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

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 (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 co-localization and in silico 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 × 10³²⁴) 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 GPR61 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 GPR61 in tibial nerve, increasing AMIGO1 in subcutaneous adipose, and increasing ATXN7L2 in the cerebellum. Functional knockout models showed GPR61 knockout increased fat mass and activity, AMIGO1 knockout increased activity, and ATXN7L2 knockout reduced body weight without affecting activity.

Conclusions: Our findings reveal pleiotropic genetic factors influencing chronotype and ease of getting up, emphasizing GPR61's rs12044778 and nearby genes like AMIGO1 and ATXN7L2. These insights advance our understanding of circadian preferences and suggest potential therapeutic interventions.