Genetic Pleiotropy Underlying Obesity and Autoimmunity Disorders: A Large-Scale Cross-Trait Genome-wide Association Analysis

We interrogate the joint genetic architecture of obesity and 17 autoimmune disorders through integrated cross-trait analysis, identifying 8 conditions with significant genetic correlations to obesity. Using Stratified Pleiotropic Locus Mapping (PLACO), we resolve 10,324 pleiotropic SNPs mapping to 52 risk loci, with Bayesian colocalization confirming nine causal variants. Multivariate gene annotation reveals 133 unique pleiotropic genes—including CLN3, SH2B1, ATP2A1 and MMEL1—enriched in hematopoietic cell differentiation and immune homeostasis pathways. Tissue-specific heritability concentrates in spleen, whole blood, and EBV-transformed lymphocytes, while immune co-localization implicates six IgD + CD38- %B cell-related traits as pathological conduits. Drug-target prioritization nominates 92 candidates, establishing core mechanisms for comorbidity.