Shared genetic architecture and causality between autism spectrum disorder and irritable bowel syndrome, pain, and fatigue

Abstract Autism spectrum disorder (ASD) often co-occurs with functional somatic syndromes (FSS), such as irritable bowel syndrome (IBS), pain, and fatigue. However, the underlying genetic mechanisms and causality have not been well studied. Using large-scale genome-wide association study (GWAS) data, we investigated the shared genetic architecture and causality between ASD and FSS. Specifically, we first estimated genetic correlations and then conducted a multi-trait analysis of GWAS (MTAG) to detect potential novel genetic variants for single traits. Afterwards, polygenic risk scores (PRS) of ASD were derived from GWAS and MTAG to examine the associations with phenotypes in the large Dutch Lifelines cohort. Finally, we performed Mendelian randomization (MR) to evaluate the causality. We observed positive genetic correlations between ASD and FSS (IBS: rg = 0.27, adjusted p = 2.04×10− 7; pain: rg = 0.13, adjusted p = 1.10×10− 3; fatigue: rg = 0.33, adjusted p = 5.21×10− 9). Leveraging these genetic correlations, we identified 4 novel genome-wide significant independent loci for ASD by conducting MTAG, including NEDD4L, MFHAS1, RP11-10A14.4, and C8orf74. PRS of ASD derived from both GWAS and MTAG were associated with ASD and FSS symptoms in Lifelines, and MTAG-derived PRS showed a bigger effect size, larger explained variance, and smaller p-values. We did not observe significant causality using MR. Our study provided new evidence of shared genetic architecture between ASD and FSS, specifically with IBS, pain, and fatigue. The findings confirm the genetic associations between ASD and FSS, and advance our understanding of the mechanisms underlying co-occurrence.