Vitamin D-related genes are subjected to significant de novo mutation burdens in autism spectrum disorder.

Vitamin D deficiency is a putative environmental risk factor for autism spectrum disorder (ASD). Besides, de novo mutations (DNMs) play essential roles in ASD. However, it remains unclear whether vitamin D-related genes (VDRGs) carry a strong DNM burden. For the 943 reported VDRGs, we analyzed publicly-available DNMs from 4,327 ASD probands and 3,191 controls. We identified 126 and 44 loss-of-function or deleterious missense mutations in the probands and the controls, respectively, representing a significantly higher DNM burden (p = 1.06 × 10-5 ; odds ratio = 2.11). Specifically, 18 of the VDRGs were found to harbor recurrent functional DNMs in the probands, compared with only one in the controls. In addition, we found that 108 VDRGs with functional DNMs in the probands were significantly more likely to exhibit haploinsufficiency and genic intolerance (p < 0.0078). These VDRGs were also significantly interconnected and co-expressed, and also with other known ASD-risk genes (p < 0.0014), thereby forming a functional network enriched in chromatin modification, transcriptional regulation, and neuronal function. We provide straightforward genetic evidences for the first time that VDRGs with a strong degree of DNM burden in ASD and DNMs of VDRGs could be involved in the mechanism underlying in ASD pathogenesis.