Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium

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) 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.

Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite

“…Administration of recombinant FGF21 decreased the levels of dopamine and its metabolites in the nucleus accumbens, suggesting that FGF21 acts on the reward system (Talukdar et al 2016). Moreover, a genetic link between alcohol consumption and the FGF21 locus has been demonstrated in human genetic studies (Søberg et al 2017;Frayling et al 2018;Merino et al 2018). It is the same variant that was previously associated with altered macronutrient consumption (rs838133-A) (Chu et al 2013;Tanaka et al 2013).…”

“…Initially, studies found that FGF21 decreased intake of sugar or artificial sweeteners in mice and non-human primates, and that sugar induced expression of FGF21 in mice (Talukdar et al 2016;von Holstein-Rathlou et al 2016;Maekawa et al 2017). Since then, the observation that sucrose, the most abundant dietary sugar, induces FGF21 expression has been expanded to include humans (Søberg et al 2017), and a relationship with the FGF21 pathway has also been documented for alcohol intake (Schumann et al 2016;Talukdar et al 2016;Frayling et al 2018;Merino et al 2018;Søberg et al 2018).…”

“…Specifically, two SNPs were associated with higher carbohydrate intake and lower protein and fat intake (rs838133 and rs838145) (Chu et al 2013;Tanaka et al 2013). Several lines of work have since confirmed the association to the same two SNPs in the FGF21 locus (Søberg et al 2017;Frayling et al 2018;Merino et al 2018), and the association has been expanded to include regulation of alcohol (see above). The first reports separated food intake into the three major nutrient classes (protein, fat and carbohydrate), and the newer studies have subdivided them to investigate whether any single component drives the association.…”

“…; Merino et al . ), and the association has been expanded to include regulation of alcohol (see above). The first reports separated food intake into the three major nutrient classes (protein, fat and carbohydrate), and the newer studies have subdivided them to investigate whether any single component drives the association.…”

“…; Merino et al . ). It is the same variant that was previously associated with altered macronutrient consumption (rs838133‐A) (Chu et al .…”