Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder

Liping Hou; Sarah E. Bergen; Nirmala Akula; Jie Song; Christina M. Hultman; Mikael Landén; Mazda Adli; Martin Alda; Raffaella Ardau; Barbara Arias; Jean Michel Aubry; Lena Backlund; Judith A. Badner; Thomas B. Barrett; Michael Bauer; Bernhard T. Baune; Frank Bellivier; Antonio Benabarre; Susanne Bengesser; Wade H. Berrettini; Abesh Kumar Bhattacharjee; Joanna M. Biernacka; Armin Birner; Cinnamon S. Bloss; Clara Brichant-Petitjean; Elise T. Bui; William Byerley; Pablo Cervantes; Caterina Chillotti; Sven Cichon; Francesc Colom; William Coryell; David W. Craig; Cristiana Cruceanu; Piotr M. Czerski; Tony Davis; Alexandre Dayer; Franziska Degenhardt; Maria Del Zompo; J. Raymond DePaulo; Howard J. Edenberg; Bruno Étain; Peter Falkai; Tatiana Foroud; Andreas J. Forstner; Louise Frisén; Mark A. Frye; Janice M. Fullerton; Sébastien Gard; Julie S. Garnham; Elliot S. Gershon; Fernando S. Goes; Tiffany A. Greenwood; Maria Grigoroiu-Serbanescu; Joanna Hauser; Urs Heilbronner; Stefanie Heilmann-Heimbach; Stefan Herms; Maria Hipolito; Shashi Hitturlingappa; Per Hoffmann; Andrea Hofmann; Stephane Jamain; Esther Jiménez; Jean Pierre Kahn; Layla Kassem; John R. Kelsoe; Sarah Kittel-Schneider; Sebastian Kliwicki; Daniel L. Koller; Barbara König; Nina Lackner; Gonzalo Laje; Maren Lang; Catharina Lavebratt; William B. Lawson; Marion Leboyer; Susan G. Leckband; Chunyu Liu; Anna Maaser; Pamela B. Mahon; Wolfgang Maier; Mario Maj; Mirko Manchia; Lina Martinsson; Michael J. McCarthy; Susan L. McElroy; Melvin G. McInnis; Rebecca McKinney; Philip B. Mitchell; Marina Mitjans; Francis M. Mondimore; Palmiero Monteleone; Thomas W. Mühleisen; Caroline M. Nievergelt; Markus M. Nöthen; Tomas Novák; John I. Nurnberger; Evaristus A. Nwulia; Urban Ösby; Andrea Pfennig; James B. Potash; Peter Propping; Andreas Reif; Eva Reininghaus; John Rice; Marcella Rietschel; Guy A. Rouleau; Janusz K. Rybakowski; Martin Schalling; William A. Scheftner; Peter R. Schofield; Nicholas J. Schork; Thomas G. Schulze; Johannes Schumacher; Barbara W. Schweizer; Giovanni Severino; Tatyana Shekhtman; Paul D. Shilling; Christian Simhandl; Claire M. Slaney; Erin N. Smith; Alessio Squassina; Thomas Stamm; Pavla Stopkova; Fabian Streit; Jana Strohmaier; Szabolcs Szelinger; Sarah K. Tighe; Alfonso Tortorella; Gustavo Turecki; Eduard Vieta; Julia Volkert; Stephanie H. Witt; Adam Wright; Peter P. Zandi; Peng Zhang; Sebastian Zollner; Francis J. McMahon

