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

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 (n=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 colocalization 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, P=4.9 x10 ) 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 understanding of circadian preferences and suggest potential therapeutic interventions.

Significance: This study investigates the genetic underpinnings of chronotype preferences and ease of getting up, with a focus on the orphan G protein-coupled receptor GPR61 and the locus lead variant rs12044778. By combining genomic data with functional analysis, we provide mechanistic insight into a locus for morning chronotype and ease of getting in the morning. We identified the variant rs12044778 as a key regulator of and nearby genes and influencing circadian and metabolic traits. Our findings shed light on the intricate genetic networks governing circadian rhythms, suggesting potential therapeutic targets for disorders of the circadian rhythm.