Multitrait Genome-Wide Association Analysis of Macronutrient Intake Identifies 12 Novel Loci for Dietary Intake and Unravels Genetic Overlap with Lifestyle Traits and Cardiometabolic Diseases

Abstract

Suboptimal diets are associated with increased risk of type 2 diabetes, cardiovascular disease and cancer. Genome-wide association studies (GWAS) for individual macronutrients have facilitated the discovery of two relevant loci (FGF-21, FTO), however a single-nutrient approach may preclude the discovery of additional relevant loci. Here, we conducted a multi-trait macronutrient GWAS for carbohydrate, fat, and protein in the UK Biobank to factor in the significant correlation among macronutrient intake. In the UK Biobank, dietary data were collected from over 210,000 individuals aged 37-74 using the Oxford WebQ, a web-based 24 hour diet recall. For multi-trait GWAS, we combined GWAS association evidence of ∼11m imputed variants in participants of European ancestry (n =192,005) for percent of carbohydrate, fat, and protein adjusted for age and sex by applying the CPASSOC package. We identified 14 independent genome-wide significant (Pυ x 10-8) loci for macronutrient intake. We discovered loci associated with lipid metabolism (APOE, GCKR, SLC39A8, PPP1R3B, MLXIPL), alcohol intake (ADH1B, KLB), and new candidate genes (CCDC171, PSMD7, ARL17B, METTL4), and replicated previously associated loci with dietary intake (FGF-21 and FTO). Of the 14 signals, 12 replicated (P003C;0.0036) in multi-trait analyses using previous GWAS on dietary intake from the CHARGE Consortium (n =91,114). Tissue enrichment analysis across 53 tissues in GTEx revealed enrichment of gene expression in the cerebellum. Genome-wide genetic correlations across 234 traits with publicly available GWAS data indicated shared biological links between dietary intake and lifestyle factors (smoking and education) as well as type 2 diabetes and coronary artery disease (P<2.14x10-4). The present findings expand our understanding of the genetic architecture of dietary intake and the shared genetic links with related traits. Disclosure H.S. Dashti: None. J. Merino: None. J.M. Lane: None. J.C. Florez: Consultant; Self; Intarcia Therapeutics, Inc.. Consultant; Spouse/Partner; Santen. M.K. Rutter: Consultant; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Consultant; Self; Ascensia Diabetes Care, Roche Diabetes Care Health and Digital Solutions. R. Saxena: None.