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)
Project #
Application #
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Parsian, Abbas
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Guo, Xiaoyun; Qiu, Wenying; Garcia-Milian, Rolando et al. (2017) Genome-wide significant, replicated and functional risk variants for Alzheimer's disease. J Neural Transm (Vienna) 124:1455-1471
Qiu, Wenying; Guo, Xiaoyun; Lin, Xiandong et al. (2017) Transcriptome-wide piRNA profiling in human brains of Alzheimer's disease. Neurobiol Aging 57:170-177
Zuo, Lingjun; Tan, Yunlong; Li, Chiang-Shan R et al. (2016) Associations of rare nicotinic cholinergic receptor gene variants to nicotine and alcohol dependence. Am J Med Genet B Neuropsychiatr Genet 171:1057-1071
Zuo, Lingjun; Wang, Zhiren; Tan, Yunlong et al. (2016) piRNAs and Their Functions in the Brain. Int J Hum Genet 16:53-60
Cao, Yuping; Shen, Jingjin; Li, Wen et al. (2016) The symptom trajectories to clinical remission in Chinese patients with unipolar major depressive disorder. Asia Pac Psychiatry 8:309-311
Zuo, Lingjun; Tan, Yunlong; Wang, Zhiren et al. (2016) Long noncoding RNAs in psychiatric disorders. Psychiatr Genet 26:109-16
Zuo, Lingjun; Tan, Yunlong; Zhang, Xiangyang et al. (2015) A New Genomewide Association Meta-Analysis of Alcohol Dependence. Alcohol Clin Exp Res 39:1388-95
Wang, Ke-Sheng; Tonarelli, Silvina; Luo, Xingguang et al. (2015) Polymorphisms within ASTN2 gene are associated with age at onset of Alzheimer's disease. J Neural Transm (Vienna) 122:701-8
Zuo, Lingjun; Saba, Laura; Lin, Xiandong et al. (2015) Significant association between rare IPO11-HTR1A variants and attention deficit hyperactivity disorder in Caucasians. Am J Med Genet B Neuropsychiatr Genet 168:544-56
Zuo, Lingjun; Wang, Tong; Lin, Xiandong et al. (2015) Sex difference of autosomal alleles in populations of European and African descent. Genes Genomics 37:1007-1016

Showing the most recent 10 out of 27 publications