Examination of the Involvement of Cholinergic-Associated Genes in Nicotine Behaviors in European and African Americans

Abstract

We evaluated the evidence for association between a manually curated set of genes and nicotine behaviors in European and African Americans. Although no genes were associated after multiple testing correction, this study has several strengths: by manually curating a set of genes we circumvented the limitations inherent in many pathway analyses and tested several genes that had not yet been examined in a human genetic study; gene-based tests are a useful way to test for association with a set of genes; and these genes were collected based on literature review and conversations with experts, highlighting the importance of scientific collaboration.

The genetic epidemiology of substance use disorder: A review

“…In general, genetic association studies of alcohol highlight the importance of genes related to (1) alcohol metabolism (ADH); (2) processing of alcohol intermediates (e.g., ADH1B, ADH1C , and ALDH2 ) (Cui et al, 2009; Macgregor et al, 2009) and (3) neurotransmission pathways thought to be involved with stimulus-reward processing in the brain including dopaminergic (e.g., DRD2 , MAOA , COMT ), serotonergic ( HTR3A , HTR1B , HTR3B ), GABAergic ( GABRA1 , GABRA2, GAD1 , KCNJ9/GIRK3 ), and glutamtergic ( GRIN2C ) pathways. Some of these genes have demonstrated functional significance either in animal, human, or molecular genetic studies of SUD (Addolorato et al, 2006; Lobo & Nestler, 2011; Melroy-Greif et al, 2017; Thanos et al, 2001; Vanyukov et al, 2007). SUD is generally characterized as a signalling imbalance through striatal inhibitory D2-like dopamine receptors (DRD2) although this is not necessarily consistent across all drugs.…”

“…For example, although several significant genetic associations have been reported, few associations for nicotine dependence have replicated (Lerman & Berrettini, 2003; Quaak, van Schayck, Knaapen, & van Schooten, 2009). This may be due to a variety of reasons including: (1) low effect sizes of variants where each significant variant detected by a genetic association study will have a small influence on an SUD (Marjoram, Zubair, & Nuzhdin, 2014); (2) insufficient power to detect significant associations resulting from low sample sizes particularly in single-site studies (Visscher, Brown, McCarthy, & Yang, 2012); (3) phenotypic heterogeneity due to variance in the measurement of SUDs across samples that may reflect different stages of SUD; (4) genetic heterogeneity characterized by an outcome arising from multiple sets of genes or genetic mechanisms that likely decrease the power to detect a significant genetic association specific to a substance; (5) racial/ethnic inconsistency between discovery and replication samples (i.e., participants of European ancestry in the discovery sample and African ancestry in the replication sample) that result in a failure to reproduce significant genetic association across samples as a result of differences in ancestry-related local haplotype structures at loci associated with SUD (Enoch, 2013; Melroy-Greif, et al, 2017; Polimanti, Yang, Zhao, & Gelernter, 2015; Verweij, et al, 2012) and (6) phenotypic comorbidity where the SUD diagnosis, itself, may have multiple subtypes (i.e., single-drug versus poly-drug dependence, rate of time from initiation to the development of dependence, or comorbidity between substance dependence and psychiatric conditions) with shared genetic and environmental architecture (Bi, et al, 2014; Palmer et al, 2014). Consequently, there remains discrepancies in the convergence of results from different genetic epidemiology study designs (Vrieze, McGue, Miller, Hicks, & Iacono, 2013).…”

The role of a priori-identified addiction and smoking gene sets in smoking behaviors

“…Identifying the key genes that intracellularly interact with them and whether they contribute to heritable variation in smoking phenotypes can lead to biological insight and potentially novel therapeutic targets. Melroy-Greif et al 13 performed an extensive literature search, in collaboration with experts in the field of nicotinic acetylcholine receptor (nAChR) research, to identify a set of 107 such genes involved in the upregulation, function, processing, and downstream effects of nAChR signaling (only 36 of these overlap with the Smokescreen Array gene set). Melroy-Greif et al 13 posited that this set of genes that are involved in nAChR upregulation, known to occur in reponse to nicotine exposure, play a role in smoking behaviors.…”

“…Melroy-Greif et al 13 performed an extensive literature search, in collaboration with experts in the field of nicotinic acetylcholine receptor (nAChR) research, to identify a set of 107 such genes involved in the upregulation, function, processing, and downstream effects of nAChR signaling (only 36 of these overlap with the Smokescreen Array gene set). Melroy-Greif et al 13 posited that this set of genes that are involved in nAChR upregulation, known to occur in reponse to nicotine exposure, play a role in smoking behaviors. While Melroy-Greif et al 13 did not find significant gene set associations with smoking phenotypes, GWAS sample sizes have since increased dramatically 7 , leading to greater statistical power to detect such associations.…”

“…Melroy-Greif et al 13 posited that this set of genes that are involved in nAChR upregulation, known to occur in reponse to nicotine exposure, play a role in smoking behaviors. While Melroy-Greif et al 13 did not find significant gene set associations with smoking phenotypes, GWAS sample sizes have since increased dramatically 7 , leading to greater statistical power to detect such associations.…”