Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms

被引：37

作者：

Adkins, Amy E. ^{[1
,2
,35
,36
]}

Hack, Laura M. ^{[1
,2
]}

Bigdeli, Tim B. ^{[2
]}

Williamson, Vernell S. ^{[1
,2
]}

McMichael, G. Omari ^{[1
,2
]}

Mamdani, Mohammed ^{[1
,2
]}

Edwards, Alexis C. ^{[1
,2
]}

Aliev, Fazil ^{[1
,2
,35
]}

Chan, Robin F. ^{[1
,3
]}

Bhandari, Poonam ^{[3
]}

Raabe, Richard C. ^{[4
]}

Alaimo, Joseph T. ^{[4
]}

Blackwell, GinaMari G. ^{[4
]}

Moscati, Arden ^{[1
,2
]}

Poland, Ryan S. ^{[2
]}

Rood, Benjamin ^{[2
]}

Patterson, Diana G. ^{[5
]}

Walsh, Dermot ^{[6
]}

Whitfield, John B. ^{[7
]}

Zhu, Gu ^{[7
]}

Montgomery, Grant W. ^{[7
]}

Henders, Anjali K. ^{[7
]}

Martin, Nicholas G. ^{[7
]}

Heath, Andrew C. ^{[8
]}

Madden, Pamela A. F. ^{[8
]}

Frank, Josef ^{[9
]}

Ridinger, Monika ^{[11
]}

Wodarz, Norbert ^{[11
]}

Soyka, Michael ^{[12
,13
]}

Zill, Peter ^{[13
]}

Ising, Marcus ^{[14
]}

Noethen, Markus M. ^{[15
,16
,17
]}

Kiefer, Falk ^{[10
]}

Rietschel, Marcella ^{[9
]}

Gelernter, Joel ^{[18
,19
,20
,22
]}

Sherva, Richard ^{[26
]}

Koesterer, Ryan ^{[26
]}

Almasy, Laura ^{[23
]}

Zhao, Hongyu ^{[20
,21
]}

Kranzler, Henry R. ^{[24
,25
]}

Farrer, Lindsay A. ^{[22
,26
,27
,28
,29
,30
]}

Maher, Brion S. ^{[31
]}

Prescott, Carol A. ^{[32
]}

Dick, Danielle M. ^{[1
,2
,3
,35
,36
]}

Bacanu, Silviu A. ^{[1
,2
]}

Mathies, Laura D. ^{[4
]}

Davies, Andrew G. ^{[1
,4
]}

Vladimirov, Vladimir I. ^{[1
,2
,33
,34
]}

Grotewiel, Mike ^{[1
,3
]}

Bowers, M. Scott ^{[1
,2
,4
,37
]}

机构：

[1] Virginia Commonwealth Univ, Alcohol Res Ctr, Richmond, VA USA

[2] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA

[3] Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA USA

[4] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA USA

[5] Shaftesbury Sq Hosp, Belfast, Antrim, North Ireland

[6] Hlth Res Board, Dublin 2, Ireland

[7] Royal Brisbane & Womens Hosp, Genet Epidemiol, QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia

[8] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

[9] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany

[10] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Addict Behav & Addict Med, Mannheim, Germany

[11] Univ Regensburg, Univ Hosp Regensburg, Dept Psychiat, Regensburg, Germany

[12] Privatklin Meiringen, Meiringen, Switzerland

[13] Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany

[14] Max Planck Inst Psychiat, Dept Mol Psychol, Munich, Germany

[15] Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany

[16] Univ Bonn, Inst Human Genet, Bonn, Germany

[17] Univ Bonn, German Ctr Neurodegenerat Dis DZNE, Bonn, Germany

[18] Yale Univ Sch Med, Dept Psychiat, New Haven, CT USA

[19] Yale Univ Sch Med, Dept Neurobiol, New Haven, CT USA

[20] Yale Univ Sch Med, Dept Genet, New Haven, CT USA

[21] Yale Univ Sch Med, Dept Biostat, New Haven, CT USA

[22] VA CT Healthcare Ctr, Dept Psychiat, West Haven, CT USA

[23] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA

[24] Univ Penn, Dept Psychiat, Treatment Res Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

[25] VISN 4 MIRECC, Philadelphia VA Med Ctr, Philadelphia, PA USA

[26] Boston Univ, Sch Med, Dept Med Biomed Genet, Boston, MA 02118 USA

[27] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[28] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA

[29] Boston Univ, Sch Med, Dept Epidemiol, Boston, MA 02118 USA

[30] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[31] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA

[32] Univ Southern Calif, Dept Psychol, Los Angeles, CA USA

[33] Johns Hopkins Univ, Lieber Inst Brain Dev, Baltimore, MD USA

[34] Virginia Commonwealth Univ, Sch Pharm, Ctr Biomarker Res & Personalized Med, Richmond, VA USA

[35] Virginia Commonwealth Univ, Dept Psychol, POB 842018, Richmond, VA 23284 USA

[36] Virginia Commonwealth Univ, Coll Behav & Emot Hlth Inst, POB 842018, Richmond, VA 23284 USA

[37] Northwestern Univ, Dept Biomed Engn, Faulk Ctr Mol Therapeut, 1801 Maple Ave, Evanston, IL 60201 USA

来源：

ALCOHOL-CLINICAL AND EXPERIMENTAL RESEARCH | 2017年 / 41卷 / 05期

基金：

英国惠康基金;

关键词：

Alcohol Dependence; COL6A3; KLF12; LOC339975; RYR3; NATIONAL EPIDEMIOLOGIC SURVEY; TISSUE-PLASMINOGEN ACTIVATOR; DOPAMINE D-1 RECEPTORS; WIDE ASSOCIATION; CAENORHABDITIS-ELEGANS; NONCODING RNA; WITHDRAWAL; EXPRESSION; DROSOPHILA; GENETICS;

D O I：

10.1111/acer.13362

中图分类号：

R194 [卫生标准、卫生检查、医药管理];

学科分类号：

摘要：

BackgroundAlcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified. MethodsWe conducted a genomewide association study in 706 related AD cases and 1,748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms (MOs) to assess the role of orthologous genes in ethanol (EtOH)-response behaviors. We tested 1 primate-specific gene for expression differences in case/control postmortem brain tissue. ResultsWe detected significant association in COL6A3 and suggestive association in 2 previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta-analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling-induced convulsions in mice. Loss of function of the KLF12 ortholog in C.elegans impaired development of acute functional tolerance (AFT). Klf12 expression correlated with locomotor activation following EtOH injection in mice. Loss of function of the RYR3 ortholog reduced EtOH sensitivity in C.elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer EtOH in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens (NAc). ConclusionsWe detect association between AD and COL6A3, KLF12, RYR3, and LOC339975. Despite nonreplication of COL6A3, KLF12, and RYR3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.

引用

页码：911 / 928

页数：18

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