An integrative approach prioritizes the orphan GPR61 genomic region in tissue-specific regulation of chronotype.

Sleep advances : a journal of the Sleep Research Society
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Abstract

STUDY OBJECTIVES: Chronotype, a manifestation of circadian rhythms, affects morning or evening preferences and ease of getting up. This study explores the genetic basis of morning chronotype and ease of getting up, focusing on the G-protein-coupled receptor locus, GPR61.METHODS: We analyzed the genetic correlation between chronotype and ease of getting up using linkage disequilibrium score regression with summary statistics from the UK Biobank ( = 453,379). We prioritized shared signals between chronotype and ease of getting up using the Human Genetic Evidence (HuGE) score. We assessed the significance of GPR61 and the lead variant rs12044778 through co-localization and analyses from ENCODE, Genotype-Tissue Expression, Hi-C, and Knockout Mouse Project databases to explore potential regulatory roles of causal genes.RESULTS: We identified a strong genetic correlation (Rg = 0.80,  = 4.9 × 10) between chronotype and ease of getting up. Twenty-three genes, including three circadian core clock components, had high HuGE scores for both traits. Lead variant rs12044778 in was prioritized for its high HuGE score (45) and causal pleiotropy (posterior probability = 0.98). This morningness variant influenced gene expression in key tissues: decreasing in tibial nerve, increasing in subcutaneous adipose, and increasing in the cerebellum. Functional knockout models showed knockout increased fat mass and activity, knockout increased activity, and knockout reduced body weight without affecting activity.CONCLUSIONS: Our findings reveal pleiotropic genetic factors influencing chronotype and ease of getting up, emphasizing 's rs12044778 and nearby genes like and . These insights advance our understanding of circadian preferences and suggest potential therapeutic interventions.

Year of Publication
2025
Journal
Sleep advances : a journal of the Sleep Research Society
Volume
6
Issue
2
Pages
zpaf030
Date Published
04/2025
ISSN
2632-5012
DOI
10.1093/sleepadvances/zpaf030
PubMed ID
40612388
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