Abstract
The heritability of nicotine dependence based on family studies is substantial. Nevertheless, knowledge of the underlying genetic architecture remains meager. Our aim was to identify novel genetic variants responsible for interindividual differences in smoking behavior. We performed a genome‐wide association study on 1715 ever smokers ascertained from the population‐based Finnish Twin Cohort enriched for heavy smoking. Data imputation used the 1000 Genomes Phase I reference panel together with a whole genome sequence‐based Finnish reference panel. We analyzed three measures of nicotine addiction—smoking quantity, nicotine dependence and nicotine withdrawal. We annotated all genome‐wide significant SNPs for their functional potential. First, we detected genome‐wide significant association on 16p12 with smoking quantity (P = 8.5 × 10−9), near CLEC19A. The lead‐SNP stands 22 kb from a binding site for NF‐κB transcription factors, which play a role in the neurotrophin signaling pathway. However, the signal was not replicated in an independent Finnish population‐based sample, FINRISK (n = 6763). Second, nicotine withdrawal showed association on 2q21 in an intron of TMEM163 (P = 2.1 × 10−9), and on 11p15 (P = 6.6 × 10−8) in an intron of AP2A2, and P = 4.2 × 10−7 for a missense variant in MUC6, both involved in the neurotrophin signaling pathway). Third, association was detected on 3p22.3 for maximum number of cigarettes smoked per day (P = 3.1 × 10−8) near STAC. Associating CLEC19A and TMEM163 SNPs were annotated to influence gene expression or methylation. The neurotrophin signaling pathway has previously been associated with smoking behavior. Our findings further support the role in nicotine addiction.
Highlights
Smoking is a major risk factor for non-communicable diseases, with the largest public health burden due to chronic obstructive pulmonary disease, cancers and cardiovascular diseases (USDHHS 2014)
Nicotine binds to nicotinic acetylcholine receptors in the brain
We identified novel loci accounting for interindividual differences in nicotine withdrawal (NW) and smoking quantity
Summary
Smoking is a major risk factor for non-communicable diseases, with the largest public health burden due to chronic obstructive pulmonary disease, cancers and cardiovascular diseases (USDHHS 2014). For the majority of smokers, persistent tobacco use is motivated by nicotine dependence (ND) (Moss et al 2012). Nicotine binds to nicotinic acetylcholine receptors (nAChRs) in the brain. Stimulation of nAChRs induces the release of various neurotransmitters, such as dopamine, which has a key role in drug-induced reward by creating the perceptions of pleasure and reward (Nestler 2005). Repeated exposure to nicotine leads to neuroadaptation (Wang & Sun 2005), during which the Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
