Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4

被引：1015

作者：

Sklar, Pamela ^{[1
,2
,3
]}

Ripke, Stephan ^{[2
,3
,4
]}

Scott, Laura J. ^{[5
,6
]}

Andreassen, Ole A. ^{[7
,8
]}

Cichon, Sven ^{[9
,10
,11
]}

Craddock, Nick ^{[12
]}

Edenberg, Howard J. ^{[13
]}

Nurnberger, John I., Jr. ^{[14
]}

Rietschel, Marcella ^{[15
]}

Blackwood, Douglas ^{[16
,17
]}

Corvin, Aiden ^{[18
,19
]}

Flickinger, Matthew ^{[5
,6
]}

Guan, Weihua ^{[5
,6
]}

Mattingsdal, Morten ^{[7
,20
]}

McQuillin, Andrew ^{[21
]}

Kwan, Phoenix ^{[5
,6
]}

Wienker, Thomas F. ^{[22
]}

Daly, Mark ^{[2
,3
,4
]}

Dudbridge, Frank ^{[23
]}

Holmans, Peter A. ^{[12
,24
]}

Lin, Danyu ^{[25
]}

Burmeister, Margit ^{[26
]}

Greenwood, Tiffany A. ^{[27
]}

Hamshere, Marian L. ^{[12
,28
]}

Muglia, Pierandrea ^{[28
]}

Smith, Erin N. ^{[29
,30
]}

Zandi, Peter P. ^{[31
]}

Nievergelt, Caroline M. ^{[27
]}

McKinney, Rebecca ^{[27
]}

Shilling, Paul D. ^{[27
]}

Schork, Nicholas J. ^{[29
,30
]}

Bloss, Cinnamon S. ^{[29
,30
]}

Foroud, Tatiana ^{[14
]}

Koller, Daniel L. ^{[14
]}

Gershon, Elliot S. ^{[32
]}

Liu, Chunyu ^{[32
]}

Badner, Judith A. ^{[32
]}

Scheftner, William A. ^{[33
]}

Lawson, William B. ^{[34
]}

Nwulia, Evaristus A. ^{[34
]}

Hipolito, Maria ^{[34
]}

Coryell, William ^{[35
]}

Rice, John ^{[36
]}

Byerley, William ^{[37
]}

McMahon, Francis J. ^{[38
]}

Schulze, Thomas G. ^{[15
,38
,39
]}

Berrettini, Wade ^{[40
]}

Lohoff, Falk W. ^{[40
]}

Potash, James B. ^{[31
]}

Mahon, Pamela B. ^{[31
]}

机构：

[1] Mt Sinai Sch Med, Dept Psychiat, Div Psychiat Genom, New York, NY USA

[2] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[3] Harvard Univ, Sch Med, Boston, MA USA

[4] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA

[5] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA

[6] Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[7] Univ Oslo, Inst Clin Med, European Network Bipolar Res Expert Ctr ENBREC Gr, Oslo, Norway

[8] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway

[9] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany

[10] Univ Bonn, Dept Genom, Life & Brain Ctr, D-5300 Bonn, Germany

[11] Res Ctr Juelich, Inst Neurosci & Med INM 1, Julich, Germany

[12] Cardiff Univ, Sch Med, Med Res Council MRC Ctr Neuropsychiat Genet & Gen, Cardiff, S Glam, Wales

[13] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Dept Med & Mol Genet, Indianapolis, IN USA

[14] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN USA

[15] Heidelberg Univ, Dept Genet Epidemiol Psychiat, Cent Inst Mental Hlth Mannheim, D-6800 Mannheim, Germany

[16] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland

[17] Univ Edinburgh, Western Gen Hosp, Mol Med Ctr, Med Genet Sect, Edinburgh, Midlothian, Scotland

[18] Trinity Coll Dublin, Neuropsychiat Genet Res Grp, Dept Psychiat, Dublin, Ireland

[19] Trinity Coll Dublin, Inst Mol Med, Dublin, Ireland

[20] Sorlandet Hosp HF, Kristiansand, Norway

[21] UCL, Mol Psychiat Lab, Res Dept Mental Hlth Sci, London, England

[22] Univ Bonn, Inst Med Biometry Informat & Epidemiol, D-5300 Bonn, Germany

[23] Univ London, London Sch Hyg & Trop Med, London, England

[24] Cardiff Univ, Sch Med, Biostat & Bioinformat Unit, Cardiff, S Glam, Wales

[25] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA

[26] Univ Michigan, Dept Psychiat, Dept Human Genet, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA

[27] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[28] GlaxoSmithKline Res & Dev Ltd, Neurosci Ctr Excellence Drug Discovery, Verona, Italy

[29] Scripps Translat Sci Inst, La Jolla, CA USA

[30] Scripps Hlth, La Jolla, CA USA

[31] Johns Hopkins Univ & Hosp, Dept Mental Hlth, Baltimore, MD USA

[32] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA

[33] Rush Univ, Med Ctr, Chicago, IL 60612 USA

[34] Howard Univ, Coll Med, Dept Psychiat & Behav Sci, Washington, DC USA

[35] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA

[36] Washington Univ, Sch Med, St Louis, MO USA

[37] Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94143 USA

[38] NIMH, US Natl Inst Hlth, Bethesda, MD 20892 USA

[39] Univ Gottingen, Dept Psychiat, Gottingen, Germany

[40] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA

[41] Translat Genom Res Inst, Phoenix, AZ USA

[42] Portland VA Med Ctr, Portland, OR USA

[43] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat SGDP Ctr, London WC2R 2LS, England

[44] Ctr Addict & Mental Hlth, Mol Neuropsychiat & Dev Lab, Toronto, ON, Canada

[45] Princess Margaret Hosp, Dept Biostat, Toronto, ON M4X 1K9, Canada

[46] Ctr Addict & Mental Hlth, Psychiat Neurogenet Sect, Toronto, ON, Canada

[47] Univ Dundee, Sch Med, Dundee, Scotland

[48] Royal Victoria Infirm, Sch Neurol Neurobiol & Psychiat, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England

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

[50] HudsonAlpha Inst Biotechnol, Huntsville, AL USA

来源：

NATURE GENETICS | 2011年 / 43卷 / 10期

基金：

美国国家卫生研究院; 英国惠康基金;

关键词：

CACNA1C; RISK; SCHIZOPHRENIA; GENETICS; ANK3;

D O I：

10.1038/ng.943

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 x 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.

引用

页码：977 / U162

页数：9

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