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

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• 作者：Sven Cichon¹ ; ² ; ³ ; ⁴⁵ ; ^{sven.cichon@uni-bonn.de} ; Thomas  ; W. Mü ; hleisen² ; ³ ; ⁴⁵ ; Franziska  ; A. Degenhardt² ; ³ ; Manuel Mattheisen² ; ³ ; ⁴ ; Xavier Miró ; ⁵ ; Jana Strohmaier⁶ ; Michael Steffens⁴ ; Christian Meesters⁴ ; Stefan Herms² ; ³ ; Moritz Weingarten² ; ³ ; Lutz Priebe² ; ³ ; Britta Haenisch² ; ³ ; Michael Alexander² ; ³ ; Jennifer Vollmer² ; ³ ; René ; Breuer⁶ ; Christine Schmä ; l⁶ ; Peter Tessmann² ; ³ ; Susanne Moebus⁷ ; H.-Erich Wichmann⁸ ; ⁹ ; ¹⁰ ; Stefan Schreiber¹¹ ; Bertram Mü ; ller-Myhsok¹² ; Susanne Lucae¹² ; Sté ; phane Jamain¹³ ; ¹⁴ ; ¹⁵ ; Marion Leboyer¹³ ; ¹⁴ ; ¹⁵ ; Frank Bellivier¹³ ; ¹⁴ ; ¹⁵ ; Bruno Etain¹³ ; ¹⁴ ; ¹⁵ ; Chantal Henry¹³ ; ¹⁴ ; ¹⁵ ; Jean-Pierre Kahn¹⁶ ; Simon Heath¹⁷ ; Bipolar Disorder Genome Study (BiGS) Consortium¹⁸ ; Marian Hamshere¹⁹ ; Michael  ; C. O'Donovan¹⁹ ; Michael  ; J. Owen¹⁹ ; Nick Craddock¹⁹ ; Markus Schwarz²⁰ ; Helmut Vedder²⁰ ; Jutta Kammerer-Ciernioch²⁰ ; Andreas Reif²¹ ; Johanna Sasse²² ; Michael Bauer²² ; Martin Hautzinger²³ ; Adam Wright²⁴ ; ²⁵ ; Philip  ; B. Mitchell²⁴ ; ²⁵ ; Peter  ; R. Schofield²⁶ ; ²⁷ ; Grant  ; W. Montgomery²⁸ ; Sarah  ; E. Medland²⁸ ; Scott  ; D. Gordon²⁸ ; Nicholas  ; G. Martin²⁸ ; Omar Gustafsson²⁹ ; Ole Andreassen²⁹ ; ³⁰ ; Srdjan Djurovic²⁹ ; ³⁰ ; ³¹ ; Engilbert Sigurdsson³² ; Stacy Steinberg³³ ; Hreinn Stefansson³³ ; Kari Stefansson³³ ; ³⁴ ; Lejla Kapur-Pojskic³⁵ ; Liliana Oruc³⁶ ; Fabio Rivas³⁷ ; Fermí ; n Mayoral³⁷ ; Alexander Chuchalin³⁸ ; Gulja Babadjanova³⁸ ; Alexander  ; S. Tiganov³⁹ ; Galina Pantelejeva³⁹ ; Lilia  ; I. Abramova³⁹ ; Maria Grigoroiu-Serbanescu⁴⁰ ; Carmen  ; C. Diaconu⁴¹ ; Piotr  ; M. Czerski⁴² ; Joanna Hauser⁴² ; Andreas Zimmer⁵ ; Mark Lathrop¹⁷ ; Thomas  ; G. Schulze⁴³ ; Thomas  ; F. Wienker⁴ ; Johannes Schumacher³ ; Wolfgang Maier⁴⁴ ; Peter Propping³ ; Marcella Rietschel⁶ ; ⁴⁵ ; Markus  ; M. Nö ; then² ; ³ ; ⁴⁵
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：11 March 2011
• 年：2011
• 卷：88
• 期：3
• 页码：396
• 全文大小：56 K

文摘

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.