Genetic overlap and shared risk loci between autism spectrum disorder and cardiometabolic traits

Autism spectrum disorder (ASD) is a neurodevelopmental condition affecting 2% of the global population. Beyond core symptoms such as social communication deficits and repetitive behaviors, individuals with ASD are at increased risk of cardiometabolic comorbidities, including obesity, diabetes, and cardiovascular disease. Here, we investigate the shared genetic architecture between ASD and cardiometabolic traits using large genome-wide association studies datasets and advanced statistical approaches: the bivariate causal mixture (MiXeR) model and pleiotropy-informed conditional false discovery rate (pleioFDR). Our results show significant polygenic overlap between ASD and several cardiometabolic phenotypes, despite almost negligible genetic correlation between the traits. Specifically, we observed small positive genetic correlations within the shared component for ASD and metabolic traits, such as body mass index, type 2 diabetes, and total cholesterol. In contrast, negative correlations emerged between ASD and cardiovascular traits, including diastolic and systolic blood pressure, pulse pressure, and coronary artery disease. Finally, we identified 100 shared loci mapping to 124 genes, suggesting shared biological mechanisms underlying these phenotypes. Most shared loci between ASD and metabolic traits exhibited concordant effects, while those common with cardiovascular traits involving blood pressure and pulse showed discordant effects. These findings may guide the development of more targeted interventions and personalized strategies to manage ASD and its associated cardiometabolic health comorbidities.