Elsevier

Biological Psychiatry

Volume 67, Issue 1, 1 January 2010, Pages 12-19
Biological Psychiatry

Archival Report
Meta-Analysis of 15 Genome-Wide Linkage Scans of Smoking Behavior

https://doi.org/10.1016/j.biopsych.2009.08.028Get rights and content

Background

A genetic contribution to smoking behavior is well-established. To identify loci that increase the risk for smoking behavior, many genome-wide linkage scans have been performed with various smoking behavior assessments. Numerous putative susceptibility loci have been identified, but only a few of these were replicated in independent studies.

Methods

We used genome search meta-analysis (GSMA) to identify risk loci by pooling all available independent genome scan results on smoking behavior. Additionally, to minimize locus heterogeneity, subgroup analyses of the smoking behavior assessed by the Fagerstrom Test for Nicotine Dependence (FTND) and maximum number of cigarettes smoked in a 24-hour period (MaxCigs24) were carried out. Samples of European ancestry were also analyzed separately.

Results

A total number of 15 genome scan results were available for analysis, including 3404 families with 10,253 subjects. Overall, the primary GSMA across all smoking behavior identified a genome-wide suggestive linkage in chromosome 17q24.3-q25.3 (pSR = .001). A secondary analysis of FTND in European-ancestry samples (625 families with 1878 subjects) detected a genome-wide suggestive linkage in 5q33.1–5q35.2 (pSR = .0076). Subgroup analysis of MaxCigs24 (966 families with 3273 subjects) identified a genome-wide significant linkage in 20q13.12-q13.32 (pSR = .00041, pOR = .048), where a strongly supported nicotine dependence candidate gene, CHRNA4, is located.

Conclusions

The regions identified in the current study deserve close attention and will be helpful for candidate gene identification or target re-sequencing studies in the future.

Section snippets

Study Samples

To identify existing genome-wide linkage studies on smoking behavior, we conducted a computerized literature search of the PubMed database with the following keywords and subject terms: “linkage,” “smoking,” “nicotine dependence,” “genome-wide,” or “genomewide.” Review articles on genetics of smoking behavior were also screened. The genome scans included in the current GSMA were required to meet the following criteria: 1) whole genome linkage scan on smoking-related traits performed in humans;

Results

First, we performed the primary 30-cM bin width GSMA over all independent genome scans on smoking behavior, encompassing 3404 families with 10,253 genotyped subjects. Figure 1 illustrates the weighted and unweighted pSR for all bins across the genome. The full details of genetic regions showing bins with nominal significance in weighted analysis are shown in Table 2, and the unweighted analysis results are also included as a comparison with weighted analysis. The strongest evidence for a

Discussion

The current GSMA, which included 3404 families with 10,253 subjects, has identified many regions with varying degrees of evidence of linkage for smoking behavior. In the primary 30-cM GSMA of combined smoking behavior, genome-wide suggestive linkage was detected at chromosome 17q24.3-q25.3. The fact that we did not identify any bins with genome-wide significant evidence for linkage in the primary analysis might imply the possible relatively higher genetic heterogeneity due to a variety of

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