doi:10.1093/hmg/ddw181

Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder

Liping Hou, Sarah E. Bergen, Nirmala Akula, Jie Song, Christina M. Hultman, Mikael Landén, Mazda Adli, Martin Alda, Raffaella Ardau, Barbara Arias, Jean Michel Aubry, Lena Backlund, Judith A. Badner, Thomas B. Barrett, Michael Bauer, Bernhard T. Baune, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Wade H. BerrettiniAbesh Kumar Bhattacharjee, Joanna M. Biernacka, Armin Birner, Cinnamon S. Bloss, Clara Brichant-Petitjean, Elise T. Bui, William Byerley, Pablo Cervantes, Caterina Chillotti, Sven Cichon, Francesc Colom, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Tony Davis, Alexandre Dayer, Franziska Degenhardt, Maria Del Zompo, J. Raymond DePaulo, Howard J. Edenberg, Bruno Étain, Peter Falkai, Tatiana Foroud, Andreas J. Forstner, Louise Frisén, Mark A. Frye, Janice M. Fullerton, Sébastien Gard, Julie S. Garnham, Elliot S. Gershon, Fernando S. Goes, Tiffany A. Greenwood, Maria Grigoroiu-Serbanescu, Joanna Hauser, Urs Heilbronner, Stefanie Heilmann-Heimbach, Stefan Herms, Maria Hipolito, Shashi Hitturlingappa, Per Hoffmann, Andrea Hofmann, Stephane Jamain, Esther Jiménez, Jean Pierre Kahn, Layla Kassem, John R. Kelsoe, Sarah Kittel-Schneider, Sebastian Kliwicki, Daniel L. Koller, Barbara König, Nina Lackner, Gonzalo Laje, Maren Lang, Catharina Lavebratt, William B. Lawson, Marion Leboyer, Susan G. Leckband, Chunyu Liu, Anna Maaser, Pamela B. Mahon, Wolfgang Maier, Mario Maj, Mirko Manchia, Lina Martinsson, Michael J. McCarthy, Susan L. McElroy, Melvin G. McInnis, Rebecca McKinney, Philip B. Mitchell, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Thomas W. Mühleisen, Caroline M. Nievergelt, Markus M. Nöthen, Tomas Novák, John I. Nurnberger, Evaristus A. Nwulia, Urban Ösby, Andrea Pfennig, James B. Potash, Peter Propping, Andreas Reif, Eva Reininghaus, John Rice, Marcella Rietschel, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, William A. Scheftner, Peter R. Schofield, Nicholas J. Schork, Thomas G. Schulze, Johannes Schumacher, Barbara W. Schweizer, Giovanni Severino, Tatyana Shekhtman, Paul D. Shilling, Christian Simhandl, Claire M. Slaney, Erin N. Smith, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Sarah K. Tighe, Alfonso Tortorella, Gustavo Turecki, Eduard Vieta, Julia Volkert, Stephanie H. Witt, Adam Wright, Peter P. Zandi, Peng Zhang, Sebastian Zollner, Francis J. McMahon

Research output: Contribution to journal › Article › peer-review

124 Scopus citations

Abstract

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of > 9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P= 5.87×10^-9; odds ratio (OR)=1.12) and markers within ERBB2 (rs2517959, P= 4.53×10^-9; OR=1.13). No significant X-chromosome associations were detected and Xlinked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

Original language	English
Pages (from-to)	3383-3394
Number of pages	12
Journal	Human molecular genetics
Volume	25
Issue number	15
DOIs	https://doi.org/10.1093/hmg/ddw181
State	Published - Aug 1 2016

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10.1093/hmg/ddw181

Cite this

Hou, L., Bergen, S. E., Akula, N., Song, J., Hultman, C. M., Landén, M., Adli, M., Alda, M., Ardau, R., Arias, B., Aubry, J. M., Backlund, L., Badner, J. A., Barrett, T. B., Bauer, M., Baune, B. T., Bellivier, F., Benabarre, A., Bengesser, S., ... McMahon, F. J. (2016). Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder. Human molecular genetics, 25(15), 3383-3394. https://doi.org/10.1093/hmg/ddw181

