A genetic investigation of sex bias in the prevalence of attention-deficit/hyperactivity disorder
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Background Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. 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 (n = 20,183 cases, n = 35,191 controls) and Swedish population register 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 female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98–1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11–1.18], p = 1.5E-15). Conclusions Overall, this study supports a greater familial burden of risk in female individuals 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.
Martin , J , Walters , R K , Demontis , D , Mattheisen , M , Hong Lee , S , Robinson , E , Brikell , I , Ghirardi , L , Larsson , H , Lichtenstein , P , Eriksson , N , 23andMe Research Team , Psychiatric Genomics Consortium: ADHD Subgroup , iPSYCH–Broad ADHD Workgroup , Werge , T , Mortensen , P B , Pedersen , M G , Mors , O , Nordentoft , M , Hougaard , D M , Bybjerg-Grauholm , J , Wray , N R , Franke , B , Faraone , S V , O'Donovan , M C , Thapar , A , Børglum , A D , Neale , B M & Kent , L 2018 , ' A genetic investigation of sex bias in the prevalence of attention-deficit/hyperactivity disorder ' , Biological Psychiatry , vol. 83 , no. 12 , pp. 1044-1053 . https://doi.org/10.1016/j.biopsych.2017.11.026
Copyright 2017 Society of Biological Psychiatry. This is an open access article under the CC BY license.
DescriptionThis work was supported by the National Human Genome Research Institute of the National Institutes of Health (NIH) (Grant No. R44HG006981 to the 23andMe Team), the Wellcome Trust (Grant No. 106047 to JM). the Australian National Health and Medical Research Council (Grant Nos. 1078901 and 1087889 to NRW). The Broad Institute and Massachusetts General Hospital investigators acknowledge support from the Stanley Medical Research Institute and NIH grants: Grant No. 1R01MH094469 (principal investigator, BMN) and Grant No. 1R01MH107649-01 (principal investigator, BMN). The iPSYCH team acknowledges funding from the Lundbeck Foundation (Grant Nos. R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, the European Research Council (Project No. 294838), the European Community’s Horizon 2020 Programme (H2020/2014-2020) under Grant No. 667302 (Comorbid Conditions of ADHD), the Novo Nordisk Foundation for supporting the Danish National Biobank resource, and grants from Aarhus and Copenhagen universities and university hospitals, including support to the Centre for Integrative Sequencing, the GenomeDK HPC facility, and the Centre for Integrated Register-Based Research at Aarhus University.
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