Cortical differences across psychiatric disorders and associated common and rare genetic variants

Genetic studies have identified common and rare variants increasing the risk for neurodevelopmental and psychiatric disorders (NPDs). These risk variants have also been shown to influence the structure of the cerebral cortex. However, it is unknown whether cortical differences associated with genetic variants are linked to the risk they confer for NPDs. To answer this question, we analyzed cortical thickness (CT) and surface area (SA) for common and rare variants associated with NPDs, in ∼33000 individuals from the general population and clinical cohorts, as well as ENIGMA summary statistics for 8 NPDs. Rare and common genetic variants increasing risk for NPDs were preferentially associated with total SA, while NPDs were preferentially associated with mean CT. Larger effects on mean CT, but not total SA, were observed in NPD medicated subgroups. At the regional level, genetic variants were preferentially associated with effects in sensorimotor areas, while NPDs showed higher effects in association areas. We show that schizophrenia- and bipolar-disorder- associated SNPs show positive and negative effect sizes on SA suggesting that their aggregated effects cancel out in additive polygenic models. Overall, CT and SA differences associated with NPDs do not relate to those observed across individual genetic variants and may be linked with critical non-genetic factors, such as medication and the lived experience of the disorder.