Identification of genetic loci simultaneously associated with multiple cardiometabolic traits

Abstract

Background and aims: Cardiometabolic disorders (CMD) arise from a constellation of features such as increased adiposity, hyperlipidemia, hypertension and compromised glucose control. Many genetic loci have shown associations with individual CMD-related traits, but no investigations have focused on simultaneously identifying loci showing associations across all domains. We therefore sought to identify loci associated with risk across seven continuous CMD-related traits. Methods and results: We conducted separate genome-wide association studies (GWAS) for systolic and diastolic blood pressure (SBP/DBP), hemoglobin A1c (HbA1c), low- and high- density lipoprotein cholesterol (LDL-C/HDL-C), waist-to-hip-ratio (WHR), and triglycerides (TGs) in the UK Biobank (N = 356,574–456,823). Multiple loci reached genome-wide levels of significance (N = 145–333) for each trait, but only four loci (in/near VEGFA, GRB14-COBLL1, KLF14, and RGS19-OPRL1) were associated with risk across all seven traits (P < 5 × 10−8). We sought replication of these four loci in an independent set of seven trait-specific GWAS meta-analyses. GRB14-COBLL1 showed the most consistent replication, revealing nominally significant associations (P < 0.05) with all traits except DBP. Conclusions: Our analyses suggest that very few loci are associated in the same direction of risk with traits representing the full spectrum of CMD features. We identified four such loci, and an understanding of the pathways between these loci and CMD risk may eventually identify factors that can be used to identify pathologic disturbances that represent broadly beneficial therapeutic targets.