Neuregulin signaling pathway in smoking behavior

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.

The Older Finnish Twin Cohort — 45 Years of Follow-up

“…These analyses have been based on alcohol and smoking behavior data from the surveys, as well as from the structured psychiatric interviews conducted as part of the NAG study. Additionally, we used the FTC data in our targeted hypothesis-driven study of the neuregulin signaling pathway (Gupta et al, 2017). Our neuregulin signaling pathway-targeted analyses resulted in identification of SNPs with regulatory potential and provide evidence for the involvement of the pathway in smoking behavior and comorbid diseases.…”

On the Modulatory Roles of Neuregulins/ErbB Signaling on Synaptic Plasticity

“…Although, herein, the description of NRGs/ErbB-dependent roles in the modulation of synaptic plasticity has been focused on the hippocampus and midbrain DA nuclei, it should be considered that emerging evidence also documented NRGs-induced regulation of synaptic plasticity in other brain areas, and several reports mainly obtained in transgenic mice with altered NRGs/ErbB signaling support that the proper NRGs/ErbB tone (neither too much nor too little) is essential for various cognitive functions and behaviors. Since dysfunctions in NRGs/ErbB signaling have been linked to different neurological and psychiatric disorders, including schizophrenia, bipolar disorder, autism spectrum disorders, genetic intellectual disabilities, AD, major depressive disorder, PD, and addiction [23,46,[136][137][138][139][141][142][143][144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159], intense research efforts should be aimed at deciphering NRGs-dependent mechanisms causing pathological defects, as this might have noticeable implications on the understanding and treatment of different serious brain diseases.…”

Sex-specific sensitivity to methamphetamine-induced schizophrenia-relevant behaviours in neuregulin 1 type III overexpressing mice

“…Quantitative trait loci in NRG1 are associated with smoking behaviours (e.g. smoking initiation, nicotine dependence and nicotine withdrawal) (Gupta et al, 2017), while a single nucleotide polymorphism (SNP) in NRG1 is associated with cannabis dependence in an African-American population (Han et al, 2012). Also, individuals with a SNP in type IV NRG1 who experience stressful life events are more likely to develop alcohol use disorders and consume tobacco (Vaht et al, 2017).…”