Abstract
Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10-6) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.
Highlights
Macronutrient intake refers to the proportion of calories consumed from carbohydrate, fat, and protein dietary sources and is an important modifiable risk factor for prevalent diseases such as obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), and cancer [1]
In this study including data from up to 91,114 participants from European ancestry, we identified 12 suggestively significant loci (P < 1 × 10−6) associated with macronutrient intake including four genome-wide significant loci in combined meta-analysis from discovery and replication cohort studies
Meta-analysis including up to 123,659 individuals supported a novel common variant in Retinoic Acid Receptor Beta (RARB) locus associated with 0.20% higher carbohydrate intake, a novel rare variant in the DRAM1 locus
Summary
Macronutrient intake refers to the proportion of calories consumed from carbohydrate, fat, and protein dietary sources and is an important modifiable risk factor for prevalent diseases such as obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), and cancer [1]. Genetic analyses of eating behavior, including those in family studies, have suggested that the familybased heritability of macronutrient intake ranges between 20–40% [7]. This information has generated interest in pinpointing specific genetic loci that influence macronutrient intake [7, 8]. Previous genome-wide association (GWA) study for macronutrient intake have identified associations between a genetic variant mapping near the fibroblast growth factors 21 gene (FGF21) [9]. Earlier GWA investigations have provided evidence for the association between an obesity and fat-mass associated locus (FTO) with protein intake, where individuals carrying the BMI-raising allele reported diets higher in protein [9, 12]
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