Chronotype, or morningness-eveningness preference, is a behavioral manifestation of an individual?s underlying timing of the circadian rhythm relative to environmental cues and the molecular basis of its links to metabolism remains poorly understood. N-glycosylation is a post-translational modification that is important for the folding, stability and secretion of proteins, and our recent findings implicate causal roles for N-glycosylation changes in chronotype. Our recent collaborative GWAS in 697,828 participants from the UK Biobank and 23andMe identified 351 loci for self-reported chronotype, including at ALG10 and ALG10B, paralogous genes that encode enzymes required for addition of the final glucose residue to assembling N-glycan precursors in the endoplasmic reticulum lumen. Pathway analyses confirmed enrichment of other N-glycosylation pathway enzymes in chronotype GWAS, reinforcing the importance of this pathway. Furthermore, ALG10B genetic variants were found in our published GWAS of self-reported sleep duration, and in GWAS of objective measures of sleep and activity timing in 85,760 UK Biobank participants with 7-day accelerometry. Functional follow-up by modeling ALG10 knockdown in Drosophila brain identified sleep disturbances and epilepsy. Here we propose to use and adapt glycoscience tools developed under the NIH Common Fund Glycoscience Program to determine the molecular consequences on the glycoproteome of perturbation of ALG10B/ALG10 enzymes and to better understand the connections between circadian rhythms and N- glycosylation in both human cellular models and the Drosophila brain. This work will directly expand understanding of human relevant molecular mechanisms that drive timing of the internal circadian rhythm (Aim 2 of the parent grant) and its links with metabolism.

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We have found that enzymes important in modifying specific proteins with sugar molecules are important for determining morningness-eveningness preference in people, and disrupting the version of these enzymes in flies results in sleep disturbances and epilepsy. The goal of this project is to understand the key proteins and processes modified by these enzymes that lead to changes in rhythmic behavior and morningness- eveningness in both human cellular models and the brain of fruit flies, and explore the link between rhythms, sugar modification and metabolism.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Zaghloul, Norann
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Massachusetts General Hospital
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Prasad, Bharati; Saxena, Richa; Goel, Namni et al. (2018) Genetic Ancestry for Sleep Research: Leveraging Health Inequalities to Identify Causal Genetic Variants. Chest 153:1478-1496
Chen, Han; Cade, Brian E; Gleason, Kevin J et al. (2018) Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men. Am J Respir Cell Mol Biol 58:391-401
Vera, Beatriz; Dashti, Hassan S; Gómez-Abellán, Purificación et al. (2018) Modifiable lifestyle behaviors, but not a genetic risk score, associate with metabolic syndrome in evening chronotypes. Sci Rep 8:945
Mukherjee, Sutapa; Saxena, Richa; Palmer, Lyle J (2018) The genetics of obstructive sleep apnoea. Respirology 23:18-27
Grant, Leilah K; Cain, Sean W; Chang, Anne-Marie et al. (2018) Impaired cognitive flexibility during sleep deprivation among carriers of the Brain Derived Neurotrophic Factor (BDNF) Val66Met allele. Behav Brain Res 338:51-55
Vetter, Céline; Dashti, Hassan S; Lane, Jacqueline M et al. (2018) Night Shift Work, Genetic Risk, and Type 2 Diabetes in the UK Biobank. Diabetes Care 41:762-769
Lopez-Minguez, Jesus; Dashti, Hassan S; Madrid-Valero, Juan J et al. (2018) Heritability of the timing of food intake. Clin Nutr :
Lane, Jacqueline M; Liang, Jingjing; Vlasac, Irma et al. (2017) Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits. Nat Genet 49:274-281
Kyle, Simon D; Sexton, Claire E; Feige, Bernd et al. (2017) Sleep and cognitive performance: cross-sectional associations in the UK Biobank. Sleep Med 38:85-91
Johnson, Dayna A; Lane, Jacqueline; Wang, Rui et al. (2017) Greater Cognitive Deficits with Sleep-disordered Breathing among Individuals with Genetic Susceptibility to Alzheimer Disease. The Multi-Ethnic Study of Atherosclerosis. Ann Am Thorac Soc 14:1697-1705

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