Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder

Sven Cichon; Thomas W. Mühleisen; Franziska A. Degenhardt; Manuel Mattheisen; Xavier Miró; Jana Strohmaier; Michael Steffens; Christian Meesters; Stefan Herms; Moritz Weingarten; Lutz Priebe; Britta Haenisch; Michael Alexander; Jennifer Vollmer; René Breuer; Christine Schmäl; Peter Tessmann; Susanne Moebus; H. Erich Wichmann; Stefan Schreiber; Bertram Müller-Myhsok; Susanne Lucae; Stéphane Jamain; Marion Leboyer; Frank Bellivier; Bruno Etain; Chantal Henry; Jean Pierre Kahn; Simon Heath; Marian Hamshere; Michael C. O'Donovan; Michael J. Owen; Nick Craddock; Markus Schwarz; Helmut Vedder; Jutta Kammerer-Ciernioch; Andreas Reif; Johanna Sasse; Michael Bauer; Martin Hautzinger; Adam Wright; Philip B. Mitchell; Peter R. Schofield; Grant W. Montgomery; Sarah E. Medland; Scott D. Gordon; Nicholas G. Martin; Omar Gustafsson; Ole Andreassen; Srdjan Djurovic; Engilbert Sigurdsson; Stacy Steinberg; Hreinn Stefansson; Kari Stefansson; Lejla Kapur-Pojskic; Liliana Oruc; Fabio Rivas; Fermín Mayoral; Alexander Chuchalin; Gulja Babadjanova; Alexander S. Tiganov; Galina Pantelejeva; Lilia I. Abramova; Maria Grigoroiu-Serbanescu; Carmen C. Diaconu; Piotr M. Czerski; Joanna Hauser; Andreas Zimmer; Mark Lathrop; Thomas G. Schulze; Thomas F. Wienker; Johannes Schumacher; Wolfgang Maier; Peter Propping; Marcella Rietschel; Markus M. Nöthen

doi:10.1016/j.ajhg.2011.01.017

Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder

Sven Cichon, Thomas W. Mühleisen, Franziska A. Degenhardt, Manuel Mattheisen, Xavier Miró, Jana Strohmaier, Michael Steffens, Christian Meesters, Stefan Herms, Moritz Weingarten, Lutz Priebe, Britta Haenisch, Michael Alexander, Jennifer Vollmer, René Breuer, Christine Schmäl, Peter Tessmann, Susanne Moebus, H. Erich Wichmann, Stefan SchreiberBertram Müller-Myhsok, Susanne Lucae, Stéphane Jamain, Marion Leboyer, Frank Bellivier, Bruno Etain, Chantal Henry, Jean Pierre Kahn, Simon Heath, Marian Hamshere, Michael C. O'Donovan, Michael J. Owen, Nick Craddock, Markus Schwarz, Helmut Vedder, Jutta Kammerer-Ciernioch, Andreas Reif, Johanna Sasse, Michael Bauer, Martin Hautzinger, Adam Wright, Philip B. Mitchell, Peter R. Schofield, Grant W. Montgomery, Sarah E. Medland, Scott D. Gordon, Nicholas G. Martin, Omar Gustafsson, Ole Andreassen, Srdjan Djurovic, Engilbert Sigurdsson, Stacy Steinberg, Hreinn Stefansson, Kari Stefansson, Lejla Kapur-Pojskic, Liliana Oruc, Fabio Rivas, Fermín Mayoral, Alexander Chuchalin, Gulja Babadjanova, Alexander S. Tiganov, Galina Pantelejeva, Lilia I. Abramova, Maria Grigoroiu-Serbanescu, Carmen C. Diaconu, Piotr M. Czerski, Joanna Hauser, Andreas Zimmer, Mark Lathrop, Thomas G. Schulze, Thomas F. Wienker, Johannes Schumacher, Wolfgang Maier, Peter Propping, Marcella Rietschel, Markus M. Nöthen

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

191 Scopus citations

Abstract

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 × 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 × 10^-4; odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 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.

