title: A missense mutation in human fatty acid amide hydrolase associated with problem drug use.
abstract: Problem drug use and dependence are neurobehavioral disorders of complex origin. Although environmental factors contribute to drug abuse and addiction, genetic factors also play a significant role estimated at 40-60% of the total risk. Nonetheless, the precise identities of human genes that confer vulnerability to problem drug use remain mostly unknown. Here, we describe a natural single nucleotide polymorphism in the human gene that encodes the principal endocannabinoid-inactivating enzyme, fatty acid amide hydrolase (FAAH), that in homozygous form is strongly associated with both street drug use and problem drug/alcohol use. This single nucleotide polymorphism results in a missense mutation (385C-->A) that converts a conserved proline residue to threonine (Pro129-->Thr), producing a FAAH variant that displays normal catalytic properties but an enhanced sensitivity to proteolytic degradation. Collectively, these results suggest that genetic mutations in FAAH may constitute important risk factors for problem drug use and support a potential link between functional abnormalities in the endogenous cannabinoid system and drug abuse and dependence.
authors.affiliation: Departments of Molecular and Experimental Medicine, Chemistry, and Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. jcsipe@scripps.edu
authors.forename: Jack C
authors.initials: JC
authors.lastname: Sipe
authors.forename: Kyle
authors.initials: K
authors.lastname: Chiang
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Gerber
authors.forename: Ernest
authors.initials: E
authors.lastname: Beutler
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics; D000581:Amidohydrolases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D063385:Cannabinoid Receptor Modulators; D002384:Catalysis; D002942:Circular Dichroism; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D013287:Illicit Drugs; D020125:Mutation, Missense; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D051381:Rats; D019966:Substance-Related Disorders / Q000201:enzymology / Q000235:genetics*; D011795:Surveys and Questionnaires; D014508:Urea / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D063385:Cannabinoid Receptor Modulators; D013287:Illicit Drugs; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases