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

Sven Cichon (1) , Marcella Rietschel (1) , Manuel Mattheisen (1) , Franziska Degenhardt (1) , Thomas Mühleisen (1) , Peter Kirsch (1) , Christine Esslinger (1) , Stefan Herms (1) , Ditte Demontis (1) , Michael Steffens (1) , Jana Strohmaier (1) , Britta Haenisch (1) , René Breuer (1) , Piotr M. Czerski (1) , Ina Giegling (1) , Eric Strengman (1) , Christine Schmäl (1) , Ole Mors (1) , Preben Bo Mortensen (1) , David Michael Hougaard (1) , Tf Orntoft (1) , Paweł Kapelski (1) , Lutz Priebe (1) , F. Buket Basmanav (1) , Andeas J. Forstner (1) , Per Hoffmann (1) , Sandra Meier (1) , Susanne Moebus (1) , Michael Alexander (1) , Rainald Mössner (1) , Heinz-Erich Wichmann (1) , Stefan Schreiber (1) , Fernando Rivandeneira (1) , Albert Hofman (1) , André Uitterlinden (1) , Thomas F Wienker (1) , Johannes Schumacher (1) , Joanna Hauser (1) , Wolfgang Maier (1) , Rita Cantor (1) , Susanne Erk (1) , Thomas G. Schulze (1) , Nick Craddock (1) , Michael Owen (1) , Michael O'Donovan (1) , Anders Børglum (1) , Dan Rujescu (1) , Henrik Walter (1) , Andreas Meyer-Lindenberg (1) , Markus Nothen (1) , Roel A. Ophoff (1)

1 Department of Genomics

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 (i.e. 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 1,169 clinically well-characterized and ethnically homogeneous SCZ patients from a confined area of Western Europe (464 from Germany, 705 from The Netherlands) and 3,714 ethnically matched controls (1,272 and 2,442, respectively). In a subsequent follow-up study of our top GWAS results, we included an additional 2,569 SCZ patients and 4,088 controls (from Germany, The Netherlands, and Denmark). Genetic variation in a region on chromosome 11 that contains the candidate genes , , , and was significantly associated with SCZ in the combined sample (= 11,540; = 3.89 x 10, OR= 1.25). This finding was replicated in 23,206 independent samples of European ancestry (= 0.0029, OR= 1.11). 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.

Mots clés: genome-wide association study; GWAS; schizophrenia; common variation; imaging genetics

Sven Cichon, Marcella Rietschel, Manuel Mattheisen, Franziska Degenhardt, Thomas Mühleisen, et al.. Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe. Molecular Psychiatry, 2011, ⟨10.1038/mp.2011.80⟩. ⟨hal-00659044⟩