Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking

Abstract

Twin studies indicate that additive genetic effects explain most of the variance in nicotine dependence (ND), a construct emphasizing habitual heavy smoking despite adverse consequences, tolerance and withdrawal. To detect ND alleles, we assessed cigarettes per day (CPD) regularly smoked, in two European populations via whole genome association techniques. In these approximately 7500 persons, a common haplotype in the CHRNA3-CHRNA5 nicotinic receptor subunit gene cluster was associated with CPD (nominal P=6.9 x 10(-5)). In a third set of European populations (n= approximately 7500) which had been genotyped for approximately 6000 SNPs in approximately 2000 genes, an allele in the same haplotype was associated with CPD (nominal P=2.6 x 10(-6)). These results (in three independent populations of European origin, totaling approximately 15 000 individuals) suggest that a common haplotype in the CHRNA5/CHRNA3 gene cluster on chromosome 15 contains alleles, which predispose to ND.

Figure 1

A diagram of the CHRNA3 gene on Chromosome 15 is shown, with base pair number at the top. Exon 1 is on the right side of the figure. Locations of SNPs are indicated by arrows, with base pair given according to www.genome.ucsc.edu. Study of origin is noted, along with the risk allele, risk allele frequency in European-origin individuals and P value. Linkage disequilibrium values are taken from www.hapmap.org. F(RA) denotes the frequency of risk allele.

Figure 2

Haplotype Blocks and Linkage Disequilibrium in the CHRNA3 and CHRNA5 Region. Haplotype blocks (indicated by the black triangles) are shown for the CHRNA3/5 region for persons of European origin (www.hapmap.org), with LD values indicated by shading (dark grey = high LD, white = intermediate, light grey = low). Genotyped SNPs used to establish the haplotype blocks are given at the top of the figure. Risk alleles are boxed. The three studies identify the same common haplotype (the first one, with 38% allele frequency) as conveying risk, while the third and fourth haplotypes are protective, in that no risk alleles are present. Figure created using Haploview.