Aside from heterogeneity, prevalence differences may be caused by a female protective effect, whereby female individuals are resilient to developing ADHD and thus require a higher burden of genetic liability to develop it. Three family studies have observed indirect evidence for this hypothesis in the form of increased risk of ADHD in first-degree relatives of affected female individuals compared with affected male individuals, suggesting that families with an affected female individual may have a higher burden of genetic risk 29, 30, 31. Not all studies report an increase in the recurrence rate of ADHD in relatives of female probands, however 32, 33. Two molecular genetic studies tested this hypothesis more directly using ADHD GWAS discovery data to calculate the burden of common risk alleles, as estimated by polygenic risk scores (PRSs), in independent samples. In both studies, female children with ADHD-related phenotypes had higher scores for ADHD than affected male individuals 3, 34. Although these preliminary studies are consistent with the family studies mentioned above, they were based on small discovery studies. Additional tests using large GWAS datasets are needed to test whether there is an increased burden of common genetic risk variants in female individuals with ADHD.
