W63. GENETIC OVERLAP AND SHARED RISK LOCI BETWEEN AUTISM SPECTRUM DISORDER AND CARDIOMETABOLIC TRAITS

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition that affects approximately 2% of the global population. While ASD is primarily characterized by social communication difficulties and restricted, repetitive behaviors, accumulating evidence highlights that individuals with ASD are at an elevated risk for a range of physical health comorbidities, particularly cardiometabolic disorders. However, the extent to which these associations are underpinned by shared genetic factors remains poorly understood. Clarifying the genetic overlap between ASD and cardiometabolic traits could provide insights into the etiology of these comorbidities and inform more tailored clinical management strategies. To investigate the shared genetic architecture between ASD and cardiometabolic phenotypes, we leveraged summary statistics from large-scale genome-wide association studies (GWAS) covering ASD and eight cardiometabolic traits: body mass index (BMI), total cholesterol (TC), high-density lipoprotein (HDL), systolic and diastolic blood pressure (SBP and DBP), pulse pressure (PP), type 2 diabetes (T2D), and coronary artery disease (CAD). We applied two advanced statistical approaches: The bivariate causal mixture model (MiXeR) to estimate the total number of unique and shared genetic variants between ASD and each trait and pleioFDR to identify specific genetic loci jointly associated with ASD and cardiometabolic traits, independent of the direction of genetic effects. Despite low global genetic correlations between ASD and cardiometabolic traits, MiXeR revealed significant polygenic overlap, particularly with BMI and blood pressure-related traits. We observed small positive genetic correlations within the shared component between ASD and metabolic traits (BMI, T2D, and TC). In contrast, we identified negative correlations between ASD and cardiovascular traits (SBP, DBP, PP, and CAD). Through pleioFDR analysis, we identified 100 pleiotropic loci, mapping to 124 genes, that were jointly associated with ASD and at least one cardiometabolic phenotype. Most shared loci exhibited concordant effects between ASD and metabolic traits. In contrast, most shared loci between ASD and cardiovascular traits showed discordant effects, particularly blood pressure phenotypes. Our findings provide compelling evidence of shared genetic underpinnings between ASD and cardiometabolic health, with distinct patterns between metabolic and cardiovascular domains. The concordant genetic effects with metabolic traits support a potential shared biological liability, possibly involving insulin signaling, lipid metabolism, and neurodevelopmental pathways. In contrast, discordant effects with cardiovascular traits suggest different mechanisms, possibly linked to autonomic dysregulation or vascular function. These findings offer novel insights into the biological basis of physical health comorbidities in ASD and underscore the importance of personalized risk assessment.