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
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American journal of human genetics
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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.