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Title: Genome-wide association study of breakfast skipping links clock regulation with food timing

item DASHTI, HASSAN - Massachusetts General Hospital
item MERINO, JORDI - Massachusetts General Hospital
item LANE, JACQUELINE - Massachusetts General Hospital
item SONG, YANWEI - Broad Institute Of Mit/harvard
item SMITH, CAREN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item TANAKA, TOSHIKO - National Institutes Of Health (NIH)
item MCKEOWN, NICOLA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item TUCKER, CHANDLER - Massachusetts General Hospital
item SUN, DIANJIANYI - Tulane University
item BARTZ, TRACI - University Of Washington
item LI-GAO, RUIFANG - Leiden University Medical Center
item NISA, HOIRUN - Tulane University
item REUTRAKUL, SIRIMON - University Of Illinois
item LEMAITRE, ROZENN - University Of Washington
item ALSHEHR, TAHANI - Leiden University Medical Center
item DE MUTSERT, RENEE - Leiden University Medical Center
item BAZZANO, LYDIA - Tulane University
item QI, LU - Tulane University
item KNUTSON, KRISTEN - Northwestern University
item PSATY, BRUCE - University Of Washington
item MOOK-KANAMORI, DENNIS - Leiden University Medical Center
item PERICA, VESNA - University Of Split
item NEUHOUSER, MARIAN - Fred Hutchinson Cancer Research Center
item SCHEER, FRANK - Broad Institute Of Mit/harvard
item RUTTER, MARTIN - University Of Manchester
item GARAULET, MARTA - Universidad De Murcia
item SAXENA, RICHA - Massachusetts General Hospital

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/8/2019
Publication Date: 6/13/2019
Citation: Dashti, H.S., Merino, J., Lane, J.M., Song, Y., Smith, C.E., Tanaka, T., McKeown, N.M., Tucker, C., Sun, D., Bartz, T.M., Li-Gao, R., Nisa, H., Reutrakul, S., Lemaitre, R.N., Alshehr, T.M., de Mutsert, R., Bazzano, L., Qi, L., Knutson, K.L., Psaty, B.M., Mook-Kanamori, D.O., Perica, V.B., Neuhouser, M.L., Scheer, F.A., Rutter, M.K., Garaulet, M., Saxena, R. 2019. Genome-wide association study of breakfast skipping links clock regulation with food timing. American Journal of Clinical Nutrition.

Interpretive Summary: The timing of food intake (when an individual eats during the day) is a factor that can be modified to promote better weight management and chronic disease prevention. Timing of food intake is influenced by physiologic, behavioral, and environmental factors, but little is known about how genetics may play a role. Breakfast skipping has been assessed in other studies and is shown to be correlated with the timing of other meals, such as an earlier lunch among breakfast skippers. This suggests that if genetics is linked to skipping breakfast, it may also be linked to the timing of meals in general. Thus, our study aimed to examine whether genetic variants are related to skipping breakfast. To do this, we examined data on over 190,000 participants from the UK Biobank study. We identified 6 independent variants in the genome (genetic variants) that are related to regulating the circadian clock. We identified links between these variants and higher body mass, more depressive symptoms, and smoking. We also identified a link between being an evening person and skipping breakfast, but no link between the reverse (skipping breakfast and being an evening person). These results were validated in another British Cohort study, called Twin UK. However, when we tried to replicate the study in a non-British cohort, results were not the same. In conclusion, we identified 6 genetic variants associated with skipping breakfast, suggesting that clock regulation is linked to timing of meals and suggesting that eating breakfast contributes to a healthier lifestyle.

Technical Abstract: BACKGROUND: 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. OBJECTIVES: 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. METHODS: We leveraged the statistical power of the UK Biobank (n=193860) 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=2006) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n=11963). RESULTS: 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). CONCLUSIONS: 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.