Decoding the Genetic Architecture of Autistic Traits in the Aging Population

Autism research has mostly focused on diagnostic frameworks in childhood. However, autistic traits including social skills, communication, attention switching, attention to detail, and imagination, may also vary in many undiagnosed individuals beyond childhood, and the genetic architecture of autistic traits in undiagnosed aging adults remains poorly understood. Here, we performed an exome wide association study of autistic traits in adults aged [≥]40 from the UK Biobank (n = 161,269) and independently validated key findings in the SPARK cohort (n = 142,357). We identified exome wide significance at 17q21.31, represented by a lead variant associated with social skills (rs199533, {beta} = 0.081, P = 2.04 x 10-11). In addition, we identified an independent signal for communication (rs12632110, {beta} = 0.042, P = 3.07 x 10-12) and two independent signal for attention switching (rs690733, {beta} = 0.046, P = 4.26 x 10-12; rs2164272, {beta} = -0.047, P = 1.73 x 10-12). Gene-based analyses further implicate loss-of-function variation in ZSCAN2 ({beta} = 1.00, P = 2.44 x 10-6), which associated with communication differences. Enrichment analyses reveal preferential expression of implicated genes in the cerebral cortex, while phenotypic and neuroimaging analyses link those variants to cortical brain structure and regional volume. Taken together, these findings delineate the genetic architecture of autistic traits in the aging population and link genetic variation to downstream molecular and neuroanatomical mechanism.