eQTL colocalization analysis highlights novel susceptibility genes in Autism Spectrum Disorders (ASD)

Abstract

Autism Spectrum Disorders (ASD) are a group of neurodevelopmental disorders (NDDs) characterized by difficulties in social interaction and communication, repetitive behavior, and restricted interests. ASD has proven to have a strong genetic component. However, defining causal genes is still one of the main challenges in GWAS, since the vast majority (>90%) of detected signals lie within the non-coding genome. Expression quantitative trait locus (eQTL) colocalization analysis determines whether a specific variant is responsible for both a local eQTL and GWAS association and has helped leverage data and rendering gene discovery for a wide array of diseases. Here we further mine the largest ASD GWAS performed to date (18,381 cases and 27,969 controls) altogether with GWAS summary statistics from the main PGC studies (Schizophrenia, MD (Major Depression) and ADHD (Attention Deficit/Hyperactivity Disorder)), by using eQTpLot, a newly developed tool that illustrates the colocalization of GWAS and eQTL signals in a locus, and the enrichment of and correlation between the candidate gene eQTLs and trait-significant variants. This analysis points up 8 genes with a significant eQTL colocalization signal in ASD (CRHR1, KANSL1, MANBA, MAPT, MMP12, NKX2-2, PTPRE and WNT3) and one gene (SRPK2) with a marginally significant colocalization signal (r = 0.69, p < 1 × 10-6), and specifically highlights the potentially causal role of MAPT (r = 0.76, p < 1 × 10-6), NKX2-2 (r = 0.71, p-value = 2.26-02) and PTPRE (r = 0.97, p-value = 2.63-04) when restricting the analysis to brain tissue.