Pathway Analysis of Smoking Quantity in Multiple GWAS Identifies Cholinergic and Sensory Pathways

Harari, Oscar; Wang, Jen Chyong; Bucholz, Kathleen K.; Edenberg, Howard J.; Heath, Andrew C.; Martin, Nicholas G.; Pergadia, Michele L.; Montgomery, Grant; Schrage, Andrew J.; Bierut, Laura J.; Madden, Pamela; Goate, Alison M.

doi:10.1371/journal.pone.0050913

Cited by 12 publications

(10 citation statements)

References 44 publications

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“…CHRNB4 , CHRNA1 , CHRNA 3, CHRNA5, and CHRNA7 ), glutaminergic (e.g., GRM7 and GRM8 ) and dopaminergic (e.g., DRD1 , DRD2 , DRD3 , DRD4 , and DRD5 ) systems, and (3) reuptake and vesicular packaging of neurotransmitters (e.g., SLC6A4 , SLC18A2 , and SLC9A9 ) related to learning and memory (Harari et al, 2012; Liu, Fan, Liu, Cheng, & Wang, 2015; Minica et al, 2017; Yang and Li, 2016; Begum et al, 2016). Consequently, genetic association studies of alcohol as well as nicotine dependence highlight the complex nature of addiction as an outcome with physiological aspects including drug metabolism and availability within the body and brain, as well as neurobiological mechanisms related to the development of addiction.…”

Section: Genetic Association Studiesmentioning

confidence: 99%

The genetic epidemiology of substance use disorder: A review

Prom‐Wormley

Ebejer

Dick

et al. 2017

Drug and Alcohol Dependence

123

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Background Substance use disorder (SUD) remains a significant public health issue. A greater understanding of how genes and environment interact to regulate phenotypes comprising SUD will facilitate directed treatments and prevention. Methods The literature studying the neurobiological correlates of SUD with a focus on the genetic and environmental influences underlying these mechanisms was reviewed. Results from twin/family, human genetic association, gene-environment interaction, epigenetic literature, phenome-wide association studies are summarized for alcohol, nicotine, cannabinoids, cocaine, and opioids. Results There are substantial genetic influences on SUD that are expected to influence multiple neurotransmission pathways, and these influences are particularly important within the dopaminergic system. Genetic influences involved in other aspects of SUD etiology including drug processing and metabolism are also identified. Studies of gene-environment interaction emphasize the importance of environmental context in SUD. Epigenetic studies indicate drug-specific changes in gene expression as well as differences in gene expression related to the use of multiple substances. Further, gene expression is expected to differ by stage of SUD such as substance initiation versus chronic substance use. While a substantial literature has developed for alcohol and nicotine use disorders, there is comparatively less information for other commonly abused substances. Conclusions A better understanding of genetically-mediated mechanisms involved in the neurobiology of SUD provides increased opportunity to develop behavioral and biologically based treatment and prevention of SUD.

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Section: Genetic Association Studiesmentioning

confidence: 99%

The genetic epidemiology of substance use disorder: A review

Prom‐Wormley

Ebejer

Dick

et al. 2017

Drug and Alcohol Dependence

123

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“…Smoking behavior is partially genetically determined, and at least genome-wide significant associated loci were identified in European ancestry subjects 9 , 10 , where the strongest and most consistent association reported is at the 15q25.1 locus (CHRNA3-CHRNA5-CHRNB4 gene cluster). Genes associated with smoking quantity were enriched for cholinergic receptors, sensory perception of smell, and Retinoid Binding 11 .…”

Section: Introductionmentioning

confidence: 99%

Genetic Pleiotropy between Nicotine Dependence and Respiratory Outcomes

Zhang

Peng

Cheng

et al. 2017

Sci Rep

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Smoking is a major cause of respiratory conditions. To date, the genetic pleiotropy between smoking behavior and lung function/chronic obstructive pulmonary disease (COPD) have not been systematically explored. We leverage large data sets of smoking behavior, lung function and COPD, and addressed two questions, (1) whether the genetic predisposition of nicotine dependence influence COPD risk and lung function; and (2) the genetic pleiotropy follow causal or independent model. We found the genetic predisposition of nicotine dependence was associated with COPD risk, even after adjusting for smoking behavior, indicating genetic pleiotropy and independent model. Two known nicotine dependent loci (15q25.1 and 19q13.2) were associated with smoking adjusted lung function, and 15q25.1 reached genome-wide significance. At various suggestive p-value thresholds, the smoking adjusted lung function traits share association signals with cigarettes per day and former smoking, substantially greater than random chance. Empirical data showed the genetic pleiotropy between nicotine dependence and COPD or lung function. The basis of pleiotropic effect is rather complex, attributable to a large number of genetic variants, and many variants functions through independent model, where the pleiotropic variants directly affect lung function, not mediated by influencing subjects’ smoking behavior.

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“…The nearest gene to our most strongly associated CNV component on chromosome 3p26.1 deletion region is GRM7 , which is involved with glutamate receptor activation. Several previous GWAS studies of nicotine dependence-related phenotypes have reported associations to markers in GRM7 [ 39 – 42 ]. Examining gene expression levels of GRM7 in the GTEx portal ( http://www.gtexportal.org/home/gene/GRM7 ) showed higher expression in different parts of brain including the cortex, hypothalamus and hippocampus ( S7 Fig ), which included 84.3% NHW and 13.7% African Americans in their expression analysis.…”

Section: Discussionmentioning

confidence: 99%

Hemizygous Deletion on Chromosome 3p26.1 Is Associated with Heavy Smoking among African American Subjects in the COPDGene Study

et al. 2016

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Many well-powered genome-wide association studies have identified genetic determinants of self-reported smoking behaviors and measures of nicotine dependence, but most have not considered the role of structural variants, such as copy number variation (CNVs), influencing these phenotypes. Here, we included 2,889 African American and 6,187 non-Hispanic White subjects from the COPDGene cohort (http://www.copdgene.org) to carefully investigate the role of polymorphic CNVs across the genome on various measures of smoking behavior. We identified a CNV component (a hemizygous deletion) on chromosome 3p26.1 associated with two quantitative phenotypes related to smoking behavior among African Americans. This polymorphic hemizygous deletion is significantly associated with pack-years and cigarettes smoked per day among African American subjects in the COPDGene study. We sought evidence of replication in African Americans from the population based Atherosclerosis Risk in Communities (ARIC) study. While we observed similar CNV counts, the extent of exposure to cigarette smoking among ARIC subjects was quite different and the smaller sample size of heavy smokers in ARIC severely limited statistical power, so we were unable to replicate our findings from the COPDGene cohort. But meta-analyses of COPDGene and ARIC study subjects strengthened our association signal. However, a few linkage studies have reported suggestive linkage to the 3p26.1 region, and a few genome-wide association studies (GWAS) have reported markers in the gene (GRM7) nearest to this 3p26.1 area of polymorphic deletions are associated with measures of nicotine dependence among subjects of European ancestry.

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Pathway Analysis of Smoking Quantity in Multiple GWAS Identifies Cholinergic and Sensory Pathways

Cited by 12 publications

References 44 publications

The genetic epidemiology of substance use disorder: A review

The genetic epidemiology of substance use disorder: A review

Genetic Pleiotropy between Nicotine Dependence and Respiratory Outcomes

Hemizygous Deletion on Chromosome 3p26.1 Is Associated with Heavy Smoking among African American Subjects in the COPDGene Study

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