Document Detail


Genome-wide significant association signals in IPO11-HTR1A region specific for alcohol and nicotine codependence.
MedLine Citation:
PMID:  23216389     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Alcohol and nicotine codependence can be considered as a more severe subtype of alcohol dependence. A portion of its risk may be attributable to genetic factors.
METHODS: We searched for significant risk genomic regions specific for this disorder using a genome-wide association study. A total of 8,847 subjects underwent gene-disease association analysis, including (i) a discovery cohort of 818 European American cases with alcohol and nicotine codependence and 1,396 European American controls, (ii) a replication cohort of 5,704 Australian family subjects with 907 affected offspring, and (iii) a replication cohort of 449 African American cases and 480 African American controls. Additionally, a total of 38,714 subjects of European or African descent in 18 independent cohorts with 10 other nonalcoholism neuropsychiatric disorders were analyzed as contrast. Furthermore, 90 unrelated HapMap CEU individuals, 93 European brain tissue samples, and 80 European peripheral blood mononuclear cell samples underwent cis-acting expression quantitative locus (cis-eQTL) analysis.
RESULTS: We identified a significant risk region for alcohol and nicotine codependence between IPO11 and HTR1A on chromosome 5q that was reported to be suggestively associated with alcohol dependence previously. In the European American discovery cohort, 381 single nucleotide polymorphisms (SNPs) in this region were nominally associated with alcohol and nicotine codependence (p < 0.05); 57 associations of them survived region- and cohort-wide correction (α = 3.6 × 10(-6) ); and the top SNP (rs7445832) was significantly associated with alcohol and nicotine codependence at the genome-wide significance level (p = 6.2 × 10(-9) ). Furthermore, associations for 34 and 11 SNPs were replicated in the Australian and African American replication cohorts, respectively. Among these replicable associations, 4 reached genome-wide significance level in the meta-analysis of European Americans and European Australians: rs7445832 (p = 9.6 × 10(-10) ), rs13361996 (p = 8.2 × 10(-9) ), rs62380518 (p = 2.3 × 10(-8) ), and rs7714850 (p = 3.4 × 10(-8) ). Cis-eQTL analysis showed that many risk SNPs in this region had nominally significant cis-acting regulatory effects on HTR1A or IPO11 mRNA expression. Finally, no markers were significantly associated with any other neuropsychiatric disorder examined.
CONCLUSIONS: We speculate that this IPO11-HTR1A region might harbor a causal variant for alcohol and nicotine codependence.
Authors:
Lingjun Zuo; Xiang-Yang Zhang; Fei Wang; Chiang-Shan R Li; Lingeng Lu; Liefu Ye; Heping Zhang; John H Krystal; Hong-Wen Deng; Xingguang Luo
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-12-06
Journal Detail:
Title:  Alcoholism, clinical and experimental research     Volume:  37     ISSN:  1530-0277     ISO Abbreviation:  Alcohol. Clin. Exp. Res.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-25     Completed Date:  2013-11-12     Revised Date:  2014-05-08    
Medline Journal Info:
Nlm Unique ID:  7707242     Medline TA:  Alcohol Clin Exp Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  730-9     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 by the Research Society on Alcoholism.
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MeSH Terms
Descriptor/Qualifier:
Adult
African Americans / genetics
Alcoholism / complications,  genetics*
Case-Control Studies
Chromosomes, Human, Pair 5 / genetics*
European Continental Ancestry Group / genetics
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Receptor, Serotonin, 5-HT1A / genetics
Tobacco Use Disorder / complications,  genetics*
beta Karyopherins / genetics
Grant Support
ID/Acronym/Agency:
075491/Z/04//Wellcome Trust; G0601030//Medical Research Council; HHSN268200782096C//PHS HHS; K01 DA029643/DA/NIDA NIH HHS; K01 DA029643/DA/NIDA NIH HHS; M01RR165001/RR/NCRR NIH HHS; P01 CA089392/CA/NCI NIH HHS; P60AA011998/AA/NIAAA NIH HHS; R01 AA016015/AA/NIAAA NIH HHS; R01 AA016015/AA/NIAAA NIH HHS; R01AA013320/AA/NIAAA NIH HHS; R01DA013423/DA/NIDA NIH HHS; R01DA016750/DA/NIDA NIH HHS; R01MH059160/MH/NIMH NIH HHS; R01MH081803/MH/NIMH NIH HHS; R01MH59565/MH/NIMH NIH HHS; R01MH59566/MH/NIMH NIH HHS; R01MH59571/MH/NIMH NIH HHS; R01MH59586/MH/NIMH NIH HHS; R01MH59587/MH/NIMH NIH HHS; R01MH59588/MH/NIMH NIH HHS; R01MH60870/MH/NIMH NIH HHS; R01MH60879/MH/NIMH NIH HHS; R01MH61675/MH/NIMH NIH HHS; R01MH62873/MH/NIMH NIH HHS; R01MH67257/MH/NIMH NIH HHS; R01MH81800/MH/NIMH NIH HHS; R01NS45012/NS/NINDS NIH HHS; R21 AA020319/AA/NIAAA NIH HHS; R21 AA020319/AA/NIAAA NIH HHS; U01 HG004446/HG/NHGRI NIH HHS; U01HG004422/HG/NHGRI NIH HHS; U01HG004436/HG/NHGRI NIH HHS; U01HG004438/HG/NHGRI NIH HHS; U01HG004446/HG/NHGRI NIH HHS; U01MH46276/MH/NIMH NIH HHS; U01MH46282/MH/NIMH NIH HHS; U01MH46289/MH/NIMH NIH HHS; U01MH46318/MH/NIMH NIH HHS; U01MH79469/MH/NIMH NIH HHS; U01MH79470/MH/NIMH NIH HHS; U10AA008401/AA/NIAAA NIH HHS; UL1 TR000142/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/HTR1A protein, human; 0/IPO11 protein, human; 0/beta Karyopherins; 112692-38-3/Receptor, Serotonin, 5-HT1A
Comments/Corrections

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