title: Rare missense variants in CHRNB4 are associated with reduced risk of nicotine dependence.
abstract: Genome-wide association studies have identified common variation in the CHRNA5-CHRNA3-CHRNB4 and CHRNA6-CHRNB3 gene clusters that contribute to nicotine dependence. However, the role of rare variation in risk for nicotine dependence in these nicotinic receptor genes has not been studied. We undertook pooled sequencing of the coding regions and flanking sequence of the CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 genes in African American and European American nicotine-dependent smokers and smokers without symptoms of dependence. Carrier status of individuals harboring rare missense variants at conserved sites in each of these genes was then compared in cases and controls to test for an association with nicotine dependence. Missense variants at conserved residues in CHRNB4 are associated with lower risk for nicotine dependence in African Americans and European Americans (AA P = 0.0025, odds-ratio (OR) = 0.31, 95% confidence-interval (CI) = 0.31-0.72; EA P = 0.023, OR = 0.69, 95% CI = 0.50-0.95). Furthermore, these individuals were found to smoke fewer cigarettes per day than non-carriers (AA P = 6.6 × 10(-5), EA P = 0.021). Given the possibility of stochastic differences in rare allele frequencies between groups replication of this association is necessary to confirm these findings. The functional effects of the two CHRNB4 variants contributing most to this association (T375I and T91I) and a missense variant in CHRNA3 (R37H) in strong linkage disequilibrium with T91I were examined in vitro. The minor allele of each polymorphism increased cellular response to nicotine (T375I P = 0.01, T91I P = 0.02, R37H P = 0.003), but the largest effect on in vitro receptor activity was seen in the presence of both CHRNB4 T91I and CHRNA3 R37H (P = 2 × 10(-6)).
authors: Department of Psychiatry, Washington University, St Louis, MO 63110, USA.
authors: Gabe
authors: G
authors: Haller
authors: Todd
authors: T
authors: Druley
authors: Francesco L
authors: FL
authors: Vallania
authors: Robi D
authors: RD
authors: Mitra
authors: Ping
authors: P
authors: Li
authors: Gustav
authors: G
authors: Akk
authors: Joe Henry
authors: JH
authors: Steinbach
authors: Naomi
authors: N
authors: Breslau
authors: Eric
authors: E
authors: Johnson
authors: Dorothy
authors: D
authors: Hatsukami
authors: Jerry
authors: J
authors: Stitzel
authors: Laura J
authors: LJ
authors: Bierut
authors: Alison M
authors: AM
authors: Goate
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics*; D012306:Risk; D014029:Tobacco Use Disorder / Q000208:ethnology / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C447159:CHRNB4 protein, human; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic