Studies were excluded if no data on smoking quantity were available, neither of the SNPs of interest was investigated, selleck chem or if extreme smoking quantity phenotypes had been selected for analysis. Reviews, letters to the editor, and editorials were excluded if these did not present new or relevant data. Family-based studies were also excluded. Additionally, studies were excluded if an inappropriate study design was employed (e.g., DNA pooling). Search Strategy The search was performed in Scopus and PubMed. These databases were searched from the first date available in each database up to May 12, 2010, using the following search terms: ��CHRNA5 or CHRNA3 or CHRNB4��; ��rs16969968 or rs1051730��; ��smok* and 15q2*.�� Once articles had been collected, references were hand searched for additional studies of interest.

The titles and abstracts of studies identified by these search strategies were examined, and those clearly fitting the inclusion or exclusion criteria were retained or excluded, respectively (initial screening conducted by JW). Of the remaining studies, a more thorough examination of the full text and supplementary material (if available) was required to determine retention or rejection (full-text assessment conducted by JW). All duplications were deleted. Where studies reported previously published data, we included data from only one of the publications, namely that reporting the largest sample. Ten percent of all studies identified by the search strategy were additionally assessed for eligibility by a second reviewer (interrater agreement >90%).

Disagreements between reviewers were resolved by mutual consent. Data Extraction For each study the following data were extracted: (a) authors and year of publication, (b) sample characteristics (ancestry and disease state), (c) SNP(s) studied, and (d) M, SD, and N for cigarettes per day by genotype. Genotype frequencies were used to calculate deviation from Hardy�CWeinberg equilibrium (HWE). Ancestry was coded as European or ��other,�� given the paucity of studies reporting data on non-European samples. To be coded as European, a sample had to be comprised of at least 95% European individuals. Data Analyses Given the high LD between rs16969968 and rs1051730 (European: r2 = .902, Japanese/Chinese: r2 = 1.000, African: r2 = unavailable; calculated using HapMap data in conjunction with SNAP [http://www.

broadinstitute.org/mpg/snap/ldsearchpw.php]), we initially conducted pooled analyses incorporating data from all samples, regardless of SNP studied, omitting one dataset if data on both SNPs had been collected for a sample. The standard additive Drug_discovery model of genetic action was used for evaluation. Small study bias was assessed using the Egger test (Egger, Davey Smith, Schneider, & Minder, 1997) for both pooled and independent SNP analyses.