BMI-genome interactions regulate global gene expression with emphasis in brain and gut

Area of Science:

• Genomics
• Environmental Health
• Systems Biology

Background:

• Genome-wide association studies (GWAS) identify genetic variants (SNPs) linked to disease but often overlook environmental influences.
• Body mass index (BMI) is a significant physiological factor implicated in various disorders, yet its role as an environmental mediator for SNP effects is underexplored.

Purpose of the Study:

• To investigate the interaction between SNPs and BMI in regulating gene expression across diverse tissues.
• To identify BMI-dynamic expression quantitative trait loci (BMI-eQTLs) and understand their underlying mechanisms.

Main Methods:

• Employed an interaction approach to detect SNPs whose regulatory capacity is modulated by BMI.
• Analyzed gene expression patterns across the BMI spectrum in various tissues, including brain and gut.
• Developed predictive models incorporating BMI-by-SNP interactions to identify disease-associated genes.

Main Results:

• Discovered BMI-eQTLs in multiple tissues, notably brain and gut, distinct from the primary BMI effects observed in endocrine tissues.
• Identified cell type, enhancers, and inflammatory cytokines as key factors contributing to BMI-eQTL.
• Models utilizing BMI-by-SNP interactions outperformed SNP-only models in discovering replicating disease-associated genes.

Conclusions:

• Neither genetic predisposition (SNPs) nor BMI alone fully explains complex cellular responses.
• Integrating environmental factors, such as BMI, significantly enhances the power of gene discovery for complex diseases.
• BMI-eQTLs represent a novel layer of gene regulation influenced by environmental context, crucial for understanding disease etiology.