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

ABSTRACT 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 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 x10 324 ) 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 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 in silico 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 GPR61 and nearby genes AMIGO1 and ATXN7L2 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.