{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T10:57:50Z","timestamp":1773313070590,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,9]]},"group-title":"Physiology","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"crossref","award":["NNF18CC0034900"],"award-info":[{"award-number":["NNF18CC0034900"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"crossref","award":["NNF17OC0025806"],"award-info":[{"award-number":["NNF17OC0025806"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["5U01 HG009080"],"award-info":[{"award-number":["5U01 HG009080"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Alcohol is an ancient and enduring component of the human diet, yet it is a dose-dependent cytotoxin and teratogen, raising the possibility that endogenous, state-dependent mechanisms constrain intake. Growth differentiation factor 15 (GDF15) is an endocrine hormone that rises during pregnancy\u2014predominantly via secretion from blastocyst-derived placental trophoblasts into the maternal circulation\u2014and is also induced in other tissues, particularly hepatocytes, by toxins and cellular stress. However, its function in humans remains unclear. Here, we show that circulating GDF15 levels are elevated 5-fold in individuals with alcohol dependence, identify a rare loss-of-function variant in the GDF15 receptor gene GFRAL associated with approximately 2.6 additional UK alcohol units (\u223c21 g ethanol) per week, and demonstrate that recombinant GDF15 reduces alcohol drinking in mice. Collectively, these findings support a model in which GDF15 acts as an endocrine signal induced by chronic alcohol exposure\u2014and potentially during pregnancy\u2014to limit alcohol intake in humans.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>GDF15 is markedly elevated in humans with alcohol dependence<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>A truncating GFRAL variant associates with higher alcohol intake in UK Biobank<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>GFRAL frameshift disrupts GDF15\u2013RET signaling in vitro<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Recombinant GDF15 suppresses voluntary alcohol intake in mice<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"709997v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.06.709997","type":"posted-content","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T22:00:13Z","timestamp":1773093613000},"source":"Crossref","is-referenced-by-count":0,"title":["A loss-of-function variant in GFRAL associates with increased alcohol consumption in humans"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0484-8522","authenticated-orcid":false,"given":"Johanne Marie","family":"Justesen","sequence":"first","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"},{"name":"Department of Biomedical Data Science, Stanford University, Stanford, California, 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3861-4484","authenticated-orcid":false,"given":"Kimmie Vestergaard","family":"S\u00f8rensen","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jayashri","family":"Seshadri","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3529-8228","authenticated-orcid":false,"given":"Jens Skjoldan","family":"Svenningsen","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9069-6475","authenticated-orcid":false,"given":"Matthew","family":"Aguirre","sequence":"additional","affiliation":[{"name":"Department of Biomedical Data Science, Stanford University, Stanford, California, 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9759-157X","authenticated-orcid":false,"given":"Yosuke","family":"Tanigawa","sequence":"additional","affiliation":[{"name":"Department of Biomedical Data Science, Stanford University, Stanford, California, 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8185-5937","authenticated-orcid":false,"given":"Robert","family":"Minneker","sequence":"additional","affiliation":[{"name":"Department of Biomedical Data Science, Stanford University, Stanford, California, 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0199-8733","authenticated-orcid":false,"given":"Amalie Rasmussen","family":"Lanng","sequence":"additional","affiliation":[{"name":"Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900, Hellerup, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8526-1079","authenticated-orcid":false,"given":"Cecilie","family":"B\u00e6ch-Laursen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7466-9055","authenticated-orcid":false,"given":"Emilie Skytte","family":"Andersen","sequence":"additional","affiliation":[{"name":"Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900, Hellerup, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2977-9970","authenticated-orcid":false,"given":"Louise J.","family":"Skov","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"},{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9648-0971","authenticated-orcid":false,"given":"Sebastian B.","family":"J\u00f8rgensen","sequence":"additional","affiliation":[{"name":"External Exploration and Innovation Unit, Novo Nordisk A\/S, 2760 M\u00e5l\u00f8v, 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