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

Area of Science:

• Immunogenetics
• Systems biology
• Human genetics

Background:

• Body mass index (BMI) is linked to increased risk for various diseases.
• The specific immune cell regulatory mechanisms connecting BMI to genetic disease associations are not well understood.

Purpose of the Study:

• To investigate the immune cell-specific genetic regulatory pathways linking BMI to disease risk.
• To identify specific immune cell types and genes involved in BMI-related disease susceptibility.

Main Methods:

• Utilized a cell-stratified Mendelian randomization framework.
• Integrated BMI genome-wide association study (GWAS) data with immune cell eQTL data from 28 cell types.
• Employed SuSiE colocalization to find shared causal variants between BMI loci and immune gene expression.

Main Results:

• Identified 1326 variants regulating 1426 genes across 28 immune cell types.
• Genetically predicted BMI associated with 26 disease outcomes in primary analyses.
• Cell-stratified analyses revealed 87 significant associations for 17 diseases, with CD4+ T cells playing a major role.

Conclusions:

• CD4+ T cell regulatory contexts are prioritized as potential immunogenetic mediators between BMI and multi-system disease risk.
• Findings suggest specific immune features, like TRAF3 and FGFR1, are recurrently involved.
• Further validation in diverse populations and mechanistic studies are warranted.