Genome-wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample

Abstract

Smoking is a major risk factor for several somatic diseases, and is also emerging as a causal factor for neuropsychiatric disorders. Genome-wide association (GWA) and candidate gene studies for smoking behavior and nicotine dependence (ND) have disclosed too few predisposing variants to account for the high estimated heritability. Prior large-scale GWA studies have had very limited phenotypic definitions of relevance to smoking-related behavior, which has likely impeded the discovery of genetic effects. We performed genome-wide association analyses on 1114 adult twins ascertained for ever smoking from the population-based Finnish Twin Cohort study. The availability of 17 smoking-related phenotypes allowed us to comprehensively portray the dimensions of smoking behavior, clustered into the domains of smoking initiation, amount smoked, and ND. Our results highlight a locus on 16p12.3, with several SNPs in the vicinity of CLEC19A showing association (P<1×10−6) with smoking quantity. Interestingly, CLEC19A is located close to a previously reported attention deficit hyperactivity disorder (ADHD) linkage locus and an evident link between ADHD and smoking has been established. Intriguing preliminary association (P<1×10−5) was detected between DSM-IV ND diagnosis and several SNPs in ERBB4, coding for a Neuregulin receptor, on 2q33. The association between ERBB4 and DSM-IV ND diagnosis was replicated in an independent Australian sample. Interestingly, in the paper by Turner et al., significant increase in ErbB4 and Neuregulin 3 (Nrg3) expression was revealed following chronic nicotine exposure and withdrawal in mice. Turner et al. also detected an association between NRG3 SNPs and smoking cessation success in a clinical trial. ERBB4 has previously been associated with schizophrenia; further, it is located within an established schizophrenia linkage locus and within a linkage locus for a smoker phenotype identified in this sample. As a conclusion, we disclose novel tentative evidence for the involvement of ERBB4 in ND, suggesting the involvement of the Neuregulin/ErbB signalling pathway in addictions and providing a plausible link between the high co-morbidity of schizophrenia and ND.

Neuregulin-ERBB Signaling in the Nervous System and Neuropsychiatric Diseases

“…There is no evidence yet for a link of NRG1 to autism although impaired hippocampal LTP and contextual fear memory deficits in mice modeling Angelman syndrome, a disorder related to the autism spectrum, can be reversed by ErbB inhibitors (Kaphzan et al, 2012). Recently, NRG3 and ERBB4 SNPs have been associated with nicotine dependence and with successful smoking cessation (Loukola et al, 2014; Turner et al, 2013). This is intriguing because smoking is more prevalent among schizophrenic patients than in the general population.…”

DISC1 as a Possible Genetic Contribution to Opioid Dependence in a Polish Sample

“…Recently, several GWASs have been published for alcohol dependence (Gelernter et al, 2014a;Kapoor et al, 2014;Treutlein et al, 2009;Wetherill et al, 2015), nicotine dependence (Gelernter et al, 2015;Loukola et al, 2014), cannabis dependence (Agrawal et al, 2011), and opioid dependence (Nielsen et al, 2010). However, the GWAS sometimes did not provide conclusive evidence for genetic factors previously reported as associated with dependence in single-candidate gene studies.…”

Genome‐wide meta‐analysis identifies a novel susceptibility signal at CACNA2D3 for nicotine dependence

“…Over the past few decades, many large-scale genome-wide association (GWA) studies and meta-analyses have identified a number of single nucleotide polymorphisms (SNPs) associated with the risk of ND and smoking-related behaviors [Bierut et al, 2007; David et al, 2012; Gelernter et al, 2015; Gizer and Ehlers 2015; Hancock et al, 2015; Liu et al, 2010; Loukola et al, 2014; Nishizawa et al, 2015; Rice et al, 2012; Thorgeirsson et al, 2008; Thorgeirsson et al, 2010; Tobacco and Genetics Consortium 2010; Uhl et al, 2008; Zuo et al, 2013]. Among them, the α3/α5/β4 cholinergic nicotinic receptor subunit gene cluster on chromosome 15 consistently shows the most significant replicable risk effect on ND, smoking cessation, smoking quantity, and other smoking-related traits [Thorgeirsson et al, 2008; Thorgeirsson et al, 2010].…”