Original language	English (US)
Pages (from-to)	372-381
Number of pages	10
Journal	American Journal of Human Genetics
Volume	88
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2011.01.017
State	Published - Mar 11 2011
Externally published	Yes

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2011.01.017

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Cichon, S., Mühleisen, T. W., Degenhardt, F. A., Mattheisen, M., Miró, X., Strohmaier, J., Steffens, M., Meesters, C., Herms, S., Weingarten, M., Priebe, L., Haenisch, B., Alexander, M., Vollmer, J., Breuer, R., Schmäl, C., Tessmann, P., Moebus, S., Wichmann, H. E., ... Nöthen, M. M. (2011). Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder. American Journal of Human Genetics, 88(3), 372-381. https://doi.org/10.1016/j.ajhg.2011.01.017

Cichon, S, Mühleisen, TW, Degenhardt, FA, Mattheisen, M, Miró, X, Strohmaier, J, Steffens, M, Meesters, C, Herms, S, Weingarten, M, Priebe, L, Haenisch, B, Alexander, M, Vollmer, J, Breuer, R, Schmäl, C, Tessmann, P, Moebus, S, Wichmann, HE, Schreiber, S, Müller-Myhsok, B, Lucae, S, Jamain, S, Leboyer, M, Bellivier, F, Etain, B, Henry, C, Kahn, JP, Heath, S, Hamshere, M, O'Donovan, MC, Owen, MJ, Craddock, N, Schwarz, M, Vedder, H, Kammerer-Ciernioch, J, Reif, A, Sasse, J, Bauer, M, Hautzinger, M, Wright, A, Mitchell, PB, Schofield, PR, Montgomery, GW, Medland, SE, Gordon, SD, Martin, NG, Gustafsson, O, Andreassen, O, Djurovic, S, Sigurdsson, E, Steinberg, S, Stefansson, H, Stefansson, K, Kapur-Pojskic, L, Oruc, L, Rivas, F, Mayoral, F, Chuchalin, A, Babadjanova, G, Tiganov, AS, Pantelejeva, G, Abramova, LI, Grigoroiu-Serbanescu, M, Diaconu, CC, Czerski, PM, Hauser, J, Zimmer, A, Lathrop, M, Schulze, TG, Wienker, TF, Schumacher, J, Maier, W, Propping, P, Rietschel, M & Nöthen, MM 2011, 'Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder', American Journal of Human Genetics, vol. 88, no. 3, pp. 372-381. https://doi.org/10.1016/j.ajhg.2011.01.017

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abstract = "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 × 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 × 10-4; odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 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.",

author = "Sven Cichon and M{\"u}hleisen, {Thomas W.} and Degenhardt, {Franziska A.} and Manuel Mattheisen and Xavier Mir{\'o} and Jana Strohmaier and Michael Steffens and Christian Meesters and Stefan Herms and Moritz Weingarten and Lutz Priebe and Britta Haenisch and Michael Alexander and Jennifer Vollmer and Ren{\'e} Breuer and Christine Schm{\"a}l and Peter Tessmann and Susanne Moebus and Wichmann, {H. Erich} and Stefan Schreiber and Bertram M{\"u}ller-Myhsok and Susanne Lucae and St{\'e}phane Jamain and Marion Leboyer and Frank Bellivier and Bruno Etain and Chantal Henry and Kahn, {Jean Pierre} and Simon Heath and Marian Hamshere and O'Donovan, {Michael C.} and Owen, {Michael J.} and Nick Craddock and Markus Schwarz and Helmut Vedder and Jutta Kammerer-Ciernioch and Andreas Reif and Johanna Sasse and Michael Bauer and Martin Hautzinger and Adam Wright and Mitchell, {Philip B.} and Schofield, {Peter R.} and Montgomery, {Grant W.} and Medland, {Sarah E.} and Gordon, {Scott D.} and Martin, {Nicholas G.} and Omar Gustafsson and Ole Andreassen and Srdjan Djurovic and Engilbert Sigurdsson and Stacy Steinberg and Hreinn Stefansson and Kari Stefansson and Lejla Kapur-Pojskic and Liliana Oruc and Fabio Rivas and Ferm{\'i}n Mayoral and Alexander Chuchalin and Gulja Babadjanova and Tiganov, {Alexander S.} and Galina Pantelejeva and Abramova, {Lilia I.} and Maria Grigoroiu-Serbanescu and Diaconu, {Carmen C.} and Czerski, {Piotr M.} and Joanna Hauser and Andreas Zimmer and Mark Lathrop and Schulze, {Thomas G.} and Wienker, {Thomas F.} and Johannes Schumacher and Wolfgang Maier and Peter Propping and Marcella Rietschel and N{\"o}then, {Markus M.}",