@article{1bbb5680c98f4ce1a6ac724796a9dd99,

title = "Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder",

abstract = "Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of > 9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P= 5.87×10-9; odds ratio (OR)=1.12) and markers within ERBB2 (rs2517959, P= 4.53×10-9; OR=1.13). No significant X-chromosome associations were detected and Xlinked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.",

author = "Liping Hou and Bergen, {Sarah E.} and Nirmala Akula and Jie Song and Hultman, {Christina M.} and Mikael Land{\'e}n and Mazda Adli and Martin Alda and Raffaella Ardau and Barbara Arias and Aubry, {Jean Michel} and Lena Backlund and Badner, {Judith A.} and Barrett, {Thomas B.} and Michael Bauer and Baune, {Bernhard T.} and Frank Bellivier and Antonio Benabarre and Susanne Bengesser and Berrettini, {Wade H.} and Bhattacharjee, {Abesh Kumar} and Biernacka, {Joanna M.} and Armin Birner and Bloss, {Cinnamon S.} and Clara Brichant-Petitjean and Bui, {Elise T.} and William Byerley and Pablo Cervantes and Caterina Chillotti and Sven Cichon and Francesc Colom and William Coryell and Craig, {David W.} and Cristiana Cruceanu and Czerski, {Piotr M.} and Tony Davis and Alexandre Dayer and Franziska Degenhardt and {Del Zompo}, Maria and DePaulo, {J. Raymond} and Edenberg, {Howard J.} and Bruno {\'E}tain and Peter Falkai and Tatiana Foroud and Forstner, {Andreas J.} and Louise Fris{\'e}n and Frye, {Mark A.} and Fullerton, {Janice M.} and S{\'e}bastien Gard and Garnham, {Julie S.} and Gershon, {Elliot S.} and Goes, {Fernando S.} and Greenwood, {Tiffany A.} and Maria Grigoroiu-Serbanescu and Joanna Hauser and Urs Heilbronner and Stefanie Heilmann-Heimbach and Stefan Herms and Maria Hipolito and Shashi Hitturlingappa and Per Hoffmann and Andrea Hofmann and Stephane Jamain and Esther Jim{\'e}nez and Kahn, {Jean Pierre} and Layla Kassem and Kelsoe, {John R.} and Sarah Kittel-Schneider and Sebastian Kliwicki and Koller, {Daniel L.} and Barbara K{\"o}nig and Nina Lackner and Gonzalo Laje and Maren Lang and Catharina Lavebratt and Lawson, {William B.} and Marion Leboyer and Leckband, {Susan G.} and Chunyu Liu and Anna Maaser and Mahon, {Pamela B.} and Wolfgang Maier and Mario Maj and Mirko Manchia and Lina Martinsson and McCarthy, {Michael J.} and McElroy, {Susan L.} and McInnis, {Melvin G.} and Rebecca McKinney and Mitchell, {Philip B.} and Marina Mitjans and Mondimore, {Francis M.} and Palmiero Monteleone and M{\"u}hleisen, {Thomas W.} and Nievergelt, {Caroline M.} and N{\"o}then, {Markus M.} and Tomas Nov{\'a}k and Nurnberger, {John I.} and Nwulia, {Evaristus A.} and Urban {\"O}sby and Andrea Pfennig and Potash, {James B.} and Peter Propping and Andreas Reif and Eva Reininghaus and John Rice and Marcella Rietschel and Rouleau, {Guy A.} and Rybakowski, {Janusz K.} and Martin Schalling and Scheftner, {William A.} and Schofield, {Peter R.} and Schork, {Nicholas J.} and Schulze, {Thomas G.} and Johannes Schumacher and Schweizer, {Barbara W.} and Giovanni Severino and Tatyana Shekhtman and Shilling, {Paul D.} and Christian Simhandl and Slaney, {Claire M.} and Smith, {Erin N.} and Alessio Squassina and Thomas Stamm and Pavla Stopkova and Fabian Streit and Jana Strohmaier and Szabolcs Szelinger and Tighe, {Sarah K.} and Alfonso Tortorella and Gustavo Turecki and Eduard Vieta and Julia Volkert and Witt, {Stephanie H.} and Adam Wright and Zandi, {Peter P.} and Peng Zhang and Sebastian Zollner and McMahon, {Francis J.}",

