Immune Cell-Stratified Regulatory Contexts Associated With BMI-Related Multi-System Disease Risk: A Cell-Stratified...

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.

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.

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.

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.