MARTIN, J., et al. [incl. co-author Oades (RDO)] A genetic investigation of sex bias in the prevalence of attention-deficit/hyperactivity disorder. 2018, Biological Psychiatry, 83, 1044-1053.

ADHD shows substantial heritability & is 2-7 times more common in males than in females. -- We examined 2 putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity & higher burden of risk in female cases.

0/ We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium & iPSYCH Project (n = 20,183 cases, n = 35,191 controls) & Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls). n = 77,905 cases, n = 1,874,637 population controls
1/ Genetic correlation analyses using 2-methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1.

2/ Analyses of population data, however, indicated that females with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder & congenital malformations), potentially indicating some clinical & etiological heterogeneity.

3/ 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).

4/ In contrast, epidemiological sibling analyses revealed that the siblings of females with ADHD are at higher familial risk for ADHD than the siblings of affected males (odds ratio [confidence interval] = 1.14 [1.11-1.18], p = 1.5E-15).

a) Overall, this study supports a greater familial burden of risk in females with ADHD & some clinical & etiological heterogeneity, based on epidemiological analyses.

b) However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence