Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Am J Clin Nutr. 2019 Aug 1;110(2):473-484. doi: 10.1093/ajcn/nqz076.
Little is known about the contribution of genetic variation to food timing, and breakfast has been determined to exhibit the most heritable meal timing. As breakfast timing and skipping are not routinely measured in large cohort studies, alternative approaches include analyses of correlated traits.
The aim of this study was to elucidate breakfast skipping genetic variants through a proxy-phenotype genome-wide association study (GWAS) for breakfast cereal skipping, a commonly assessed correlated trait.
We leveraged the statistical power of the UK Biobank (n = 193,860) to identify genetic variants related to breakfast cereal skipping as a proxy-phenotype for breakfast skipping and applied several in silico approaches to investigate mechanistic functions and links to traits/diseases. Next, we attempted validation of our approach in smaller breakfast skipping GWAS from the TwinUK (n = 2,006) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n = 11,963).
In the UK Biobank, we identified 6 independent GWAS variants, including those implicated for caffeine (ARID3B/CYP1A1), carbohydrate metabolism (FGF21), schizophrenia (ZNF804A), and encoding enzymes important for N6-methyladenosine RNA transmethylation (METTL4, YWHAB, and YTHDF3), which regulates the pace of the circadian clock. Expression of identified genes was enriched in the cerebellum. Genome-wide correlation analyses indicated positive correlations with anthropometric traits. Through Mendelian randomization (MR), we observed causal links between genetically determined breakfast skipping and higher body mass index, more depressive symptoms, and smoking. In bidirectional MR, we demonstrated a causal link between being an evening person and skipping breakfast, but not vice versa. We observed association of our signals in an independent breakfast skipping GWAS in another British cohort (P = 0.032), TwinUK, but not in a meta-analysis of non-British cohorts from the CHARGE consortium (P = 0.095).
Our proxy-phenotype GWAS identified 6 genetic variants for breakfast skipping, linking clock regulation with food timing and suggesting a possible beneficial role of regular breakfast intake as part of a healthy lifestyle.
遗传变异对进食时间的影响知之甚少，而早餐已被确定为遗传可变性最大的用餐时间。由于在大型队列研究中通常不会常规测量早餐时间和不吃早餐的情况，因此可以选择分析相关特征。
本研究旨在通过早餐麦片不吃的关联特征全基因组关联研究（GWAS），阐明与不吃早餐相关的遗传变异。
我们利用英国生物库（n=193860）的统计能力，鉴定与早餐麦片不吃相关的遗传变异，将其作为不吃早餐的替代表型，并应用多种计算方法来研究其机制功能以及与特征/疾病的关联。接下来，我们试图在规模较小的英国双胞胎（n=2006）和基因组流行病学中与心脏和衰老研究的队列（CHARGE）联盟（n=11963）的早餐不吃 GWAS 中验证我们的方法。
在英国生物库中，我们确定了 6 个独立的 GWAS 变异，包括与咖啡因（ARID3B/CYP1A1）、碳水化合物代谢（FGF21）、精神分裂症（ZNF804A）和编码对 N6-甲基腺苷 RNA 转甲基化（METTL4、YWHAB 和 YTHDF3）至关重要的酶有关的变异，这些变异调节生物钟的节奏。鉴定基因的表达在小脑富集。全基因组相关性分析表明与人体测量特征呈正相关。通过孟德尔随机化（MR），我们观察到遗传决定的不吃早餐与更高的体重指数、更多的抑郁症状和吸烟之间存在因果关系。在双向 MR 中，我们证明了具有晚型特征与不吃早餐之间存在因果关系，但反之则不然。我们在英国另一个队列（TwinUK）的独立不吃早餐 GWAS 中观察到了我们信号的关联（P=0.032），但在 CHARGE 联盟非英国队列的荟萃分析中则没有（P=0.095）。
我们的替代表型 GWAS 确定了 6 个与不吃早餐相关的遗传变异，将时钟调节与进食时间联系起来，并表明有规律地吃早餐作为健康生活方式的一部分可能具有有益作用。
