Genome-wide Association Study of Smoking Initiation and Current Smoking

Department of Biological Psychology, Center for Neurogenomic and Cognitive Research, VU University Amsterdam, The Netherlands.
The American Journal of Human Genetics (Impact Factor: 10.93). 04/2009; 84(3):367-79. DOI: 10.1016/j.ajhg.2009.02.001
Source: PubMed


For the identification of genes associated with smoking initiation and current smoking, genome-wide association analyses were carried out in 3497 subjects. Significant genes that replicated in three independent samples (n = 405, 5810, and 1648) were visualized into a biologically meaningful network showing cellular location and direct interaction of their proteins. Several interesting groups of proteins stood out, including glutamate receptors (e.g., GRIN2B, GRIN2A, GRIK2, GRM8), proteins involved in tyrosine kinase receptor signaling (e.g., NTRK2, GRB14), transporters (e.g., SLC1A2, SLC9A9) and cell-adhesion molecules (e.g., CDH23). We conclude that a network-based genome-wide association approach can identify genes influencing smoking behavior.

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Available from: Henning Tiemeier, Oct 14, 2015
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    • "In the real data application, we identified two SNPs, rs6570989 and rs2930357, jointly associated with ND. In a recent GWAS of 3497 Dutch subjects, both of these two SNP were found to be significantly associated with current smoking [39]. These two SNPs are located in gene GRIK2 and CSMD1, respectively. "
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    ABSTRACT: Background Cox-regression-based methods have been commonly used for the analyses of survival outcomes, such as age-at-disease-onset. These methods generally assume the hazard functions are proportional among various risk groups. However, such an assumption may not be valid in genetic association studies, especially when complex interactions are involved. In addition, genetic association studies commonly adopt case-control designs. Direct use of Cox regression to case-control data may yield biased estimators and incorrect statistical inference. Results We propose a non-parametric approach, the weighted Nelson-Aalen (WNA) approach, for detecting genetic variants that are associated with age-dependent outcomes. The proposed approach can be directly applied to prospective cohort studies, and can be easily extended for population-based case-control studies. Moreover, it does not rely on any assumptions of the disease inheritance models, and is able to capture high-order gene-gene interactions. Through simulations, we show the proposed approach outperforms Cox-regression-based methods in various scenarios. We also conduct an empirical study of progression of nicotine dependence by applying the WNA approach to three independent datasets from the Study of Addiction: Genetics and Environment. In the initial dataset, two SNPs, rs6570989 and rs2930357, located in genes GRIK2 and CSMD1, are found to be significantly associated with the progression of nicotine dependence (ND). The joint association is further replicated in two independent datasets. Further analysis suggests that these two genes may interact and be associated with the progression of ND. Conclusions As demonstrated by the simulation studies and real data analysis, the proposed approach provides an efficient tool for detecting genetic interactions associated with age-at-onset outcomes.
    BMC Genetics 07/2014; 15(1):79. DOI:10.1186/1471-2156-15-79 · 2.40 Impact Factor
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    • "Interestingly, electrophysiological studies linked variants within GRM8 to increased risk of vulnerability to alcoholism (Rangaswamy and Porjesz 2008; Chen et al. 2009). Furthermore, rs2237781 within GMR8 has been identified to be at risk for smoking initiation and suggests that members of the glutamate receptor family may associate with nicotine dependence and vulnerability to addiction (Vink et al. 2009). The neurotransmitter glutamate is involved in substance abuse behavior and may influence food intake (Stanley et al. 1993). "
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    ABSTRACT: The glutamate receptor, metabotropic 8 gene (GRM8) encodes a G-protein-coupled glutamate receptor and has been associated with smoking behavior and liability to alcoholism implying a role in addiction vulnerability. Data from animal studies suggest that GRM8 may be involved in the regulation of the neuropeptide Y and melanocortin pathways and might influence food intake and metabolism. This study aimed to investigate the effects of the genetic variant rs2237781 within GRM8 on human eating behavior. The initial analysis included 548 Sorbs from Germany who have been extensively phenotyped for metabolic traits and who completed the German version of the three-factor eating questionnaire. In addition, we analyzed two independent sample sets comprising 293 subjects from another German cohort and 430 Old Order Amish individuals. Genetic associations with restraint, disinhibition, and hunger were assessed in an additive linear regression model. Among the Sorbs the major G allele of rs2237781 was significantly associated with increased restraint scores in eating behavior (P = 1.9 × 10−4; β = +1.936). The German cohort and the Old Order Amish population revealed a trend in the same direction for restraint (P = 0.242; β = +0.874; P = 0.908; β = +0.096; respectively). A meta-analysis resulted in a combined P = 3.1 × 10−3 (Z-score 2.948). Our data suggest that rs2237781 within GRM8 may influence human eating behavior factors probably via pathways involved in addictive behavior.
    09/2013; 3(5):n/a-n/a. DOI:10.1002/brb3.151
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    • "The genotypic data collection has also proven to be very valuable. Both linkage and whole genome association (GWA) studies have been conducted and the ANTR contributed in several large international gene-finding consortia , such as ENGAGE (European Network for Genetic and Genomic Epidemiology), MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium), and PGC (Psychiatric Genetics Consortium), and with success: new genes were detected for traits such as height (Lango Allen et al., 2010), BMI (Speliotes et al., 2010), menarche (Elks et al., 2010), smoking (Thorgeirsson et al., 2010; Tobacco and Genetics Consortium, 2010; Vink et al., 2009), and glucose metabolism (Dupuis et al., 2010). "
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    ABSTRACT: Over the past 25 years, the Adult Netherlands Twin Register (ANTR) has collected a wealth of information on physical and mental health, lifestyle, and personality in adolescents and adults. This article provides an overview of the sources of information available, the main research findings, and an outlook for the future. Between 1991 and 2012, longitudinal surveys were completed by twins, their parents, siblings, spouses, and offspring. Data are available for 33,957 participants, with most individuals having completed two or more surveys. Smaller projects provided in-depth phenotyping, including measurements of the autonomic nervous system, neurocognitive function, and brain imaging. For 46% of the ANTR participants, DNA samples are available and whole genome scans have been obtained in more than 11,000 individuals. These data have resulted in numerous studies on heritability, gene x environment interactions, and causality, as well as gene finding studies. In the future, these studies will continue with collection of additional phenotypes, such as metabolomic and telomere length data, and detailed genetic information provided by DNA and RNA sequencing. Record linkage to national registers will allow the study of morbidity and mortality, thus providing insight into the development of health, lifestyle, and behavior across the lifespan.
    Twin Research and Human Genetics 01/2013; 16(1):1-11. DOI:10.1017/thg.2012.140 · 2.30 Impact Factor
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