Genome-wide Association Study Identifies Genetic Variation in Neurocan as a Susceptibility Factor for Bipolar Disorder

被引：192

作者：

Cichon, Sven ^{[1
,2
,3
,4
,5
]}

Muehleisen, Thomas W. ^{[2
,3
]}

Degenhardt, Franziska A. ^{[2
,3
]}

Mattheisen, Manuel ^{[2
,3
,4
]}

Miro, Xavier ^{[5
]}

Strohmaier, Jana ^{[6
]}

Steffens, Michael ^{[4
]}

Meesters, Christian ^{[4
]}

Herms, Stefan ^{[2
,3
]}

Weingarten, Moritz ^{[2
,3
]}

Priebe, Lutz ^{[2
,3
]}

Haenisch, Britta ^{[2
,3
]}

Aexander, Michael ^{[2
,3
]}

Vollmer, Jennifer ^{[2
,3
]}

Breuer, Rene ^{[6
]}

Schmael, Christine ^{[6
]}

Tessmann, Peter ^{[2
,3
]}

Moebus, Susanne ^{[7
]}

Wichmann, H. -Erich ^{[8
,9
,10
]}

Schreiber, Stefan ^{[11
]}

Mueller-Myhsok, Bertram ^{[12
]}

Lucae, Susanne ^{[12
]}

Jamain, Stephane ^{[13
,14
,15
]}

Leboyer, Marion ^{[13
,14
,15
]}

Bellivier, Frank ^{[13
,14
,15
]}

Etain, Bruno ^{[13
,14
,15
]}

Henry, Chantal ^{[13
,14
,15
]}

Kahn, Jean-Pierre ^{[16
]}

Heath, Simon ^{[17
]}

Hamshere, Marian ^{[18
]}

O'Donovan, Michael C. ^{[18
]}

Owen, Michael J. ^{[18
]}

Craddock, Nick ^{[18
]}

Schwarz, Markus ^{[19
]}

Vedder, Helmut ^{[19
]}

Kammerer-Ciernioch, Jutta ^{[19
]}

Reif, Andreas ^{[20
]}

Sasse, Johanna ^{[21
]}

Bauer, Michael ^{[21
]}

Hautzinger, Martin ^{[22
]}

Wright, Adam ^{[23
,24
]}

Mitchell, Philip B. ^{[23
,24
]}

Schofield, Peter R. ^{[25
,26
]}

Montgomery, Grant W. ^{[27
]}

Medland, Sarah E. ^{[27
]}

Gordon, Scott D. ^{[27
]}

Martin, Nicholas G. ^{[27
]}

Gustafsson, Omar ^{[28
]}

Andreassen, Ole ^{[28
,29
]}

Djurovic, Srdjan ^{[28
,29
,30
]}

机构：

[1] Res Ctr Juelich, Inst Neurosci & Med INM 1, D-52425 Julich, Germany

[2] Univ Bonn, Life & Brain Ctr, Dept Genom, D-53127 Bonn, Germany

[3] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany

[4] Univ Bonn, Inst Med Biometry Informat & Epidemiol, D-53127 Bonn, Germany

[5] Univ Bonn, Inst Mol Psychiat, D-53127 Bonn, Germany

[6] Univ Mannheim, Dept Genet Epidemiol Psychiat, Cent Inst Mental Hlth, D-68159 Mannheim, Germany

[7] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, D-45147 Essen, Germany

[8] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, D-85764 Neuherberg, Germany

[9] Univ Munich, Inst Med Informat Biometry & Epidemiol, Chair Epidemiol, D-81377 Munich, Germany

[10] Klinikum Grosshadern, D-81377 Munich, Germany

[11] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany

[12] Max Planck Inst Psychiat, D-80804 Munich, Germany

[13] ENBREC, INSERM, U955, IMRB,Fdn Fondamental, F-94010 Creteil, France

[14] Univ Paris Est, Fac Med, F-75005 Paris, France

[15] AP HP, Dept Psychiat, Henri Mondor Albert Chenevier Grp, F-94000 Creteil, France

[16] CHU Nancy, Jeanne dArc Hosp, Dept Psychiat & Clin Psychol, F-54200 Toul, France

[17] Ctr Natl Genotypage, F-91057 Evry, France

[18] Cardiff Univ, Sch Med, Dept Psychol Med, Cardiff CF14 4XN, S Glam, Wales

[19] Psychiat Ctr Nordbaden, D-69168 Wiesloch, Germany

[20] Univ Wurzburg, Dept Psychiat, D-97070 Wurzburg, Germany

[21] Univ Hosp Carl Gustav Carus, Dept Psychiat & Psychotherapy, D-01307 Dresden, Germany

[22] Univ Tubingen, Inst Psychol, Dept Clin & Dev Psychol, D-72074 Tubingen, Germany

