title: Identification of CHRNA5 rare variants in African-American heavy smokers.
abstract: BACKGROUND
  The common CHRNA5 mis-sense coding single-nucleotide polymorphism (SNP) rs16969968:G>A (D398N) has repeatedly been shown to confer risk for heavy smoking in individuals who carry the 'A' allele (encoding the 398N amino acid). The mis-sense SNP has a minor allele frequency of ∼40% in European-Americans, but only ∼7% in African-Americans (http://www.ncbi.nlm.nih.gov/projects/SNP/). We reasoned that there might be other mis-sense variants among African-Americans that could confer the heavy smoking phenotype (defined here as ≥20 cigarettes per day), perhaps in a manner similar to that of the D398N polymorphism in Europeans.
  
  
  METHODS
  As such, we resequenced 250 African-American heavy smokers, most of whom were homozygous 'G' at rs16969968:G>A (minor allele frequency of 9.6% within the population).
  
  
  RESULTS
  Although many novel coding SNPs were not observed, we report an interesting, although rare (perhaps personal), variant in CHRNA5 that could result in nonsense-mediated decay of the aberrant transcript.
  
  
  CONCLUSIONS
  We conclude that, in African-Americans, variants (common or rare) in genes other than CHRNA5 most likely contribute toward the nicotine-dependent phenotype, either independently or in combination with variants in CHRNA5. The functional significance, on CHRNA5 expression or protein function, of the variants found here should be determined in future studies.
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Doyle
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Chou
authors.forename: Wint Thu
authors.initials: WT
authors.lastname: Saung
authors.forename: Alison T
authors.initials: AT
authors.lastname: Lai
authors.forename: Falk W
authors.initials: FW
authors.lastname: Lohoff
authors.forename: Wade H
authors.initials: WH
authors.lastname: Berrettini
mesh_terms: D001741:Black or African American / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000235:genetics*; D017384:Sequence Deletion; D014029:Tobacco Use Disorder / Q000235:genetics*
chemical_list: C447158:CHRNA5 protein, human; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic