Autism Spectrum Disorder (ASD) comprises a complex of neurodevelopmental disorders primarily characterized by deficits in verbal communication, impaired social interaction and repetitive behaviors. The complex genetic architecture of ASD encompasses profound clinical heterogeneity, which poses huge challenges in understanding its pathophysiology. We conducted a large scale association analysis of the MSSNG whole genome sequencing data to elucidate potential modifiers of ASD severity. Using linear regression, we have directly tested the association between 6,198,166 SNPs and Vineland Adaptive Behavior Scale Scores a standardized metric for measuring severity across multiple ASD spectra.

The most significant variants direct us to a significant haplostretch chr3p21 (pval 3.68e-12) of SNPs, n = 132) containing variants on chromosome 3 including a highly interesting nonsynonymous SNV rs11539148 within the QARS gene (NM_001272073:c.A821G:p.N274S MAF = 0.0391) a glutaminyl-tRNA synthetase coding gene crucial in brain development. Furthermore, we analyzed eQTLs for QARS, and found decreased expression across several datasets, a result consistent with the observed effect. The effect further potentially explains differences in significant changes in head circumference. To leverage the size of the region we conducted a pathway enrichment analysis of the set of highly significant loci. The most significant categories include brain development and structural component of the myelin sheath. Genes categorized as neurological, developmental and immune-related constitute 65% of all the genes contributing to these pathways.

Our analysis has detected a region that may be a hallmark of severity in ASD. As the genetic predisposition may be different for almost every ASD individual, understanding the common mechanisms for endophenotypes may help elucidate ASD causal mechanisms.