Identification of genetic loci simultaneously associated with multiple cardiometabolic traits

Authors: WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); ARORA, AMIT - University Of Arizona; NEWELL, MICHELLE - University Of Arizona; BLAND, VICTORIA - University Of Arizona; ZHOU, JIN - University Of Arizona; PIRASTU, NICOLA - University Of Edinburgh; Ordovas, Jose; KLIMENTIDIS, YANN - University Of Arizona

Submitted to: Nutrition Metabolism and Cardiovascular Disease
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/4/2022
Publication Date: 1/7/2022
Citation: Wood, A.C., Arora, A., Newell, M., Bland, V.L., Zhou, J., Pirastu, N., Ordovas, J.M., Klimentidis, Y.C. 2022. Identification of genetic loci simultaneously associated with multiple cardiometabolic traits. Nutrition Metabolism and Cardiovascular Disease. https://doi.org/10.1016/j.numecd.2022.01.002.
DOI: https://doi.org/10.1016/j.numecd.2022.01.002

Interpretive Summary: Cardiometabolic disorders (CMDs) arise from a constellation of features such as higher body fat, excess fats in the blood (e.g., high cholesterol), hypertension and difficulties regulating blood sugar levels. 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 are in the genome where variation was associated with risk across seven continuous CMD-related traits. These analyses identified multiple genes which were associated with each CMD trait individually, but only four of these (in/near VEGFA, GRB14-COBLL1, KLF14, and RGS19-OPRL1) were associated with risk across all seven traits. 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 disturbances in the body that represent drug targets that will have the maximum beneficial effect on reducing or treating CMDs.

Technical Abstract: 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. 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. 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.