Meta-analysis and imputation refines the association of 15q25 with smoking quantity

Abstract

Smoking is a leading global cause of disease and mortality1. We performed a genomewide meta-analytic association study of smoking-related behavioral traits in a total sample of 41,150 individuals drawn from 20 disease, population, and control cohorts. Our analysis confirmed an effect on smoking quantity (SQ) at a locus on 15q25 (P=9.45e-19) that includes three genes encoding neuronal nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3, CHRNB4). We used data from the 1000 Genomes project to investigate the region using imputation, which allowed analysis of virtually all common variants in the region and offered a five-fold increase in coverage over the HapMap. This increased the spectrum of potentially causal single nucleotide polymorphisms (SNPs), which included a novel SNP that showed the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

Association of cigarette smoking and CRP levels with DNA methylation in α-1 antitrypsin deficiency

“…22 The major limitation of the current study is relatively small number of CpG sites tested with pre-selection of the CpG sites, based on their relevance to cancer. Several biologically interesting candidate CpG sites such as those in the F2RL3 and the α/β nicotinic cholinergic receptors on chromosome 15q25 (i.e., determinants of smoking intensity), [5][6][7] are not included on the Cancer Panel I platform and were not evaluated in this cohort. It is therefore of future interest to assess association of other CpG sites with smoking related phenotypes and CRP level in AAT-deficient subjects.…”

“…[5][6][7] Since tobacco smoking associates with severe airflow limitation in alpha-1 antitrypsin (aaT) deficiency and tobacco smoking are confirmed risk factors for chronic obstructive pulmonary disease. We hypothesized that variable DNa methylation would be associated with smoking and inflammation, as reflected by the level of c-reactive protein (cRp) in aaT-deficient subjects.…”

D-Amino Acid Aberrations in Cerebrospinal Fluid and Plasma of Smokers

“…Although genetic variants in genes encoding neuronal nicotinic acetylcholine receptor subunits (eg, CHRNA3 and CHRNA5) are associated with smoking quantity, the explained variances by such single-nucleotide polymorphisms are low (Tobacco and Genetics Consortium, 2010;Liu et al, 2010). This suggests that other pathways, such as the glutamatergic neurotransmission system, have a role in smoking behavior.…”

Gene-Centric Analysis of Serum Cotinine Levels in African and European American Populations

“…The average 1975The average -2007 annual age adjusted per 100 000 incidence and mortality rates of lung cancer in African Americans was found to be 81.8 and 63.4, respectively, in comparison with 64.1 and 53.9 for European Americans (Ries et al, 2008). Recent genome-wide association studies (GWAS) have identified several genetic variants that influence nicotine intake, including a strong, replicated association between genetic variants in the chromosome 15 nicotinic receptor subunit cluster and smoking quantity in European Americans (Liu et al, 2010;Thorgeirsson et al, 2008;Thorgeirsson et al, 2010;Tobacco and Genetics Consortium, 2010).…”