Potential role for immune-related genes in autism spectrum disorders: Evidence from genome-wide association meta-analysis of autistic traits

The clinical heterogeneity of autism spectrum disorders majorly challenges their genetic study. Autism spectrum disorderssymptoms occur in milder forms in the general population, as autistic-like traits, and share genetic factors with autismspectrum disorders. Here, we investigate the genetics of individual autistic-like traits to improve our understanding ofautism spectrum disorders. We meta-analysed four population-based genome-wide association studies investigatingfour autistic-like traits – ‘attention-to-detail’, ‘imagination’, ‘rigidity’ and ‘social-skills’ (n=4600). Using autism spectrumdisorder summary statistics from the Psychiatric Genomic Consortium (N=46,350), we applied polygenic risk scoreanalyses to understand the genetic relationship between autism spectrum disorders and autistic-like traits. UsingMAGMA, we performed gene-based and gene co-expression network analyses to delineate involved genes and pathways.We identified two novel genome-wide significant loci – rs6125844 and rs3731197 – associated with ‘attention-to-detail’.We demonstrated shared genetic aetiology between autism spectrum disorders and ‘rigidity’. Analysing top variantsand genes, we demonstrated a role of the immune-related genes RNF114, CDKN2A, KAZN, SPATA2 and ZNF816A inautistic-like traits. Brain-based genetic expression analyses further linked autistic-like traits to genes involved in immunefunctioning, and neuronal and synaptic signalling. Overall, our findings highlight the potential of the autistic-like trait–based approach to address the challenges of genetic research in autism spectrum disorders. We provide novel insightsshowing a potential role of the immune system in specific autism spectrum disorder dimensions