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A genetic investigation of sex bias in the prevalence of attention-deficit/hyperactivity disorder

Martin, Joanna, Walters, Raymond K., Demontis, Ditte, Mattheisen, Manuel, Lee, S. Hong, Robinson, Elise, Brikell, Isabell, Ghirardi, Laura, Larsson, Henrik, Lichtenstein, Paul, Eriksson, Nicholas, 23andMe Research Team, , Psychiatric Genomics Consortium: ADHD Subgroup, , iPSYCH–Broad ADHD Workgroup, , Anney, Richard, Werge, Thomas, Mortensen, Preben Bo, Giortz Pedersen, Marianne, Mors, Ole, Nordentoft, Merete, Hougaard, David M., Bybjerg-Grauholm, Jonas, Wray, Naomi R., Franke, Barbara, Faraone, Stephen V., O'Donovan, Michael Conlon, Thapar, Anita, Borglum, Anders D. and Neale, Benjamin M. 2018. A genetic investigation of sex bias in the prevalence of attention-deficit/hyperactivity disorder. Biological Psychiatry 83 (12) , pp. 1044-1053. 10.1016/j.biopsych.2017.11.026

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Abstract

Background Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. Methods We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (20,183 cases, 35,191 controls) and Swedish populationregister data (N=77,905 cases, N=1,874,637 population controls). Results Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that females with ADHD may be at especially high risk of certain comorbid developmental conditions (i.e. autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score (PRS) analysis did not support a higher burden of ADHD common risk variants in female cases (OR=1.02 [0.98-1.06], p=0.28). In contrast, epidemiological sibling analyses revealed that the siblings of females with ADHD are at higher familial risk of ADHD than siblings of affected males (OR=1.14, [95% CI: 1.11-1.18], p=1.5E-15). Conclusions Overall, this study supports a greater familial burden of risk in females with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: Additional authors - 23andMe Research Team Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, David A. Hinds, Bethann S. Hromatka, Karen E. Huber, Aaron Kleinman, Nadia K. Litterman, Matthew H. McIntyre, Joanna L. Mountain, Carrie A.M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Vladimir Vacic, Catherine H. Wilson Psychiatric Genomics Consortium: ADHD Subgroup Özgür Albayrak, Richard J.L. Anney, Alejandro Arias Vasquez, Maria Jesús Arranz, Philip Asherson, Tobias Banaschewski, Tobias J. Banaschewski, Claiton Bau, Joseph Biederman, Preben Bo Mortensen, Anders Børglum, Jan K. Buitelaar, Miguel Casas, Alice Charach, Bru Cormand, Jennifer Crosbie, Soeren Dalsgaard, Mark J. Daly, Ditte Demontis, Astrid Dempfle, Alysa E. Doyle, Richard P. Ebstein, Josephine Elia, Stephen V. Faraone, Stephen V. Faraone, Manuel Föcker, Barbara Franke, Christine Freitag, Joel Gelernter, Michael Gill, Eugenio Grevet, Jan Haavik, Hakon Hakonarson, Ziarih Hawi, Johannes Hebebrand, Beate Herpertz-Dahlmann, Amaia Hervas, Anke Hinney, Sarah Hohmann, Peter Holmans, Mara Hutz, Abel Ickowitz, Stefan Johansson, Lindsey Kent, Sarah Kittel-Schneider, Henry Kranzler, Jonna Kuntsi, Nanda Lambregts-Rommelse, Kate Langley, Gerd Lehmkuhl, Klaus-Peter Lesch, Sandra K. Loo, Joanna Martin, James J. McGough, Sarah E. Medland, Jobst Meyer, Eric Mick, Frank Middletion, Ana Miranda, Fernando Mulas, Aisling Mulligan, Benjamin M. Neale, Stan F. Nelson, T. Trang Nguyen, Michael C. O’Donovan, Robert D. Oades, Michael J. Owen, Haukur Palmason, Josep Antoni Ramos-Quiroga, Andreas Reif, Tobias J. Renner, Luis Rhode, Marta Ribasés, Marcella Rietschel, Stephan Ripke, Olga Rivero, Herbert Roeyers, Marcel Romanos, Jasmin Romanos, Nina Roth Mota, Aribert Rothenberger, Cristina Sánchez-Mora, Russell Schachar, Helmut Schäfer, André Scherag, Benno G. Schimmelmann, Joseph Sergeant, Judith Sinzig, Susan L. Smalley, Edmund J.S. Sonuga-Barke, Hans-Christoph Steinhausen, Patrick F. Sullivan, Anita Thapar, Margaret Thompsom, Alexandre Todorov, Irwin Waldman, Susanne Walitza, Raymond Walters, Yufeng Wang, Andreas Warnke, Nigel Williams, Stephanie H. Witt, Li Yang, Tetyana Zayats, Yanli Zhang-James iPSYCH–Broad ADHD Workgroup Esben Agerbo, Thomas Damm Als, Marie Bækved-Hansen, Rich Belliveau, Anders D. Børglum, Jonas Bybjerg-Grauholm, Felecia Cerrato, Kimberly Chambert, Claire Churchhouse, Søren Dalsgaard, Mark J. Daly, Ditte Demontis, Ashley Dumont, Jacqueline Goldstein, Jakob Grove, Christine S. Hansen, Mads Engel Hauberg, Mads V. Hollegaard, David M. Hougaard, Daniel P. Howrigan, Hailiang Huang, Julian Maller, Alicia R. Martin, Joanna Martin, Manuel Mattheisen, Jennifer Moran, Ole Mors, Preben Bo Mortensen, Benjamin M. Neale, Merete Nordentoft, Jonatan Pallesen, Duncan S. Palmer, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Timothy Poterba, Jesper Buchhave Poulsen, Stephan Ripke, Elise B. Robinson, F. Kyle Satterstrom, Christine Stevens, Patrick Turley, Raymond K. Walters, Thomas Werge Thomas Werge j, o, p, Preben Bo Mortensen j, k, m, n, Marianne Giørtz Pedersen j, m, n, Ole Mors j, s, Merete Nordentoft j, q, David M. Hougaard j, r, Jonas Bybjerg-Grauholm j, r, Naomi R. Wray t, Barbara Franke w, Stephen V. Faraone h, x, Michael C. O’Donovan i, Anita Thapar i, Anders D. Børglum j, k, l, Benjamin M. Neale
Publisher: Elsevier
ISSN: 0006-3223
Date of First Compliant Deposit: 23 November 2017
Date of Acceptance: 16 November 2017
Last Modified: 29 Dec 2018 21:44
URI: http://orca.cf.ac.uk/id/eprint/107008

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