinnGen Study} and Yukinori Okada and B{\o}rglum, {Anders D.} and Peter Joshi and Adam Auton and David Hinds and Neale, {Benjamin M.} and Walters, {Raymond K.} and {23andMe Research Team} and {iPSYCH Consortium} and Nivard, {Michel G.} and Perry, {John R. B.} and Andrea Ganna",
note = "Funding Information: We thank G. Davey Smith for insightful comments. This research was conducted by using the UK Biobank resource under application no. 31063. A.G. was supported by the Academy of Finland Fellowship (no. 323116). This work was supported by the Medical Research Council (Unit Programme number MC_UU_12015/2). M.G.N. is a fellow of the Jacobs Foundation and is supported by ZonMw grant nos. 849200011 and 531003014 from the Netherlands Organization for Health Research and Development and a VENI grant awarded by the Dutch Research Council (VI.Veni.191G.030). A. Abdellaoui is supported by the Foundation Volksbond Rotterdam and ZonMw grant no. 849200011 from the Netherlands Organization for Health Research and Development. The FinnGen project is funded by 2 grants from Business Finland (nos. HUS 4685/31/2016 and UH 4386/31/2016) and 11 industry partners (AbbVie, AstraZeneca UK, Biogen MA, Celgene Corporation, Celgene International II S{\`a}rl, Genentech, Merck Sharp & Dohme Corp, Pfizer, GlaxoSmithKline, Sanofi, Maze Therapeutics, Janssen Biotech). We thank the following biobanks for collecting the FinnGen project samples: Auria Biobank (https://www.auria.fi/biopankki/); THL Biobank (https://thl.fi/en/web/thl-biobank); Helsinki Biobank (https://www.helsinginbiopankki.fi/fi/etusivu); Biobank Borealis of Northern Finland (https://www.ppshp.fi/Tutkimus-ja-opetus/Biopankki/Pages/ Biobank-Borealis-briefly-in-English.aspx); Finnish Clinical Biobank Tampere (https:// www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere); Biobank of Eastern Finland (https://ita-suomenbiopankki.fi/en/); Central Finland Biobank (https://www.ksshp.fi/fi-FI/Potilaalle/Biopankki); Finnish Red Cross Blood Service Biobank (https://www.veripalvelu.fi/verenluovutus/biopankkitoiminta); and Terveystalo Biobank (https://www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/ Biopankki/). All Finnish Biobanks are members of the BBMRI.fi infrastructure (http:// www.bbmri.fi/). We thank the research participants and employees of 23andMe who contributed to this study. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = may,
day = "1",
doi = "https://doi.org/10.1038/s41588-021-00846-7",
language = "English",
volume = "53",
pages = "663--671",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "5",
}