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Rare ADH Variant Constellations are Specific for Alcohol Dependence
Zuo, Lingjun1; Zhang, Heping2; Malison, Robert T.1; Li, Chiang-Shan R.1; Zhang, Xiang-Yang3; Wang, Fei1; Lu, Lingeng2; Lu, Lin4; Wang, Xiaoping5; Krystal, John H.1,6,7; Zhang, Fengyu8; Deng, Hong-Wen9; Luo, Xingguang1
刊名ALCOHOL AND ALCOHOLISM
2013
DOI10.1093/alcalc/ags104
48期:1页:9-14
收录类别SCI ; SSCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Substance Abuse
研究领域[WOS]Substance Abuse
关键词[WOS]GENOME-WIDE ASSOCIATION ; MENTAL-DISORDERS ; GENE-CLUSTER ; DISEASE ; PROFILES ; LINKAGE
英文摘要

Aims: Some of the well-known functional alcohol dehydrogenase (ADH) gene variants (e.g. ADH1B*2, ADH1B*3 and ADH1C*2) that significantly affect the risk of alcohol dependence are rare variants in most populations. In the present study, we comprehensively examined the associations between rare ADH variants [minor allele frequency (MAF) < 0.05] and alcohol dependence, with several other neuropsychiatric and neurological disorders as reference. Methods: A total of 49,358 subjects in 22 independent cohorts with 11 different neuropsychiatric and neurological disorders were analyzed, including 3 cohorts with alcohol dependence. The entire ADH gene cluster (ADH7-ADH1C-ADH1B-ADH1A-ADH6-ADH4-ADH5 at Chr4) was imputed in all samples using the same reference panels that included whole-genome sequencing data. We stringently cleaned the phenotype and genotype data to obtain a total of 870 single nucleotide polymorphisms with 0 < MAF < 0.05 for association analysis. Results: We found that a rare variant constellation across the entire ADH gene cluster was significantly associated with alcohol dependence in European-Americans (Fp1: simulated global P = 0.045), European-Australians (Fp5: global P = 0.027; collapsing: P = 0.038) and African-Americans (Fp5: global P = 0.050; collapsing: P = 0.038), but not with any other neuropsychiatric disease. Association signals in this region came principally from ADH6, ADH7, ADH1B and ADH1C. In particular, a rare ADH6 variant constellation showed a replicable association with alcohol dependence across these three independent cohorts. No individual rare variants were statistically significantly associated with any disease examined after group- and region-wide correction for multiple comparisons. Conclusion: We conclude that rare ADH variants are specific for alcohol dependence. The ADH gene cluster may harbor a causal variant(s) for alcohol dependence.

语种英语
WOS记录号WOS:000312652300003
项目编号K01DA029643 ; K24DA017899 ; R01DA016750 ; R01 AA016015 ; R21 AA020319 ; 17616 ; U01HG004422 ; U01HG004436 ; U01HG004438 ; U01HG004446 ; U10AA008401 ; R01AA013320 ; P60AA011998 ; R01DA013423 ; P01 CA089392 ; HHSN268200782096C ; R01NS45012 ; M01RR165001 ; R01MH059160 ; R01MH59565 ; R01MH59566 ; R01MH59571 ; R01MH59586 ; R01MH59587 ; R01MH59588 ; R01MH60870 ; R01MH60879 ; R01MH61675 ; R01MH62873 ; R01MH081803 ; R01MH67257 ; R01MH81800 ; U01MH46276 ; U01MH46282 ; U01MH46289 ; U01MH46318 ; U01MH79469 ; U01MH79470 ; G0601030 ; 075491/Z/04 ; 904-61-090 ; 904-61-193 ; 480-04-004 ; 400-05-717 ; 56-464-1419 ; EU/WLRT-2001-01254 ; 10-000-1002
资助机构National Institute on Drug Abuse (NIDA) ; National Institute on Alcohol Abuse and Alcoholism (NIAAA) ; National Alliance for Research on Schizophrenia and Depression (NARSAD) ; NIH GWAS Data Repository ; National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI) ; GENEVA Coordinating Center ; NIAAA ; NIDA ; National Cancer Institute ; Division of Neuroscience, the NIA National Institute of Neurological Disorders and Stroke (NINDS) ; NINDS Human Genetics Resource Center DNA and Cell Line Repository ; NIH ; Center for Inherited Disease Research (CIDR) ; Division of Adult and Community Health, Centers for Disease Control and Prevention ; NIH Office of Research on Women&prime ; s Health (ORWH) ; Department of Veterans Affairs ; University of Maryland General Clinical Research Center ; National Center for Research Resources, NIH ; National Institute of Mental Health ; NIMH Genetics Initiative for Bipolar Disorder ; Genetic Association Information Network (GAIN) ; Genetic Consortium for Late Onset Alzheimer&prime ; s Disease ; Autism Genome Project, the MARC: Risk Mechanisms in Alcoholism and Co-morbidity ; Molecular Genetics of Schizophrenia Collaboration ; Medical Research Council ; Wellcome Trust ; University of Oxford ; Netherlands Scientific Organization (NWO Genomics, SPI) ; Centre for Neurogenomics and Cognitive Research (CNCR-VU) ; Netherlands Study of Depression and Anxiety (NESDA) ; Netherlands Twin Register (NTR) ; European Union ; ZonMW (geestkracht program) ; Tetragenex Pharmaceuticals
引用统计
被引频次:20[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/65603
专题中国药物依赖性研究所
作者单位1.Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06516 USA
2.Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06516 USA
3.Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA
4.Peking Univ, Natl Inst Drug Dependence, Beijing 100871, Peoples R China
5.Shanghai Jiao Tong Univ, Dept Neurol, Peoples Hosp 1, Shanghai 200030, Peoples R China
6.Yale New Haven Med Ctr, Psychiat Serv, New Haven, CT 06504 USA
7.VA Connecticut Healthcare Syst, VA Alcohol Res Ctr, West Haven, CT USA
8.Johns Hopkins Univ Med Campus, Lieber Inst Brain Dev, Baltimore, MD USA
9.Tulane Univ, Sch Publ Hlth & Trop Med, Dept Biostat, New Orleans, LA USA
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GB/T 7714
Zuo, Lingjun,Zhang, Heping,Malison, Robert T.,et al. Rare ADH Variant Constellations are Specific for Alcohol Dependence[J]. ALCOHOL AND ALCOHOLISM,2013,48(1):9-14.
APA Zuo, Lingjun.,Zhang, Heping.,Malison, Robert T..,Li, Chiang-Shan R..,Zhang, Xiang-Yang.,...&Luo, Xingguang.(2013).Rare ADH Variant Constellations are Specific for Alcohol Dependence.ALCOHOL AND ALCOHOLISM,48(1),9-14.
MLA Zuo, Lingjun,et al."Rare ADH Variant Constellations are Specific for Alcohol Dependence".ALCOHOL AND ALCOHOLISM 48.1(2013):9-14.
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