The Manifestation Of Genetic Risk For Attention Deficit Hyperactivity Disorder In Females And Males In The General Population

Abstract

Abstract Attention Deficit Hyperactivity Disorder (ADHD) is a common, heritable childhood disorder that is more commonly diagnosed in males than females. Several family and molecular genetic studies suggest that females may require a higher burden of genetic risk to manifest the disorder, however the evidence for this effect is mixed and requires replication. Another possibility for the discrepancy in prevalence rate by sex is that females at high genetic risk for ADHD are routinely under-diagnosed with ADHD and instead this genetic risk manifests itself in other ways, e.g. through other diagnoses. To address these possibilities, we utilised Swedish whole population registry data and data on a subset of Swedish twins who were genotyped. In a sample of N=21,784 individuals, we found evidence that full siblings of females with diagnosed ADHD are at higher risk for an ADHD diagnosis than siblings of diagnosed males [OR=1.14 (1.11-1.18), p=1.5E-15]. However, we found no difference in ADHD polygenic risk scores (PRS) between males and females with traits of ADHD [N=1,226, OR=0.98 (0.87-1.11), p=0.70] or related neurodevelopmental disorders [N=2,719, OR=1.04 (0.96-1.13), p=0.32]. On the other hand, females diagnosed with anxiety had higher ADHD PRS than males with anxiety [N=265, OR=1.49 (1.13-1.98), p=0.0048], suggesting that genetic risk for ADHD may manifest differently in females. A replication of these analyses in a second sample will also be presented. The results of this study provide additional evidence for an increased genetic burden of ADHD risk in females diagnosed with ADHD and their relatives, although it would appear that common genetic variants may not play a substantial role. On the other hand, common variants related to ADHD appear to predispose females more than males to anxiety, which may partly explain the lower prevalence of ADHD seen in females.