Associations between glp-1 receptor and ghrelin gene polymorphisms and alcohol use disorder in humans

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Suchankova P1,2, Yan J3,4, Schwandt ML5, Stangl BL3, Caparelli EC6, Momenan R7, Hodgkinson CA8, Goldman D8, Heilig M5, 9, Ramchandani VA3, Nilsson S10, von der Pahlen B11, Santtila P11, Sandnabba K11, Johansson A12, 2, Jern P11, 13, Leggio L1,6,14, Engel JA2, Jerlhag E2

1Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA
2Department of Pharmacology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
3Section on Human Psychopharmacology, NIAAA, NIH, Bethesda, MD, USA 4Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA
5NIAAA, NIH, Bethesda, MD, USA
6Intramural Research Program, National Institute on Drug Abuse (NIDA), NIH, Baltimore, MD, USA
7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, MD, USA
8Laboratory of Neurogenetics, NIAAA, NIH, Bethesda, MD, USA
9Department of Clinical and Experimental Medicine, Linkopings University, Linkoping, Sweden
10Department of Mathematical Statistics, Institute of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden
11Department of Psychology and Logopedics, Abo Akademi University, Turku, Finland
12Department of Psychology and Speech-Language Pathology, University of
Turku, Turku, Finland.
13Department of Behavioral Sciences and Philosophy, University of Turku, Turku, Finland
14Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, USA.

The role of the appetite stimulant and suppressing hormones ghrelin and glucagon-like peptide-1 (GLP-1), respectively, in alcohol reinforcement has been established in preclinical studies. In clinical studies exogenous ghrelin has been shown to induce craving in patients with alcohol use disorder while three months treatment with a GLP-1 agonist lowered alcohol intake in a small pilot study comprising type 2 diabetic patients. Therefore it is not farfetched to assume that genetic variations (SNPs) in these systems could affect reward and addiction regulatory mechanisms. For the past decade we have investigated variations in genes of the gut-brain axis in various cohorts. Our analyses identify mainly two SNPs in the ghrelin system and one in the GLP-1 receptor as being more frequently associated with reward-related phenotypes including alcohol use disorder, alcohol use disorder identification test (AUDIT) scores, heavy drinking days and smoking. Furthermore, we have associated two of these