Shared and divergent contribution of vitamin A and oxytocin to the aetiology of autism spectrum disorder

Rare genetic variations contribute to the heterogeneity of autism spectrum disorder (ASD) and the responses to various interventions for ASD probands. However, the associated molecular underpinnings remain unclear. Herein, we estimated the association between rare genetic variations in 410 vitamin A (VA)-related genes (VARGs) and ASD aetiology using publicly available de novo mutations (DNMs), rare inherited variants, and copy number variations (CNVs) from about 50,000 ASD probands and 20,000 normal controls (discovery and validation cohorts). Additionally, given the functional relevance of VA and oxytocin, we systematically compared the similarities and differences between VA and oxytocin with respect to ASD aetiology and evaluated their potential for clinical applications. Functional DNMs and pathogenic CNVs in VARGs contributed to ASD pathogenesis in the discovery and validation cohorts. Additionally, 324 potential VA-related biomarkers were identified, 243 of which were shared with previously identified oxytocin-related biomarkers, while 81 were unique VA biomarkers. Moreover, multivariable logistic regression analysis revealed that both VA- and oxytocin-related biomarkers were able to predict ASD aetiology for individuals carrying functional DNM in corresponding biomarkers with an average precision of 0.94. As well as, convergent and divergent functions were also identified between VA- and oxytocin-related biomarkers. The findings of this study provide a basis for future studies aimed at understanding the pathophysiological mechanisms underlying ASD while also defining a set of potential molecular biomarkers for adjuvant diagnosis and intervention in ASD. [Display omitted] •Multilevel genomic ASD data were integrated to investigate whether VARG is associated with ASD pathogenesis.•Functional DNMs and pathogenic CNVs in VARGs play a major role in ASD pathogenesis, with strong supporting evidence.•Using a combined model, 324 potential VA-related biomarkers were identified in ∼8 % of patients with ASD.•VA- and oxytocin-related biomarkers show convergent and divergent functions.•VA- & oxytocin-related biomarkers strongly predict ASD etiology in individuals with functional DNMs in corresponding biomarkers.