Abstract
CONTEXT: The locus CELSR2-PSRC1-SORT1, a primary genetic signal for lipids, has recently been implicated in different metabolic processes. Our investigation identified its association with energy metabolism. OBJECTIVE: This work aimed to determine biological mechanisms that govern diverse functions of this locus. METHODS: Genotypes for 491 265 variants in 7000 clinically characterized American Indians were previously determined using a custom-designed array specific for this longitudinally studied American Indian population. Among the genotyped individuals, 5205 had measures of fasting lipid levels and 509 had measures of resting metabolic rate (RMR) and substrate oxidation rate assessed through indirect calorimetry. A genome-wide association study (GWAS) for low-density lipoprotein cholesterol (LDL-C) levels identified a variant in CELSR2, and the molecular effect of this variant on gene expression was assessed in skeletal muscle biopsies from 207 participants, followed by functional validation in mouse myoblasts using a luciferase assay. RESULTS: A GWAS in American Indians identified rs12740374 in CELSR2 as the top signal for LDL-C levels (P = 1 × 10-22); further analysis of this variant identified an unexpected correlation with reduced RMR (effect = -44.3 kcal/day/minor-allele) and carbohydrate oxidation rate (effect = -5.21 mg/hour/kg-EMBS). Tagged variants showed a distinct linkage disequilibrium architecture in American Indians, highlighting a potential functional variant, rs6670347 (minor-allele frequency = 0.20). Positioned in the glucocorticoid receptor's core binding motif, rs6670347 is part of a skeletal muscle-specific enhancer. Human skeletal muscle transcriptome analysis showed CELSR2 as the most differentially expressed gene (P = 1.9 × 10-7), with the RMR-lowering minor allele elevating gene expression. Experiments in mouse myoblasts confirmed enhancer-based regulation of CELSR2 expression, dependent on glucocorticoids. Rs6670347 was also associated with increased oxidative phosphorylation gene expression; CELSR2, as a regulator of these genes, suggests a potential influence on energy metabolism through muscle oxidative capacity. CONCLUSION: Variants in the CELSR2/PSRC1/SORT1 locus exhibit tissue-specific effects on metabolic traits, with an independent role in muscle metabolism through glucocorticoid signaling.