It has been suggested that genetic factors may contribute to alcohol and nicotine co-dependence (AD+ND). Glutamatergic pathway plays important functional roles in addiction. Glutamatergic pathway genes have been demonstrated to be associated with smoking related traits and human variation in alcohol response by genome-wide studies. However, the genetic functional variants underlying AD+ND are largely unidentified. This study mainly aims to identify the potential functional variants underlying AD+ND in glutamatergic pathway, in particular, the variants with low frequencies or weak effects. We select five target genes, including GRIN2B (glutamate receptor, ionotropic, N-methyl D-aspartate 2B), GRM1 (glutamate receptor, metabotropic 1), GRIK1 (glutamate receptor, ionotropic, kainate 1), GLRA2 (glycine receptor, alpha 2) and NTRK2 (neurotrophic tyrosine kinase, receptor, type 2). These regions will be sequenced in a relatively large size of sample (448 AD+ND cases and 448 controls) by a novel next generation sequence approach, i.e., targeted paired-end multiplexed (TPM) sequencing. Both individual effects and joint effects of the five genes on AD+ND will be tested in two independent samples. If successful, this study would make big progress in the research on the mechanism of AD+ND and may be helpful in developing novel and effective treatment and prevention strategies for AD+ND. Furthermore, the expected findings could provide a much detailed map of genetic variants, in particular, rare variants, in the five target regions, which would lay a foundation for future investigation on genotype-phenotype relationship.

Public Health Relevance

This proposed project will search for causal loci for alcohol and nicotine co-dependence, which will help us better understand the biological basis of this phenotype. The expected findings would significantly contribute to the improvement of public health.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Exploratory/Developmental Grants (R21)
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Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Parsian, Abbas
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Yale University
Schools of Medicine
New Haven
United States
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Zuo, Lingjun; Lu, Lingeng; Tan, Yunlong et al. (2014) Genome-wide association discoveries of alcohol dependence. Am J Addict 23:526-39
Zuo, Lingjun; Wang, Kesheng; Wang, Guilin et al. (2014) Common PTP4A1-PHF3-EYS variants are specific for alcohol dependence. Am J Addict 23:411-4
Zuo, Lingjun; Wang, Kesheng; Luo, Xingguang (2014) Use of diplotypes - matched haplotype pairs from homologous chromosomes - in gene-disease association studies. Shanghai Arch Psychiatry 26:165-70
Zuo, Lingjun; Zhang, Heping; Malison, Robert T et al. (2013) Rare ADH variant constellations are specific for alcohol dependence. Alcohol Alcohol 48:9-14
Zuo, Lingjun; Saba, Laura; Wang, Kesheng et al. (2013) Exome-wide association study of replicable nonsynonymous variants conferring risk for alcohol dependence. J Stud Alcohol Drugs 74:622-5
Zuo, Lingjun; Wang, Ke-Sheng; Zhang, Xiang-Yang et al. (2013) Rare SERINC2 variants are specific for alcohol dependence in individuals of European descent. Pharmacogenet Genomics 23:395-402
Zuo, Lingjun; Zhang, Xiang-Yang; Wang, Fei et al. (2013) Genome-wide significant association signals in IPO11-HTR1A region specific for alcohol and nicotine codependence. Alcohol Clin Exp Res 37:730-9
Zuo, Lingjun; Wang, Kesheng; Zhang, Xiang-Yang et al. (2013) Association between common alcohol dehydrogenase gene (ADH) variants and schizophrenia and autism. Hum Genet 132:735-43
Pan, Yue; Luo, Xingguang; Liu, Xuefeng et al. (2013) Genome-wide association studies of maximum number of drinks. J Psychiatr Res 47:1717-24
Zuo, Lingjun; Wang, Kesheng; Zhang, Xiang-Yang et al. (2013) NKAIN1-SERINC2 is a functional, replicable and genome-wide significant risk gene region specific for alcohol dependence in subjects of European descent. Drug Alcohol Depend 129:254-64

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