{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T18:50:00Z","timestamp":1778611800870,"version":"3.51.4"},"posted":{"date-parts":[[2024,11,25]]},"group-title":"Genomics","reference-count":34,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T00:00:00Z","timestamp":1732492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,11,25]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    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\n                    <jats:italic>in-silico<\/jats:italic>\n                    analyses from ENCODE, Genotype-Tissue Expression, Hi-C, and Knockout Mouse Project databases to explore potential regulatory roles of causal genes.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We identified a strong genetic correlation (Rg=0.80, P=4.9 x10\n                    <jats:sup>324<\/jats:sup>\n                    ) 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\n                    <jats:italic>GPR61<\/jats:italic>\n                    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\n                    <jats:italic>GPR61<\/jats:italic>\n                    in tibial nerve, increasing\n                    <jats:italic>AMIGO1<\/jats:italic>\n                    in subcutaneous adipose, and increasing\n                    <jats:italic>ATXN7L2<\/jats:italic>\n                    in the cerebellum. Functional knockout models showed\n                    <jats:italic>GPR61<\/jats:italic>\n                    knockout increased fat mass and activity,\n                    <jats:italic>AMIGO1<\/jats:italic>\n                    knockout increased activity, and\n                    <jats:italic>ATXN7L2<\/jats:italic>\n                    knockout reduced body weight without affecting activity.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Our findings reveal pleiotropic genetic factors influencing chronotype and ease of getting-up, emphasizing\n                    <jats:italic>GPR61<\/jats:italic>\n                    \u2019s rs12044778 and nearby genes like\n                    <jats:italic>AMIGO1<\/jats:italic>\n                    and\n                    <jats:italic>ATXN7L2<\/jats:italic>\n                    . These insights advance understanding of circadian preferences and suggest potential therapeutic interventions.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>SIGNIFICANCE<\/jats:title>\n                  <jats:p>\n                    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\n                    <jats:italic>in silico<\/jats:italic>\n                    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\n                    <jats:italic>GPR61<\/jats:italic>\n                    and nearby genes\n                    <jats:italic>AMIGO1<\/jats:italic>\n                    and\n                    <jats:italic>ATXN7L2<\/jats:italic>\n                    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.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.11.22.624721","type":"posted-content","created":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T20:00:46Z","timestamp":1732564846000},"source":"Crossref","is-referenced-by-count":1,"title":["An integrative approach prioritizes the orphan GPR61 genomic region in tissue-specific regulation of chronotype"],"prefix":"10.64898","author":[{"given":"Cynthia","family":"Tchio","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Williams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Herman","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanna","family":"Ollila","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richa","family":"Saxena","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024112709413288000_2024.11.22.624721v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-08259-7"},{"key":"2024112709413288000_2024.11.22.624721v1.2","doi-asserted-by":"publisher","DOI":"10.3109\/07420528.2012.719971"},{"key":"2024112709413288000_2024.11.22.624721v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(14)70012-9"},{"key":"2024112709413288000_2024.11.22.624721v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2430"},{"key":"2024112709413288000_2024.11.22.624721v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0333-3"},{"key":"2024112709413288000_2024.11.22.624721v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00945-5"},{"key":"2024112709413288000_2024.11.22.624721v1.7","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa840"},{"key":"2024112709413288000_2024.11.22.624721v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-017-0011-7"},{"key":"2024112709413288000_2024.11.22.624721v1.9","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12339"},{"key":"2024112709413288000_2024.11.22.624721v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2017.178"},{"key":"2024112709413288000_2024.11.22.624721v1.11","unstructured":"(sleep.hugeamp.org) SDKP. 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