# Genetics of chronotype and impact on metabolic disease

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $168,000

## Abstract

ABSTRACT
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.

## Key facts

- **NIH application ID:** 9997505
- **Project number:** 3R01DK107859-04S1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** RICHA SAXENA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $168,000
- **Award type:** 3
- **Project period:** 2016-07-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997505

## Citation

> US National Institutes of Health, RePORTER application 9997505, Genetics of chronotype and impact on metabolic disease (3R01DK107859-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9997505. Licensed CC0.

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