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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<jats:italic>ERBB4<\/jats:italic>(a neuregulin receptor), and linkage for smoking initiation at the<jats:italic>ERBB4<\/jats:italic>locus on 2q33. Further,<jats:italic>Neuregulin3<\/jats:italic>has recently been shown to associate with nicotine withdrawal in a behavioral mouse model. In this study, we scrutinized association and linkage between 15\u2009036 common, low frequency and rare genetic variants in 10 NSP genes and phenotypes encompassing smoking and alcohol use. Using the Finnish twin family sample (<jats:italic>N<\/jats:italic>=1998 from 740 families), we detected 66 variants (representing 23 LD blocks) significantly associated (false discovery rate<jats:italic>P<\/jats:italic>&lt;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<jats:italic>NRG1<\/jats:italic>and<jats:italic>ERBB4<\/jats:italic>), 22 meQTLs (in<jats:italic>NRG3<\/jats:italic>,<jats:italic>ERBB4<\/jats:italic>and<jats:italic>PSENEN<\/jats:italic>), a missense variant in<jats:italic>NRG1<\/jats:italic>(rs113317778) and a splicing disruption variant in<jats:italic>ERBB4<\/jats:italic>(rs13385826). Majority of the QTLs in blood were replicated<jats:italic>in silico<\/jats:italic>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.<\/jats:p>","DOI":"10.1038\/tp.2017.183","type":"journal-article","created":{"date-parts":[[2017,8,22]],"date-time":"2017-08-22T13:41:17Z","timestamp":1503409277000},"page":"e1212-e1212","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Neuregulin signaling pathway in smoking behavior"],"prefix":"10.1038","volume":"7","author":[{"given":"R","family":"Gupta","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B","family":"Qaiser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T S","family":"Hiekkalinna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A B","family":"Zheutlin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Therman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Ollikainen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Ripatti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Perola","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V","family":"Salomaa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L","family":"Milani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T D","family":"Cannon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P A F","family":"Madden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T","family":"Korhonen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Kaprio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Loukola","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,8,22]]},"reference":[{"key":"BFtp2017183_CR1","unstructured":"Centers for Disease Control and Prevention (US), National Center for Chronic Disease Prevention and Health Promotion (US), Office on Smoking and Health (US) How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. 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