Immunological pathways underlying autism: Findings from Mendelian randomization and genetic colocalisation analyses.

Emerging evidence implicates the role of inflammation and immunity in autism. However, little is known about the involvement of specific immunological pathways and their causal role. In 18,381 autism cases and 27,969 controls from the PGC and the iPSYCH consortia, we investigated whether 15 cytokines implicated in the differentiation and function of CD4+ T cell subsets (TH1, TH2, TH9, TFH, TH17, TReg) could be causally linked to autism. Within a Mendelian randomization framework, we used protein quantitative trait loci (pQTLs; N=1,000-3,394) to assess the effects of genetically proxied levels of plasma cytokines on autism. We additionally used brain cortex expression quantitative trait loci (eQTLs; N= 6,601) to investigate whether genetically predicted expression of the genes encoding the cytokines of interest influence autism. We performed colocalisation to assess the possibility that the identified effects were confounded due to Linkage Disequilibrium (LD). We also assessed the possibility of reverse causation. We report consistent evidence for causal effects of genetically predicted levels of IFN-{gamma}R1, IL-12R{beta}1 (TH1), and IL-4RA, IL-5RA, IL-13RA1 (TH2) on autism. We identified brain-specific effects of genetically predicted expression of IFNGR1, IL12RB1, IL23A, which in the case of IFNGR1 and IL23A were additionally supported by evidence suggestive of colocalisation. Findings appeared unlikely to be influenced by reverse causation. Our findings are consistent with a potentially causal effect of TH1 and TH2 pathway cytokines in autism, and further research is required to elucidate the pathways via which TH1 and TH2 influence its phenotypic presentation.