title: Examination of rare missense variants in the CHRNA5-A3-B4 gene cluster to level of response to alcohol in the San Diego Sibling Pair study.
abstract: BACKGROUND
  Common variants in the CHRNA5-A3-B4 gene cluster have been shown to be associated with nicotine dependence and alcohol use disorders (AUDs) and related traits, including the level of response (LR) to alcohol. Recently, rare variants (MAF < 0.05) in CHRNB4 have been reported to be associated with a decreased risk of developing nicotine dependence. However, the role of rare variants in the CHRNA5-A3-B4 gene cluster to the LR to alcohol has not yet been established.
  
  
  METHODS
  To determine whether rare variants in the CHRNA5-A3-B4 gene cluster contribute to the LR to alcohol, the coding regions of these 3 genes were sequenced in 538 subjects from the San Diego Sibling Pair study.
  
  
  RESULTS
  The analyses identified 16 rare missense variants, 9 of which were predicted to be damaging using in silico analysis tools. Carriers of these variants were compared to noncarriers using a family-based design for each gene and for the gene cluster as a whole. In these analyses, a CHRNA5 carrier status was significantly associated with the phenotype related to the feeling of intoxication experienced during the alcohol challenge (p = 0.039).
  
  
  CONCLUSIONS
  These results indicate that rare genetic variation in the CHRNA5-A3-B4 gene cluster contributes modestly to the LR to alcohol in the San Diego Sibling Pair study and may protect against AUDs. However, replication studies are needed to confirm our findings.
authors: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, CA 94110, USA. ChoquetH@anesthesia.ucsf.edu
authors: Hélène
authors: H
authors: Choquet
authors: Geoff
authors: G
authors: Joslyn
authors: Andrew
authors: A
authors: Lee
authors: Jay
authors: J
authors: Kasberger
authors: Margaret
authors: M
authors: Robertson
authors: Gerry
authors: G
authors: Brush
authors: Marc A
authors: MA
authors: Schuckit
authors: Ray
authors: R
authors: White
authors: Eric
authors: E
authors: Jorgenson
mesh_terms: D019973:Alcohol-Related Disorders / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D005810:Multigene Family; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D011978:Receptors, Nicotinic / Q000235:genetics*
chemical_list: D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human
keywords: Alcohol Use Disorders; Cholinergic Nicotinic Receptors; Genetics; Level of Response to Alcohol; Rare Variants