One possibility is that a higher degree of genetic heterogeneity within female individuals masked any differences in PRS burden by sex in the current study. Common and rare variants may contribute additively to ADHD risk, with non-CNV carrier cases having lower ADHD PRSs than cases with large rare CNVs (45). Thus, if female cases are more likely to have a complex syndromic phenotype (as suggested by the register-based analyses), and given that such phenotypes are more likely to be associated with rare variants 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, this subgroup of female individuals could have on average lower PRSs than male individuals with ADHD. On the other hand, affected female individuals with a less severe phenotypic presentation, who are not carriers of such rare variants, could have higher PRSs than affected male individuals. If this were the case, any overall differences in PRS between the sexes could be obscured. Although the variance in ADHD PRS did not appear to differ between male and female cases (p = .31; see Supplement), limited power of this analysis prevents us from conclusively ruling out this possibility.
