Authors
Kai Cui, Yitong Shen, Meishan Lu, Jiashuo Teng, Qiuming Zou, Lili Liu, Yu Yan, Qi Qi
Published in
Diabetes, obesity & metabolism. Jul 13, 2026. Epub Jul 13, 2026.
Abstract
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.
PMID:
42443709
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.
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