Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe

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  • M. Rietschel, University of Heidelberg
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  • Manuel Mattheisen
  • J. Strohmaier, University of Heidelberg
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  • R. Breuer, University of Heidelberg
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  • C. Schmael, University of Heidelberg
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  • S. Meier, University of Heidelberg, Denmark
  • J. Nikitopoulos, University of Heidelberg
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  • T.G. Schulze, University of Heidelberg
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  • F. Degenhardt, University of Bonn
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  • T.W. Mühleisen, University of Bonn
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  • S. Herms, University of Bonn
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  • B. Haenisch, University of Bonn
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  • L. Priebe, University of Bonn
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  • F.B. Basmanav, University of Bonn
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  • A.J. Forstner, University of Bonn
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  • P. Hoffmann, University of Bonn
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  • M. Alexander, University of Bonn
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  • Johannes Schumacher, Skov, natur og biomasse, Denmark
  • M.M. Nöthen, University of Bonn
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  • M. Steffens, University of Bonn
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  • T.F. Wienker, University of Bonn
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  • P. Kirsch, Central Institute of Mental Health
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  • C. Esslinger, Central Institute of Mental Health
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  • A. Meyer-Lindenberg, Central Institute of Mental Health
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  • D. Demontis, Aarhus University, Denmark
  • A.D. Børglum, Aarhus University, Denmark
  • P.M. Czerski, Poznan University of Medical Sciences
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  • P. Kapelski, Poznan University of Medical Sciences
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  • S. Cichon, University of Bonn
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  • J. Hauser, Poznan University of Medical Sciences
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  • I. Giegling, Ludwig-Maximilians-University
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  • D. Rujescu, Ludwig-Maximilians-University
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  • E. Strengman, University Medical Center Utrecht
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  • R.A. Ophoff, University Medical Center Utrecht
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  • O. Mors, Aarhus University Hospital, Denmark
  • P.B. Mortensen, Aarhus University, Denmark
  • D.M. Hougaard, State Serum Institute, Denmark
  • T. Orntoft, Aarhus University Hospital, Denmark
  • S. Moebus, University Duisburg-Essen
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  • R. Mössner, University of Bonn
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  • W. Maier, University of Bonn
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  • H.-E. Wichmann, German Research Center for Environmental Health
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  • S. Schreiber, Christian-Albrechts-University Kiel
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  • F. Rivandeneira, Eramsmus Medical Center Rotterdam
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  • A.G. Uitterlinden, Eramsmus Medical Center Rotterdam
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  • A. Hofman, Erasmus University Medical Center
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  • Robert Cantor, Institut for Fysik, Kemi og Farmaci, Denmark
  • S. Erk, Charite Medical University Berlin
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  • H. Walter, Charite Medical University Berlin
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  • N. Craddock, Cardiff University
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  • M.J. Owen, Cardiff University
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  • M.C. O'Donovan, Cardiff University
Recent molecular studies have implicated common alleles of small to moderate effect and rare alleles with larger effect sizes in the genetic architecture of schizophrenia (SCZ). It is expected that the reliable detection of risk variants with very small effect sizes can only be achieved through the recruitment of very large samples of patients and controls (that is tens of thousands), or large, potentially more homogeneous samples that have been recruited from confined geographical areas using identical diagnostic criteria. Applying the latter strategy, we performed a genome-wide association study (GWAS) of 1169 clinically well characterized and ethnically homogeneous SCZ patients from a confined area of Western Europe (464 from Germany, 705 from The Netherlands) and 3714 ethnically matched controls (1272 and 2442, respectively). In a subsequent follow-up study of our top GWAS results, we included an additional 2569 SCZ patients and 4088 controls (from Germany, The Netherlands and Denmark). Genetic variation in a region on chromosome 11 that contains the candidate genes AMBRA1, DGKZ, CHRM4 and MDK was significantly associated with SCZ in the combined sample (n11 540; P3.89 × 10 9, odds ratio (OR)1.25). This finding was replicated in 23 206 independent samples of European ancestry (P0.0029, OR1.11). In a subsequent imaging genetics study, healthy carriers of the risk allele exhibited altered activation in the cingulate cortex during a cognitive control task. The area of interest is a critical interface between emotion regulation and cognition that is structurally and functionally abnormal in SCZ and bipolar disorder.
Original languageEnglish
JournalMolecular Psychiatry
Volume17
Issue9
Pages (from-to)906-917
Number of pages12
ISSN1359-4184
DOIs
Publication statusPublished - 1 Sep 2012
Externally publishedYes

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