Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Mol Psychiatry. 2019 Dec;24(12):1920-1932. doi: 10.1038/s41380-018-0079-4. Epub 2018 Jul 9.
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.
宏量营养素的摄入，即碳水化合物、脂肪和蛋白质所提供热量的比例，是代谢疾病的一个重要风险因素，且具有明显的家族聚集性。先前的研究已经确定了两个与宏量营养素摄入有关的遗传位点，但由于遗传变异的不完全覆盖和样本量的适度，限制了其他位点的发现。在这里，我们扩展了宏量营养素摄入的遗传图谱，在 91114 名欧洲血统参与者中确定了 12 个与任何宏量营养素摄入相关的提示性显著位点（P < 1×10）。在包括 123659 名欧洲血统参与者的联合荟萃分析中，有 4 个位点得到了复制，并达到了全基因组显著水平，揭示了两个新的位点；碳水化合物摄入的 RARB 基因座中的常见变异和蛋白质摄入的 DRAM1 基因座中的罕见变异，并证实了之前 FGF21 和 FTO 的发现。在英国生物库中 144770 名参与者的进一步分析中，除了 DRAM1 之外，两阶段分析中确定的所有关联都得到了证实。鉴定出的基因座可能对大脑和脂肪组织生物学具有重要意义，并对肥胖相关表型具有临床影响。我们的研究结果为与宏量营养素摄入相关的生物学功能提供了新的见解。
