Immune Cell‐Stratified Regulatory Contexts Associated With BMI ‐Related Multi‐System Disease Risk: A Cell‐Stratified Mendelian Randomization Study Using Single‐Cell eQTL Data

Aims Body mass index (BMI) is associated with multisystem disease risk, but the immune cell‐specific regulatory contexts underlying BMI‐related genetic associations with disease outcomes remain unclear. Methods We applied a cell‐stratified Mendelian randomization framework integrating European‐ancestry BMI GWAS data, GWAS datasets for 33 disease outcomes across five disease systems, single‐cell cis‐eQTL data from 28 peripheral blood immune cell types, and dynamic CD4 + T cell eQTL data. SuSiE‐based colocalization was used to identify BMI‐associated loci sharing causal variants with immune‐cell gene expression. These variants were used as cell‐stratified instruments for Mendelian randomization. Results Across 28 immune cell types, 1326 colocalized variants regulating 1426 genes were identified. In primary MR analyses, genetically predicted BMI showed Bonferroni‐significant associations with 26 disease outcomes. Cell‐stratified analyses identified 87 Bonferroni‐significant associations across 17 disease outcomes. Cardiovascular diseases showed the broadest cell‐stratified associations, followed by respiratory and metabolic diseases. CD4 + T cell regulatory contexts contributed one of the largest shares of prioritized associations, and BMI‐related effects varied across CD4 + T cell activation states. Cross‐disease prioritization highlighted recurrent immune feature genes, including TRAF3 and FGFR1. Conclusion These findings prioritize CD4 + T cell regulatory contexts as potential immunogenetic links between BMI and multi‐system disease risk, while requiring further validation in diverse populations and mechanistic models.