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. 2007 Jan 1;16(1):36-49.
doi: 10.1093/hmg/ddl438. Epub 2006 Nov 29.

Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs

Scott F Saccone  1 , Anthony L Hinrichs, Nancy L Saccone, Gary A Chase, Karel Konvicka, Pamela A F Madden, Naomi Breslau, Eric O Johnson, Dorothy Hatsukami, Ovide Pomerleau, Gary E Swan, Alison M Goate, Joni Rutter, Sarah Bertelsen, Louis Fox, Douglas Fugman, Nicholas G Martin, Grant W Montgomery, Jen C Wang, Dennis G Ballinger, John P Rice, Laura Jean Bierut
Affiliations

Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs

Scott F Saccone et al. Hum Mol Genet. .

Abstract

Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the beta3 nicotinic receptor subunit gene (P = 9.4 x 10(-5)). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the alpha5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 x 10(-4)). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.

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Conflict of interest statement

Conflict of Interest statement. D.G.B. and K.K. are employed by Perlegen Sciences, Inc. With the exception of D.G.B. and K.K., none of the authors or their immediate families are currently involved with, or have been involved with, any companies, trade associations, unions, litigants or other groups with a direct financial interest in the subject matter or materials discussed in this manuscript in the past 5 years.

Figures

Figure 1
Figure 1
Results of the candidate gene association analysis. The P-values from the primary analysis are plotted for each chromosome below an ideogram using the −log10(P) transformation. The bottom axis is P = 1 and the top axis is P = 10−3. Category A genes are shown below the plots in red and category B genes are shown in cyan below the category A genes. Regions on chromosomes 8 and 15, which are shown in more detail in Figure 2, are highlighted in red.
Figure 2
Figure 2
Detailed results for the top association signals. (A) The top two signals are near the CHRNB3 nicotinic receptor gene on chromosome 8. (B) The Non-synonymous SNP rs16969968 and the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic receptor genes on chromosome 15. SNPs that appear in Table 2 are labeled with dbSNP rs IDs. The track ‘UCSC Most Conserved’ (http://genome.ucsc.edu, May 2004 build, table ‘phastConsElements17way’) highlights regions conserved between human and other species including the mouse, rat and chicken; the maximum conservation score is 1000. Primary P-values are plotted in red using the –log(P) transformation. The ‘LD Bins’ track displays the distribution of SNPs from the ‘SNPs’ track into LD bins where all SNPs have r2 ≥ 0.8 in both cases and controls with the tag SNP. Only bins with more than two SNPs are shown, and bins are annotated with number of SNPs N, the minimum r2 of the tag with the other SNPs in the bin, the range of allele frequencies in the bin and the tag SNP. (C) A legend indicating the color scheme.
Figure 2
Figure 2
Detailed results for the top association signals. (A) The top two signals are near the CHRNB3 nicotinic receptor gene on chromosome 8. (B) The Non-synonymous SNP rs16969968 and the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic receptor genes on chromosome 15. SNPs that appear in Table 2 are labeled with dbSNP rs IDs. The track ‘UCSC Most Conserved’ (http://genome.ucsc.edu, May 2004 build, table ‘phastConsElements17way’) highlights regions conserved between human and other species including the mouse, rat and chicken; the maximum conservation score is 1000. Primary P-values are plotted in red using the –log(P) transformation. The ‘LD Bins’ track displays the distribution of SNPs from the ‘SNPs’ track into LD bins where all SNPs have r2 ≥ 0.8 in both cases and controls with the tag SNP. Only bins with more than two SNPs are shown, and bins are annotated with number of SNPs N, the minimum r2 of the tag with the other SNPs in the bin, the range of allele frequencies in the bin and the tag SNP. (C) A legend indicating the color scheme.
Figure 3
Figure 3
LD between markers in (A) the CHRNB3-CHRNA6 and (B) CHRNA5-CHRNA3-CHRNB4 clusters of nicotinic receptor genes.
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