Genetic associations of externalising and internalising symptoms with brain imaging and cell types among autistic individuals and the general population

Externalising and internalising symptoms span multiple psychiatric diagnoses. Although similar measures assess these traits in autistic and non-autistic populations, it remains unclear whether their polygenic influences and biological mechanisms align. This study compared genetic contributions to these symptoms in autistic individuals (SPARK, N=3,486) and the general population (ABCD, N=4,637; external datasets: Neff=523,150 externalising; Neff=132,260 internalising). Regression models tested associations between polygenic scores, demographics, and symptom outcomes. Genetic correlations were computed with 12 global and 2,159 regional brain phenotypes, and with 461 cell types across 31 superclusters. In both cohorts, higher symptoms correlated with lower maternal education, lower household income and polygenic scores for depression. The strongest associations were observed for externalising symptoms in the general population, showing negative correlations with cortical expansion and enrichment in hypothalamic and histaminergic neurons. These findings suggest shared genetic architectures but different neurobiological correlates of externalising and internalising symptoms across autism and the general population.