[23] Univ New S Wales, Sch Psychiat, Sydney, NSW 2052, Australia

[24] Prince Wales Hosp, Black Dog Inst, Randwick, NSW 2031, Australia

[25] Neurosci Res Australia, Randwick, NSW 2031, Australia

[26] Univ New S Wales, Sch Med Sci, Fac Med, Sydney, NSW 2052, Australia

[27] Queensland Inst Med Res, Brisbane, Qld 4006, Australia

[28] Oslo Univ Hosp, Dept Psychiat, N-0407 Oslo, Norway

[29] Univ Oslo, Inst Psychiat, N-0450 Oslo, Norway

[30] Oslo Univ Hosp, Dept Med Genet, N-0407 Oslo, Norway

[31] Univ Iceland, Dept Psychiat, Natl Univ Hosp, IS-101 Reykjavik, Iceland

[32] DeCODE Genet, CNS Div, IS-101 Reykjavik, Iceland

[33] Univ Iceland, Sch Med, IS-101 Reykjavik, Iceland

[34] Univ Sarajevo, Lab Human Genet, INGEB, BA-71000 Sarajevo, Bosnia & Herceg

[35] Univ Sarajevo, Ctr Clin, Psychiat Clin, BA-71000 Sarajevo, Bosnia & Herceg

[36] Civil Hosp Carlos Haya, ES-29010 Malaga, Spain

[37] Russian State Med Univ, Inst Pulmonol, Moscow 105077, Russia

[38] Russian Acad Med Sci, Mental Hlth Res Ctr, Moscow 115522, Russia

[39] Alexandru Obregia Clin Psychiat Hosp, Biometr Psychiat Genet Res Unit, RO-041914 Bucharest, Romania

[40] Romanian Acad, Stefan S Nicolau Inst Virol, RO-030304 Bucharest, Romania

[41] Poznan Univ Med Sci, Dept Psychiat, PL-60572 Poznan, Poland

[42] Univ Gottingen, Dept Psychiat & Psychotherapy, Univ Med Ctr, D-37075 Gottingen, Germany

[43] Univ Bonn, Dept Psychiat, D-53127 Bonn, Germany

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2011年 / 88卷 / 03期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

CHONDROITIN SULFATE PROTEOGLYCAN; DIAGNOSTIC INTERVIEW; PROCEDURAL VALIDITY; RISK-FACTORS; METAANALYSIS; RATIONALE; BRAIN; DISEASE; ANK3; TOOL;

D O I：

10.1016/j.ajhg.2011.01.017

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 x 10(-8); odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 x 10(-4); odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 x 10(-9) (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies.

引用

页码：372 / 381

页数：10

共 43 条

[1] A haplotype map of the human genome [J].

Altshuler, D ;

Brooks, LD ;

Chakravarti, A ;

Collins, FS ;

Daly, MJ ;

Donnelly, P ;

Gibbs, RA ;

Belmont, JW ;

Boudreau, A ;

Leal, SM ;

Hardenbol, P ;

Pasternak, S ;

Wheeler, DA ;

Willis, TD ;

Yu, FL ;

Yang, HM ;

Zeng, CQ ;

Gao, Y ;

Hu, HR ;

Hu, WT ;

Li, CH ;

Lin, W ;

Liu, SQ ;

Pan, H ;

Tang, XL ;

Wang, J ;

Wang, W ;

Yu, J ;

Zhang, B ;

Zhang, QR ;

Zhao, HB ;

Zhao, H ;

Zhou, J ;

Gabriel, SB ;

Barry, R ;

Blumenstiel, B ;

Camargo, A ;

Defelice, M ;

Faggart, M ;

Goyette, M ;

Gupta, S ;

Moore, J ;

Nguyen, H ;

Onofrio, RC ;

Parkin, M ;

Roy, J ;

Stahl, E ;

Winchester, E ;

Ziaugra, L ;

Shen, Y .

NATURE, 2005, 437 (7063) :1299-1320

[2]

*AMDP SYST, 1982, AMDP SYST ASS METH D

[3]

APA, 1994, DIAGN STAT MAN MENT, V4th

[4] Meta-analysis of two genome-wide association studies of bipolar disorder reveals important points of agreement [J].

Baum, A. E. ;

Hamshere, M. ;

Green, E. ;

Cichon, S. ;

Rietschel, M. ;

Noethen, M. M. ;

Craddock, N. ;

McMahon, F. J. .

MOLECULAR PSYCHIATRY, 2008, 13 (05) :466-467

[5] A genome-wide association study implicates diacylglycerol kinase η (DGKH) and several other genes in the etiology of bipolar disorder [J].

Baum, A. E. ;

Akula, N. ;

Cabanero, M. ;

Cardona, I. ;

Corona, W. ;

Klemens, B. ;

Schulze, T. G. ;

Cichon, S. ;

Rietschel, M. ;

Noethen, M. M. ;

Georgi, A. ;

Schumacher, J. ;

Schwarz, M. ;

Abou Jamra, R. ;

Hoefels, S. ;

Propping, P. ;

Satagopan, J. ;

Detera-Wadleigh, S. D. ;

Hardy, J. ;

McMahon, F. J. .

MOLECULAR PSYCHIATRY, 2008, 13 (02) :197-207

[6] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

[7] Practical aspects of imputation-driven meta-analysis of genome-wide association studies [J].

de Bakker, Paul I. W. ;

Ferreira, Manuel A. R. ;

Jia, Xiaoming ;

Neale, Benjamin M. ;

Raychaudhuri, Soumya ;

Voight, Benjamin F. .

HUMAN MOLECULAR GENETICS, 2008, 17 :R122-R128

[8]

ENDICOTT J, 1978, ARCH GEN PSYCHIAT, V35, P837

[9] Computer-assisted phenotype characterization for genetic research in psychiatry [J].

Fangerau, H ;

Ohlraun, S ;

Granath, RO ;

Nöthen, MM ;

Rietschel, M ;

Schulze, TG .

HUMAN HEREDITY, 2004, 58 (3-4) :122-130

[10] METHODOLOGICAL ISSUES IN USING A POLYDIAGNOSTIC APPROACH TO DEFINE PSYCHOTIC ILLNESS [J].

FARMER, AE ;

WESSELY, S ;

CASTLE, D ;

MCGUFFIN, P .

BRITISH JOURNAL OF PSYCHIATRY, 1992, 161 :824-830

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