Genetic overlap between autoimmune disorders and anorexia nervosa: insights from a large-scale cross-trait genome-wide analysis

BACKGROUND: To investigate the shared genetic architecture between autoimmune disorders and anorexia nervosa (AN), identify common risk loci and genes, and explore the underlying genetic mechanisms. METHODS: Using summary-level data from large-scale genome-wide association studies (GWAS), we assessed genetic overlap between autoimmune disorders and AN and conducted cross-trait linkage disequilibrium score regression (LDSC) analysis to identify shared loci and genes. A series of functional annotation and tissue-specific analyses were performed to explore the effects of pleiotropic genes. Genetic enrichment analyses were conducted to identify key tissues involved. Finally, bidirectional Mendelian randomization (MR) analysis was used to investigate causal relationships. RESULTS: Our study highlighted shared genetic mechanisms between six autoimmune diseases and AN. Through gene-based analysis of variants screened by PLACO (FDR < 0.05), 38 pleiotropic genes were identified at the genome-wide significance level (P < 5 × 10^-8), with strong colocalization evidence for three loci (PRKAR2A, CELSR3, and KLHDC8B). Tissue enrichment at both the SNP and gene levels revealed a crucial role for brain tissues in the pleiotropic mechanisms. Through MR analysis, we identified protective causal effects of primary sclerosing cholangitis (PSC) and Graves' disease (GD) on AN risk. CONCLUSIONS: Our findings provide strong evidence for the shared genetic architecture between autoimmune diseases and AN and offer potential insights into the underlying mechanisms involved. CONCLUSIONS: Our findings provide strong evidence for the shared genetic architecture between autoimmune diseases and AN and offer potential insights into the underlying mechanisms involved.