RGD Reference Report - Rare missense variants in CHRNB4 are associated with reduced risk of nicotine dependence. - Rat Genome Database

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Rare missense variants in CHRNB4 are associated with reduced risk of nicotine dependence.

Authors: Haller, Gabe  Druley, Todd  Vallania, Francesco L  Mitra, Robi D  Li, Ping  Akk, Gustav  Steinbach, Joe Henry  Breslau, Naomi  Johnson, Eric  Hatsukami, Dorothy  Stitzel, Jerry  Bierut, Laura J  Goate, Alison M 
Citation: Haller G, etal., Hum Mol Genet. 2012 Feb 1;21(3):647-55. doi: 10.1093/hmg/ddr498. Epub 2011 Oct 31.
RGD ID: 405849405
Pubmed: PMID:22042774   (View Abstract at PubMed)
PMCID: PMC3259016   (View Article at PubMed Central)
DOI: DOI:10.1093/hmg/ddr498   (Journal Full-text)

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)).



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CHRNA3Humannicotine dependence susceptibilityIAGP DNA:missense:cds:p.R37H (human)RGD 
CHRNB4Humannicotine dependence susceptibilityIAGP DNA:missense:cds:p.T91I and p.T375I (human)RGD 
Chrna3Ratnicotine dependence susceptibilityISOCHRNA3 (Homo sapiens)DNA:missense:cds:p.R37H (human)RGD 
Chrna3Mousenicotine dependence susceptibilityISOCHRNA3 (Homo sapiens)DNA:missense:cds:p.R37H (human)RGD 
Chrnb4Ratnicotine dependence susceptibilityISOCHRNB4 (Homo sapiens)DNA:missense:cds:p.T91I and p.T375I (human)RGD 
Chrnb4Mousenicotine dependence susceptibilityISOCHRNB4 (Homo sapiens)DNA:missense:cds:p.T91I and p.T375I (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Chrna3  (cholinergic receptor nicotinic alpha 3 subunit)
Chrnb4  (cholinergic receptor nicotinic beta 4 subunit)

Genes (Mus musculus)
Chrna3  (cholinergic receptor, nicotinic, alpha polypeptide 3)
Chrnb4  (cholinergic receptor, nicotinic, beta polypeptide 4)

Genes (Homo sapiens)
CHRNA3  (cholinergic receptor nicotinic alpha 3 subunit)
CHRNB4  (cholinergic receptor nicotinic beta 4 subunit)


Additional Information