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Am J Med Genet B Neuropsychiatr Genet. 2016 Dec;171(8):1057-1071. doi: 10.1002/ajmg.b.32476. Epub 2016 Jul 30.

Associations of rare nicotinic cholinergic receptor gene variants to nicotine and alcohol dependence.

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Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
Biological Psychiatry Research Center, Beijing Huilongguan Hospital, Beijing, China.
Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, Tennessee.
Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, Houston, Texas.
Provincial Key Laboratory of Translational Cancer Medicine, Fujian Provincial Cancer Hospital, Fuzhou, Fujian, China.
Nevada Institute of Personalized Medicine and Department of Psychology, University of Nevada, Las Vegas, Nevada.
Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Neurology, Shanghai First People's Hospital, Shanghai Jiao-Tong University, Shanghai, China.
Department of EEG and Neuroimaging, Shanghai Mental Health Center, Shanghai, China.
Provincial Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, China.
Departments of Genetics, Genomics, Informatics, Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee.


Nicotine's rewarding effects are mediated through distinct subunits of nAChRs, encoded by different nicotinic cholinergic receptor (CHRN) genes and expressed in discrete regions in the brain. In the present study, we aimed to test the associations between rare variants at CHRN genes and nicotine dependence (ND), and alcohol dependence (AD). A total of 26,498 subjects with nine different neuropsychiatric disorders in 15 independent cohorts, which were genotyped on Illumina, Affymetrix, or PERLEGEN microarray platforms, were analyzed. Associations between rare variants (minor allele frequency (MAF) <0.05) at CHRN genes and nicotine dependence, and alcohol dependence were tested. The mRNA expression of all Chrn genes in whole mouse brain and 10 specific brain areas was investigated. All CHRN genes except the muscle-type CHRNB1, including eight genomic regions containing 11 neuronal CHRN genes and three genomic regions containing four muscle-type CHRN genes, were significantly associated with ND, and/or AD. All of these genes were expressed in the mouse brain. We conclude that CHRNs are associated with ND (mainly) and AD, supporting the hypothesis that the full catalog of ND/AD risk genes may contain most neuronal nAChRs-encoding genes.


CHRN; alcohol dependence; mRNA expression; nAChR; nicotine dependence; rare variant

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