note = "Funding Information: The Australian cohort collection was supported by the Australian National Health and Medical Research Council (NHMRC) Program Grants 510135 (PBM) and 1037196 (PBM & PRS); and Project Grants 1063960 (JMF & PRS) and 1066177 (JMF). The Swiss samples were funded by the Swiss National Science Foundation (grant number 32003B_125469 and NCCR Synapsy, Jean-Michel Aubry and Alexandre Dayer). Most importantly, we thank the individuals and families who have participated in and contributed time and data to these studies. Funding Information: This work was supported by the National Institute of Mental Health (NIMH) Intramural Research Program (ZIA-MH00284311; NCT00001174) and a NARSAD Young Investigator Award to L.H. Funding Information: The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by a supplement to the University of Miami grants DA006227 & DA033684 and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 & MH101814), the University of Chicago (MH090951, MH090937, MH101820, MH101825), the University of North Carolina - Chapel Hill (MH090936 & MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St Louis (MH101810), and the University of Pennsylvania (MH101822). The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/12/2015. Funding Information: The Swedish samples were funded by the Stanley Center for Psychiatric Research, Broad Institute from a grant from Stanley Medical Research Institute, the Swedish Research Council (K2014-62X-21445-05-3, K2012-63X-21445-03-2, K2014-62X-14647-12-51 and K2010-61P-21568-01-4), the S{\"o}derstr{\"o}m-K{\"o}nigska Foundation (SLS-472751), the Swedish foundation for Strategic Research (KF10-0039), and the China Scholarship Council. We would like to thank all of the participants who have kindly given their time and DNA to participate in our research, the Swedish quality register for bipolar disorders (Bipola€R), and data collectors at the Department of Medical Epidemiology and Biostatistics (MEB) at Karolinska Institutet for help with recruitment of participants. Funding Information: M.M.N. is a member of the DFG-funded Excellence-Cluster ImmunoSensation. M.M.N. also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. The study was supported by the German Research Foundation (DFG; grant ConLiGen RI 908/7-1; grant SFB 636 Z4; grant FOR2107, RI 908/11-1 to M.R., WI 3439/3-1 to S.H.W., NO 246/10-1 to M.M.N.). Funding Information: NIMH Study 19 – Data and biomaterials were collected for the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a multi-center, longitudinal (5-8 year) project selected from responses to RFP #NIMH-98-DS-0001, {\textquoteleft}Treatment for Bipolar Disorder{\textquoteright}. The project was led by Gary Sachs, M.D., and coordinated by Massachusetts General Hospital in Boston, MA. The NIMH grant number was 2N01MH080001-001. Funding Information: The ConLiGen project was in part funded by the Deutsche Forschungsgemeinschaft (DFG; grant no. RI 908/7-1) and the Intramural Research Program of the National Institute of Mental Health (ZIA-MH00284311; NCT00001174). The Romanian sample included in the ConLiGen project was also funded by UEFISCDI, Romania (grant no. 89/2012 awarded to Maria Grigoroiu-Serbanescu, PhD) and BMBF, Germany, grant no. 01GS08144 awarded to M. M. N{\"o}then and S. Cichon). The Canadian sample has been part of a study funded by the Canadian Institutes of Health Research (grant 64410 to MA). The collection of the Barcelona sample was supported by the Centro de Investigaci{\'o}n en Red de Salud Mental (CIBERSAM), IDIBAPS (grant numbers PI080247, PI1200906, PI12/00018) and Secretaria d{\textquoteright}Universitats i Recerca del Departament d{\textquoteright}Economia i Coneixement (2014SGR1636 and 2014SGR398). Funding Information: Genotyping was funded in part by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grant 01ZX1314G to awarded to Thomas G. Schulze and Marcella Rietschel, grant 01ZX1314A to Sven Cichon and Markus M. N{\"o}then). Publisher Copyright: {\textcopyright} The Author 2016. Published by Oxford University Press. All rights reserved.",

