A loss-of-function variant in GFRAL associates with increased alcohol consumption in humans

Justesen, J. M.; Soerensen, K. V.; Seshadri, J.; Svenningsen, J. S.; Aguirre, M. P.; Tanigawa, Y.; Minneker, R.; Lanng, A. R.; Laursen, C. B.; Andersen, E. S.; Skov, L. J.; Joergensen, S. B.; Becker, U.; Knop, F. K.; Rivas, M. A.; Grarup, N.; Gillum, M. P.

doi:10.64898/2026.03.06.709997

bioRxiv · 10.64898/2026.03.06.709997

A loss-of-function variant in GFRAL associates with increased alcohol consumption in humans

Justesen, J. M.·Soerensen, K. V.·Seshadri, J.·Svenningsen, J. S.·Aguirre, M. P.·Tanigawa, Y.·Minneker, R.·Lanng, A. R.·Laursen, C. B.·Andersen, E. S.·Skov, L. J.·Joergensen, S. B.·Becker, U.·Knop, F. K.·Rivas, M. A.·Grarup, N.·Gillum, M. P.

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Abstract

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--predominantly via secretion from blastocyst-derived placental trophoblasts into the maternal circulation--and 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 ([~]21 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--and potentially during pregnancy--to limit alcohol intake in humans. HighlightsO_LIGDF15 is markedly elevated in humans with alcohol dependence C_LIO_LIA truncating GFRAL variant associates with higher alcohol intake in UK Biobank C_LIO_LIGFRAL frameshift disrupts GDF15-RET signaling in vitro C_LIO_LIRecombinant GDF15 suppresses voluntary alcohol intake in mice C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/709997v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@13630fborg.highwire.dtl.DTLVardef@c9bebforg.highwire.dtl.DTLVardef@109fd63org.highwire.dtl.DTLVardef@da971f_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Justesen, J. M., Soerensen, K. V., Seshadri, J., Svenningsen, J. S., Aguirre, M. P., Tanigawa, Y., Minneker, R., Lanng, A. R., Laursen, C. B., Andersen, E. S., Skov, L. J., Joergensen, S. B., Becker, U., Knop, F. K., Rivas, M. A., Grarup, N., Gillum, M. P.. 2026-03-09. A loss-of-function variant in GFRAL associates with increased alcohol consumption in humans. https://doi.org/10.64898/2026.03.06.709997

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