Genetic analyses identify widespread sex-differential participation bias

Nicola Pirastu; Mattia Cordioli; Priyanka Nandakumar; Gianmarco Mignogna; Abdel Abdellaoui; Benjamin Hollis; Masahiro Kanai; Veera M. Rajagopal; Pietro Della Briotta Parolo; Nikolas Baya; Caitlin E. Carey; Juha Karjalainen; Thomas D. Als; Matthijs D. Van Der Zee; Felix R. Day; Ken K. Ong; Takayuki Morisaki; Eco De Geus; Rino Bellocco; Yukinori Okada; Anders D. Børglum; Peter Joshi; Adam Auton; David Hinds; Benjamin M. Neale; Raymond K. Walters; Michel G. Nivard; John R. B. Perry; Andrea Ganna

doi:10.1038/s41588-021-00846-7

Genetic analyses identify widespread sex-differential participation bias

Nicola Pirastu
, Mattia Cordioli
, Priyanka Nandakumar
, Gianmarco Mignogna
, Abdel Abdellaoui
, Benjamin Hollis
, Masahiro Kanai
, Veera M. Rajagopal
, Pietro Della Briotta Parolo
, Nikolas Baya
, Caitlin E. Carey
, Juha Karjalainen
, Thomas D. Als
, Matthijs D. Van Der Zee
, Felix R. Day
, Ken K. Ong
, Takayuki Morisaki
, Eco De Geus
, Rino Bellocco
, Yukinori Okada

Anders D. Børglum, Peter Joshi, Adam Auton, David Hinds, Benjamin M. Neale, Raymond K. Walters, Michel G. Nivard, John R. B. Perry, Andrea Ganna

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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.

Original language	English
Pages (from-to)	663-671
Number of pages	18
Journal	Nature Genetics
Volume	53
Issue number	5
Early online date	22 Apr 2021
DOIs	https://doi.org/10.1038/s41588-021-00846-7
Publication status	Published - May 2021

Funding

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\u00E0rl, 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.

Funders	Funder number
Biogen MA
Foundation Volksbond Rotterdam
Maze Therapeutics
Netherlands Organization for Health Research and Development
Pfizer
Genentech
GlaxoSmithKline
Sanofi
Janssen Biotech
Celgene
AbbVie
Merck Sharp and Dohme
Medical Research Council	MC_UU_12015/2
Medical Research Council
ZonMw	531003014, 849200011
ZonMw
Academy of Finland	323116
Academy of Finland
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	VI.Veni.191G.030
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Jacobs Foundation
Business Finland	HUS 4685/31/2016, UH 4386/31/2016
Business Finland

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Genetic analyses identify widespread sexdifferential participation biasFinal published version, 4.62 MBLicence: Article 25fa Dutch Copyright Act

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Pirastu, N., Cordioli, M., Nandakumar, P., Mignogna, G., Abdellaoui, A., Hollis, B., Kanai, M., Rajagopal, V. M., Parolo, P. D. B., Baya, N., Carey, C. E., Karjalainen, J., Als, T. D., Van Der Zee, M. D., Day, F. R., Ong, K. K., Morisaki, T., De Geus, E., Bellocco, R., ... Ganna, A. (2021). Genetic analyses identify widespread sex-differential participation bias. Nature Genetics, 53(5), 663-671. https://doi.org/10.1038/s41588-021-00846-7

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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.",

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Pirastu, N, Cordioli, M, Nandakumar, P, Mignogna, G, Abdellaoui, A, Hollis, B, Kanai, M, Rajagopal, VM, Parolo, PDB, Baya, N, Carey, CE, Karjalainen, J, Als, TD, Van Der Zee, MD, Day, FR, Ong, KK, Morisaki, T, De Geus, E, Bellocco, R, Okada, Y, Børglum, AD, Joshi, P, Auton, A, Hinds, D, Neale, BM, Walters, RK, Nivard, MG, Perry, JRB & Ganna, A 2021, 'Genetic analyses identify widespread sex-differential participation bias', Nature Genetics, vol. 53, no. 5, pp. 663-671. https://doi.org/10.1038/s41588-021-00846-7

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AU - Pirastu, Nicola

AU - Cordioli, Mattia

AU - Nandakumar, Priyanka

AU - Mignogna, Gianmarco

AU - Abdellaoui, Abdel

AU - Hollis, Benjamin

AU - Kanai, Masahiro

AU - Rajagopal, Veera M.

AU - Parolo, Pietro Della Briotta

AU - Baya, Nikolas

AU - Carey, Caitlin E.

AU - Karjalainen, Juha

AU - Als, Thomas D.

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AU - Bellocco, Rino

AU - Okada, Yukinori

AU - Børglum, Anders D.

AU - Joshi, Peter

AU - Auton, Adam

AU - Hinds, David

AU - Neale, Benjamin M.

AU - Walters, Raymond K.

AU - Nivard, Michel G.

AU - Perry, John R. B.

AU - Ganna, Andrea

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N2 - 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.

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JO - Nature Genetics

JF - Nature Genetics

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Genetic analyses identify widespread sex-differential participation bias

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