year = "2016",

month = aug,

day = "1",

doi = "10.1093/hmg/ddw181",

language = "English",

volume = "25",

pages = "3383--3394",

journal = "Human molecular genetics",

issn = "0964-6906",

number = "15",

}

Hou, L, Bergen, SE, Akula, N, Song, J, Hultman, CM, Landén, M, Adli, M, Alda, M, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Badner, JA, Barrett, TB, Bauer, M, Baune, BT, Bellivier, F, Benabarre, A, Bengesser, S, Berrettini, WH, Bhattacharjee, AK, Biernacka, JM, Birner, A, Bloss, CS, Brichant-Petitjean, C, Bui, ET, Byerley, W, Cervantes, P, Chillotti, C, Cichon, S, Colom, F, Coryell, W, Craig, DW, Cruceanu, C, Czerski, PM, Davis, T, Dayer, A, Degenhardt, F, Del Zompo, M, DePaulo, JR, Edenberg, HJ, Étain, B, Falkai, P, Foroud, T, Forstner, AJ, Frisén, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Gershon, ES, Goes, FS, Greenwood, TA, Grigoroiu-Serbanescu, M, Hauser, J, Heilbronner, U, Heilmann-Heimbach, S, Herms, S, Hipolito, M, Hitturlingappa, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kelsoe, JR, Kittel-Schneider, S, Kliwicki, S, Koller, DL, König, B, Lackner, N, Laje, G, Lang, M, Lavebratt, C, Lawson, WB, Leboyer, M, Leckband, SG, Liu, C, Maaser, A, Mahon, PB, Maier, W, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, McInnis, MG, McKinney, R, Mitchell, PB, Mitjans, M, Mondimore, FM, Monteleone, P, Mühleisen, TW, Nievergelt, CM, Nöthen, MM, Novák, T, Nurnberger, JI, Nwulia, EA, Ösby, U, Pfennig, A, Potash, JB, Propping, P, Reif, A, Reininghaus, E, Rice, J, Rietschel, M, Rouleau, GA, Rybakowski, JK, Schalling, M, Scheftner, WA, Schofield, PR, Schork, NJ, Schulze, TG, Schumacher, J, Schweizer, BW, Severino, G, Shekhtman, T, Shilling, PD, Simhandl, C, Slaney, CM, Smith, EN, Squassina, A, Stamm, T, Stopkova, P, Streit, F, Strohmaier, J, Szelinger, S, Tighe, SK, Tortorella, A, Turecki, G, Vieta, E, Volkert, J, Witt, SH, Wright, A, Zandi, PP, Zhang, P, Zollner, S & McMahon, FJ 2016, 'Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder', Human molecular genetics, vol. 25, no. 15, pp. 3383-3394. https://doi.org/10.1093/hmg/ddw181

TY - JOUR

T1 - Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder

AU - Hou, Liping

AU - Bergen, Sarah E.

AU - Akula, Nirmala

AU - Song, Jie

AU - Hultman, Christina M.

AU - Landén, Mikael

AU - Adli, Mazda

AU - Alda, Martin

AU - Ardau, Raffaella

AU - Arias, Barbara

AU - Aubry, Jean Michel

AU - Backlund, Lena

AU - Badner, Judith A.

AU - Barrett, Thomas B.

AU - Bauer, Michael

AU - Baune, Bernhard T.

AU - Bellivier, Frank

AU - Benabarre, Antonio

AU - Bengesser, Susanne

AU - Berrettini, Wade H.

AU - Bhattacharjee, Abesh Kumar

AU - Biernacka, Joanna M.

AU - Birner, Armin

AU - Bloss, Cinnamon S.

AU - Brichant-Petitjean, Clara

AU - Bui, Elise T.

AU - Byerley, William

AU - Cervantes, Pablo

AU - Chillotti, Caterina

AU - Cichon, Sven

AU - Colom, Francesc

AU - Coryell, William

AU - Craig, David W.

AU - Cruceanu, Cristiana

AU - Czerski, Piotr M.

AU - Davis, Tony

AU - Dayer, Alexandre

AU - Degenhardt, Franziska

AU - Del Zompo, Maria

AU - DePaulo, J. Raymond

AU - Edenberg, Howard J.

