Polygenic overlap and shared genomic loci between anorexia nervosa and cardiometabolic traits suggest shared...

Anorexia nervosa (AN) is a serious psychiatric disorder with prominent metabolic features. Although extensive AN-metabolic genetic correlations have been observed, few studies have thoroughly investigated their shared genetic mechanisms. Based on large-scale genome-wide association studies, this study examines the shared genetic architecture between AN and seven common cardiometabolic traits (body mass index, low-density lipoproteins, systolic blood pressure, diastolic blood pressure, type 2 diabetes, coronary artery disease, and metabolic syndrome). MiXeR and linkage-disequilibrium score regression were adopted to quantify the genetic overlap. A conditional/conjunctional FDR framework was employed to identify shared genomic loci. Gene-based enrichment analyses were performed for the shared genes to reveal the overlapping biological mechanisms. Bayesian genetic colocalization tests were performed for the shared lead SNPs to further prioritize colocalized shared variants. We identified moderate to substantial polygenic overlap between AN and cardiometabolic traits and 43 unique shared genomic loci with mixed effect directions. Genes mapped to the shared loci were enriched for biological processes relevant to brain cell growth and migration, cytoplasmic region, water transport, and muscle development. Furthermore, we identified eight colocalized shared variants, which demonstrated genetic associations and potential interactions with drugs for somatic conditions such as cardiometabolic abnormalities and neuropsychiatric disorders. Overall, this study comprehensively characterizes the genetic relationship between AN and cardiometabolic traits, detects novel genetic mechanisms underlying AN, and reveals the biological underpinnings and clinical implications of the AN-metabolic component. Our findings provide novel insights into AN etiology and gene-based treatment or prevention measures for AN.