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

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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. Highlights: GDF15 is markedly elevated in humans with alcohol dependence A truncating GFRAL variant associates with higher alcohol intake in UK Biobank GFRAL frameshift disrupts GDF15–RET signaling in vitro Recombinant GDF15 suppresses voluntary alcohol intake in mice Graphical
Funding Information
  • Novo Nordisk Fonden (NNF18CC0034900)
  • Novo Nordisk Fonden (NNF17OC0025806)
  • National Institutes of Health (5U01 HG009080)

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