AU - Étain, Bruno

AU - Falkai, Peter

AU - Foroud, Tatiana

AU - Forstner, Andreas J.

AU - Frisén, Louise

AU - Frye, Mark A.

AU - Fullerton, Janice M.

AU - Gard, Sébastien

AU - Garnham, Julie S.

AU - Gershon, Elliot S.

AU - Goes, Fernando S.

AU - Greenwood, Tiffany A.

AU - Grigoroiu-Serbanescu, Maria

AU - Hauser, Joanna

AU - Heilbronner, Urs

AU - Heilmann-Heimbach, Stefanie

AU - Herms, Stefan

AU - Hipolito, Maria

AU - Hitturlingappa, Shashi

AU - Hoffmann, Per

AU - Hofmann, Andrea

AU - Jamain, Stephane

AU - Jiménez, Esther

AU - Kahn, Jean Pierre

AU - Kassem, Layla

AU - Kelsoe, John R.

AU - Kittel-Schneider, Sarah

AU - Kliwicki, Sebastian

AU - Koller, Daniel L.

AU - König, Barbara

AU - Lackner, Nina

AU - Laje, Gonzalo

AU - Lang, Maren

AU - Lavebratt, Catharina

AU - Lawson, William B.

AU - Leboyer, Marion

AU - Leckband, Susan G.

AU - Liu, Chunyu

AU - Maaser, Anna

AU - Mahon, Pamela B.

AU - Maier, Wolfgang

AU - Maj, Mario

AU - Manchia, Mirko

AU - Martinsson, Lina

AU - McCarthy, Michael J.

AU - McElroy, Susan L.

AU - McInnis, Melvin G.

AU - McKinney, Rebecca

AU - Mitchell, Philip B.

AU - Mitjans, Marina

AU - Mondimore, Francis M.

AU - Monteleone, Palmiero

AU - Mühleisen, Thomas W.

AU - Nievergelt, Caroline M.

AU - Nöthen, Markus M.

AU - Novák, Tomas

AU - Nurnberger, John I.

AU - Nwulia, Evaristus A.

AU - Ösby, Urban

AU - Pfennig, Andrea

AU - Potash, James B.

AU - Propping, Peter

AU - Reif, Andreas

AU - Reininghaus, Eva

AU - Rice, John

AU - Rietschel, Marcella

AU - Rouleau, Guy A.

AU - Rybakowski, Janusz K.

AU - Schalling, Martin

AU - Scheftner, William A.

AU - Schofield, Peter R.

AU - Schork, Nicholas J.

AU - Schulze, Thomas G.

AU - Schumacher, Johannes

AU - Schweizer, Barbara W.

AU - Severino, Giovanni

AU - Shekhtman, Tatyana

AU - Shilling, Paul D.

AU - Simhandl, Christian

AU - Slaney, Claire M.

AU - Smith, Erin N.

AU - Squassina, Alessio

AU - Stamm, Thomas

AU - Stopkova, Pavla

AU - Streit, Fabian

AU - Strohmaier, Jana

AU - Szelinger, Szabolcs

AU - Tighe, Sarah K.

AU - Tortorella, Alfonso

AU - Turecki, Gustavo

AU - Vieta, Eduard

AU - Volkert, Julia

AU - Witt, Stephanie H.

AU - Wright, Adam

AU - Zandi, Peter P.

AU - Zhang, Peng

AU - Zollner, Sebastian

AU - McMahon, Francis J.