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doi = "10.1016/j.ajhg.2011.01.017",

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T1 - Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder

AU - Cichon, Sven

AU - Mühleisen, Thomas W.

AU - Degenhardt, Franziska A.

AU - Mattheisen, Manuel

AU - Miró, Xavier

AU - Strohmaier, Jana

AU - Steffens, Michael

AU - Meesters, Christian

AU - Herms, Stefan

AU - Weingarten, Moritz

AU - Priebe, Lutz

AU - Haenisch, Britta

AU - Alexander, Michael

AU - Vollmer, Jennifer

AU - Breuer, René

AU - Schmäl, Christine

AU - Tessmann, Peter

AU - Moebus, Susanne

AU - Wichmann, H. Erich

AU - Schreiber, Stefan

AU - Müller-Myhsok, Bertram

AU - Lucae, Susanne

AU - Jamain, Stéphane

AU - Leboyer, Marion

AU - Bellivier, Frank

AU - Etain, Bruno

AU - Henry, Chantal

AU - Kahn, Jean Pierre

AU - Heath, Simon

AU - Hamshere, Marian

AU - O'Donovan, Michael C.

AU - Owen, Michael J.

AU - Craddock, Nick

AU - Schwarz, Markus

AU - Vedder, Helmut

AU - Kammerer-Ciernioch, Jutta

AU - Reif, Andreas

AU - Sasse, Johanna

AU - Bauer, Michael

AU - Hautzinger, Martin

AU - Wright, Adam

AU - Mitchell, Philip B.

AU - Schofield, Peter R.

AU - Montgomery, Grant W.

AU - Medland, Sarah E.

AU - Gordon, Scott D.

AU - Martin, Nicholas G.

AU - Gustafsson, Omar

AU - Andreassen, Ole

AU - Djurovic, Srdjan

AU - Sigurdsson, Engilbert

AU - Steinberg, Stacy

AU - Stefansson, Hreinn

AU - Stefansson, Kari

AU - Kapur-Pojskic, Lejla

AU - Oruc, Liliana

AU - Rivas, Fabio

AU - Mayoral, Fermín

AU - Chuchalin, Alexander

AU - Babadjanova, Gulja

AU - Tiganov, Alexander S.

AU - Pantelejeva, Galina

AU - Abramova, Lilia I.

AU - Grigoroiu-Serbanescu, Maria

AU - Diaconu, Carmen C.

AU - Czerski, Piotr M.

AU - Hauser, Joanna

AU - Zimmer, Andreas

AU - Lathrop, Mark

AU - Schulze, Thomas G.

AU - Wienker, Thomas F.

AU - Schumacher, Johannes

AU - Maier, Wolfgang

AU - Propping, Peter

AU - Rietschel, Marcella

AU - Nöthen, Markus M.

PY - 2011/3/11

Y1 - 2011/3/11

N2 - 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 × 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 × 10-4; odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 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.

AB - 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 × 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 × 10-4; odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 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.

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AN - SCOPUS:79952485391

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JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

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ER -

Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder

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