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Biol Psychiatry DOI:10.1016/j.biopsych.2017.11.026

A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder.

Publication TypeJournal Article
Year of Publication2018
AuthorsMartin, J, Walters, RK, Demontis, D, Mattheisen, M, S Lee, H, Robinson, E, Brikell, I, Ghirardi, L, Larsson, H, Lichtenstein, P, Eriksson, N, Werge, T, Mortensen, PBo, Pedersen, MGiørtz, Mors, O, Nordentoft, M, Hougaard, DM, Bybjerg-Grauholm, J, Wray, NR, Franke, B, Faraone, SV, O'Donovan, MC, Thapar, A, Børglum, AD, Neale, BM
Corporate Authors23andMe Research Team, Psychiatric Genomics Consortium: ADHD Subgroup, iPSYCH–Broad ADHD Workgroup
JournalBiol Psychiatry
Date Published2018 Jun 15

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 r 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.


Alternate JournalBiol. Psychiatry
PubMed ID29325848
PubMed Central IDPMC5992329
Grant ListG1000632 / / Medical Research Council / United Kingdom
R01 MH094469 / MH / NIMH NIH HHS / United States
U01 MH109536 / MH / NIMH NIH HHS / United States
U54 HD086984 / HD / NICHD NIH HHS / United States
R01 MH107649 / MH / NIMH NIH HHS / United States
/ / Wellcome Trust / United Kingdom
MR/L010305/1 / / Medical Research Council / United Kingdom
R44 HG006981 / HG / NHGRI NIH HHS / United States