N1 - Funding Information: The Australian cohort collection was supported by the Australian National Health and Medical Research Council (NHMRC) Program Grants 510135 (PBM) and 1037196 (PBM & PRS); and Project Grants 1063960 (JMF & PRS) and 1066177 (JMF). The Swiss samples were funded by the Swiss National Science Foundation (grant number 32003B_125469 and NCCR Synapsy, Jean-Michel Aubry and Alexandre Dayer). Most importantly, we thank the individuals and families who have participated in and contributed time and data to these studies. Funding Information: This work was supported by the National Institute of Mental Health (NIMH) Intramural Research Program (ZIA-MH00284311; NCT00001174) and a NARSAD Young Investigator Award to L.H. Funding Information: The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by a supplement to the University of Miami grants DA006227 & DA033684 and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 & MH101814), the University of Chicago (MH090951, MH090937, MH101820, MH101825), the University of North Carolina - Chapel Hill (MH090936 & MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St Louis (MH101810), and the University of Pennsylvania (MH101822). The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/12/2015. Funding Information: The Swedish samples were funded by the Stanley Center for Psychiatric Research, Broad Institute from a grant from Stanley Medical Research Institute, the Swedish Research Council (K2014-62X-21445-05-3, K2012-63X-21445-03-2, K2014-62X-14647-12-51 and K2010-61P-21568-01-4), the Söderström-Königska Foundation (SLS-472751), the Swedish foundation for Strategic Research (KF10-0039), and the China Scholarship Council. We would like to thank all of the participants who have kindly given their time and DNA to participate in our research, the Swedish quality register for bipolar disorders (Bipola€R), and data collectors at the Department of Medical Epidemiology and Biostatistics (MEB) at Karolinska Institutet for help with recruitment of participants. Funding Information: M.M.N. is a member of the DFG-funded Excellence-Cluster ImmunoSensation. M.M.N. also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. The study was supported by the German Research Foundation (DFG; grant ConLiGen RI 908/7-1; grant SFB 636 Z4; grant FOR2107, RI 908/11-1 to M.R., WI 3439/3-1 to S.H.W., NO 246/10-1 to M.M.N.). Funding Information: NIMH Study 19 – Data and biomaterials were collected for the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a multi-center, longitudinal (5-8 year) project selected from responses to RFP #NIMH-98-DS-0001, ‘Treatment for Bipolar Disorder’. The project was led by Gary Sachs, M.D., and coordinated by Massachusetts General Hospital in Boston, MA. The NIMH grant number was 2N01MH080001-001. Funding Information: The ConLiGen project was in part funded by the Deutsche Forschungsgemeinschaft (DFG; grant no. RI 908/7-1) and the Intramural Research Program of the National Institute of Mental Health (ZIA-MH00284311; NCT00001174). The Romanian sample included in the ConLiGen project was also funded by UEFISCDI, Romania (grant no. 89/2012 awarded to Maria Grigoroiu-Serbanescu, PhD) and BMBF, Germany, grant no. 01GS08144 awarded to M. M. Nöthen and S. Cichon). The Canadian sample has been part of a study funded by the Canadian Institutes of Health Research (grant 64410 to MA). The collection of the Barcelona sample was supported by the Centro de Investigación en Red de Salud Mental (CIBERSAM), IDIBAPS (grant numbers PI080247, PI1200906, PI12/00018) and Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (2014SGR1636 and 2014SGR398). Funding Information: Genotyping was funded in part by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grant 01ZX1314G to awarded to Thomas G. Schulze and Marcella Rietschel, grant 01ZX1314A to Sven Cichon and Markus M. Nöthen). Publisher Copyright: © The Author 2016. Published by Oxford University Press. All rights reserved.

PY - 2016/8/1

Y1 - 2016/8/1

N2 - Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of > 9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P= 5.87×10-9; odds ratio (OR)=1.12) and markers within ERBB2 (rs2517959, P= 4.53×10-9; OR=1.13). No significant X-chromosome associations were detected and Xlinked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

AB - Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of > 9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P= 5.87×10-9; odds ratio (OR)=1.12) and markers within ERBB2 (rs2517959, P= 4.53×10-9; OR=1.13). No significant X-chromosome associations were detected and Xlinked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

UR - http://www.scopus.com/inward/record.url?scp=85014343531&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddw181

DO - 10.1093/hmg/ddw181

M3 - Article

C2 - 27329760

AN - SCOPUS:85014343531

SN - 0964-6906

VL - 25

SP - 3383

EP - 3394

JO - Human molecular genetics

JF - Human molecular genetics

IS - 15

ER -

Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder

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