Abstract
Understanding molecular processes that link comorbid traits such as addictions and mental disorders can provide novel therapeutic targets. Neuregulin signaling pathway (NSP) has previously been implicated in schizophrenia, a neurodevelopmental disorder with high comorbidity to smoking. Using a Finnish twin family sample, we have previously detected association between nicotine dependence and ERBB4 (a neuregulin receptor), and linkage for smoking initiation at the ERBB4 locus on 2q33. Further, Neuregulin3 has recently been shown to associate with nicotine withdrawal in a behavioral mouse model. In this study, we scrutinized association and linkage between 15 036 common, low frequency and rare genetic variants in 10 NSP genes and phenotypes encompassing smoking and alcohol use. Using the Finnish twin family sample (N=1998 from 740 families), we detected 66 variants (representing 23 LD blocks) significantly associated (false discovery rate P<0.05) with smoking initiation, nicotine dependence and nicotine withdrawal. We comprehensively annotated the associated variants using expression (eQTL) and methylation quantitative trait loci (meQTL) analyses in a Finnish population sample. Among the 66 variants, we identified 25 eQTLs (in NRG1 and ERBB4), 22 meQTLs (in NRG3, ERBB4 and PSENEN), a missense variant in NRG1 (rs113317778) and a splicing disruption variant in ERBB4 (rs13385826). Majority of the QTLs in blood were replicated in silico using publicly available databases, with additional QTLs observed in brain. In conclusion, our results support the involvement of NSP in smoking behavior but not in alcohol use and abuse, and disclose functional potential for 56 of the 66 associated single-nucleotide polymorphism.
Highlights
Smoking is a major risk factor for a variety of somatic diseases and strongly associates with several neuropsychiatric disorders,[1,2,3] the most prominent comorbidity being alcohol use and dependence.[4]
Joint linkage and linkage disequilibrium (LD) tests performed with PSEUDOMARKER detected a signal for smoking initiation (SI) in seven of the ten Neuregulin signaling pathway (NSP) genes (APH1A, PSEN2, ERBB4, NRG1, NRG3, BACE1 and PSENEN; false discovery rate (FDR) P o0.05) (Supplementary Figure 2), and signal for nicotine dependence (ND) diagnosis in ERBB4 (FDR P = 0.002 for rs13385826) (Supplementary Figure 3)
Association tests performed with GEMMA identified a signal for nicotine withdrawal (NW) symptom count in ERBB4 (FDR P = 0.008, β = − 0.517 for rs13001305, and for three highly correlated single nucleotide polymorphism. Altogether (SNP): rs73989053, rs13006797, rs17328083) (Figure 1), suggesting that each copy of the effect allele lowers number of NW symptoms by half a count on a scale of 0–8 counts
Summary
Smoking is a major risk factor for a variety of somatic diseases and strongly associates with several neuropsychiatric disorders,[1,2,3] the most prominent comorbidity being alcohol use and dependence.[4] One of the key factors driving persistent smoking is nicotine dependence (ND), manifested by development of tolerance, symptoms of craving and uncontrollable use due to the high addictive potential of nicotine.[5] Abstaining from smoking results in nicotine withdrawal (NW) symptoms including, for example, irritability, depressed mood and restlessness,[6] largely contributing to the high relapse rates among smokers trying to quit.[7] Despite the availability of several smoking cessation pharmacotherapies including nicotine replacement therapy and medications such as varenicline, bupropion and cytisine, 6-month abstinence rates are at best only two- to threefold compared with pharmacologically unassisted quit attempts.[8]. Several NSP genes have previously been implicated in schizophrenia (SCZ),[9,10,11] a neurodevelopmental disorder with high comorbidity to smoking
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