TY - JOUR
T1 - Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe
AU - Rietschel, M.
AU - Mattheisen, Manuel
AU - Degenhardt, F.
AU - Muehleisen, Thomas W.
AU - Kirsch, P.
AU - Esslinger, C.
AU - Herms, Stefan
AU - Demontis, Ditte
AU - Steffens, Michael
AU - Strohmaier, Jana
AU - Haenisch, B.
AU - Breuer, R.
AU - Czerski, Piotr M.
AU - Giegling, Ina
AU - Strengman, E.
AU - Schmael, C.
AU - Mors, Ole
AU - Mortensen, Preben B.
AU - Hougaard, David M.
AU - Orntoft, T.F.
AU - Kapelski, P.
AU - Priebe, L.
AU - Basmanav, F. B.
AU - Forstner, Andreas J.
AU - Hoffmann, P.
AU - Meier, Sandra
AU - Nikitopoulos, J.
AU - Moebus, S.
AU - Alexander, M.
AU - Moessner, R
AU - Wichmann, H Erich
AU - Schreiber, S.
AU - Rivandeneira, F.
AU - Hofman, A.
AU - Uitterlinden, Andre G.
AU - Wienker, Thomas F.
AU - Schumacher, J.
AU - Hauser, Joanna
AU - Maier, Günter W
AU - Cantor, Rita M.
AU - Erk, Susanne
AU - Schulze, Thomas G.
AU - Craddock, Nick
AU - Owen, Michael J.
AU - O'Donovan, Michael C.
AU - Borglum, Anders D.
AU - Rujescu, Dan
AU - Walter, H.
AU - Meyer-Lindenberg, Andreas
AU - GRP Investigators
AU - SGENE-Plus Consortium
AU - van Os, Jim
AU - Cichon, Sven
PY - 2012/9
Y1 - 2012/9
N2 - 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 (n=11?540; P=3.89 ? 10(-9), odds ratio (OR)=1.25). This finding was replicated in 23?206 independent samples of European ancestry (P=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.
AB - 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 (n=11?540; P=3.89 ? 10(-9), odds ratio (OR)=1.25). This finding was replicated in 23?206 independent samples of European ancestry (P=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.
KW - common variation
KW - genome-wide association study
KW - GWAS
KW - imaging genetics
KW - schizophrenia
U2 - 10.1038/mp.2011.80
DO - 10.1038/mp.2011.80
M3 - Article
C2 - 21747397
SN - 1359-4184
VL - 17
SP - 906
EP - 917
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 9
ER -