Integrated Genomic and Transcriptomic Study Reveals MAPK11 and PER1 as Important Obesity Susceptibility Genes in a High-risk Hispanic/Latino Population

Background: While genome-wide association studies (GWAS) have identified over 1,000 obesity-associated loci, their functional impact on gene expression remains unclear. Moreover, many studies have not fully captured the genetic architecture of obesity in high-risk populations or considered the complexity of adiposity beyond traditional measures. To address these gaps, this study explores the genetic and transcriptomic pathways of obesity using diverse obesity phenotypes in a high-risk population. Methods: We analyzed genomic and whole blood transcriptomic data from the Cameron County Hispanic Cohort (CCHC), performing GWAS on 13 obesity-related traits. Differential expression (DE) analysis was conducted for genes near GWAS-identified SNPs (p < 5x10−6) followed by expression quantitative trait loci (eQTL) mapping and GWAS-eQTL colocalization. Results: GWAS identified 486 trait associations, including six genome-wide significant (p < 5×10−8) loci, with three novel signals linked to abdominal subcutaneous adipose tissue (SAT), body fat percent, and waist circumference. Among 3024 genes near these loci, 60 showed differential expression. Further eQTL analysis suggested two SNP-gene-trait relationships: rs543314376-MAPK11, associated with SAT volume in females, and rs963018484-PER1, linked to BMI in females. Both genes play key roles in obesity related pathways, including inflammation and circadian rhythm regulation. Conclusions: This integrative genomic-transcriptomic analysis uncovers two novel candidate genes for obesity and underscores the critical need for involving all populations and comprehensive adiposity measures in obesity research. By expanding beyond BMI in a Hispanic/Latino population, we move closer to a deeper and more inclusive understanding of obesity’s genetic architecture.