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

M. Rietschel; M. Mattheisen; F. Degenhardt; T. W. Mühleisen; P. Kirsch; C. Esslinger; S. Herms; D. Demontis; M. Steffens; J. Strohmaier; B. Haenisch; R. Breuer; P. M. Czerski; I. Giegling; E. Strengman; C. Schmael; O. Mors; P. B. Mortensen; D. M. Hougaard; T. Orntoft; P. Kapelski; L. Priebe; F. B. Basmanav; A. J. Forstner; P. Hoffmann; S. Meier; J. Nikitopoulos; S. Moebus; M. Alexander; R. Mössner; H. E. Wichmann; S. Schreiber; F. Rivandeneira; A. Hofman; A. G. Uitterlinden; T. F. Wienker; J. Schumacher; J. Hauser; W. Maier; R. M. Cantor; S. Erk; T. G. Schulze; N. Craddock; M. J. Owen; M. C. O'Donovan; A. D. Børglum; D. Rujescu; H. Walter; A. Meyer-Lindenberg; M. M. Nöthen; R. A. Ophoff; S. Cichon

doi:10.1038/mp.2011.80

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

M. Rietschel, M. Mattheisen, F. Degenhardt, T. W. Mühleisen, P. Kirsch, C. Esslinger, S. Herms, D. Demontis, M. Steffens, J. Strohmaier, B. Haenisch, R. Breuer, P. M. Czerski, I. Giegling, E. Strengman, C. Schmael, O. Mors, P. B. Mortensen, D. M. Hougaard, T. OrntoftP. Kapelski, L. Priebe, F. B. Basmanav, A. J. Forstner, P. Hoffmann, S. Meier, J. Nikitopoulos, S. Moebus, M. Alexander, R. Mössner, H. E. Wichmann, S. Schreiber, F. Rivandeneira, A. Hofman, A. G. Uitterlinden, T. F. Wienker, J. Schumacher, J. Hauser, W. Maier, R. M. Cantor, S. Erk, T. G. Schulze, N. Craddock, M. J. Owen, M. C. O'Donovan, A. D. Børglum, D. Rujescu, H. Walter, A. Meyer-Lindenberg, M. M. Nöthen, R. A. Ophoff, S. Cichon

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Abstract

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 language	English
Pages (from-to)	906-917
Number of pages	12
Journal	Molecular Psychiatry
Volume	17
Issue number	9
DOIs	https://doi.org/10.1038/mp.2011.80
Publication status	Published - Sept 2012
Externally published	Yes

Bibliographical note

Funding Information:
We are grateful to all of the patients who contributed to this study. We also thank the probands from the community-based cohorts of PopGen, KORA, the Heinz Nixdorf Recall (HNR) study, the Rotterdam Elderly Study, as well as the Munich controls. This study was supported by the German Federal Ministry of Education and Research (BMBF), within the context of the National Genome Research Network plus (NGFNplus) and the MooDS-Net (grant 01GS08144 to SC and MMN, grant 01GS08147 to MR). MMN also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. Further funding came from the European Union Seventh Framework Programme (FP7/2007–2011) under grant agreement no. 242257 (ADAMS). The Heinz Nixdorf Recall cohort was established with the support of the Heinz Nixdorf Foundation (Dr G Schmidt, Chairman). This study was also supported by The Polish Ministry of Science and Higher Education (grant N N402 244035 to PMC), The Danish Council for Strategic Research (grant no. 2101–07-0059), H Lundbeck A/S, the Faculty of Health Sciences, Aarhus University and the Stanley Medical Research Institute. Genotyp-ing of the Dutch samples from Utrecht was sponsored by NIMH funding, R01 MH078075.

ASJC Scopus Subject Areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/mp.2011.80

Cite this

Rietschel, M., Mattheisen, M., Degenhardt, F., Mühleisen, T. W., Kirsch, P., Esslinger, C., Herms, S., Demontis, D., Steffens, M., Strohmaier, J., Haenisch, B., Breuer, R., Czerski, P. M., Giegling, I., Strengman, E., Schmael, C., Mors, O., Mortensen, P. B., Hougaard, D. M., ... Cichon, S. (2012). Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe. Molecular Psychiatry, 17(9), 906-917. https://doi.org/10.1038/mp.2011.80

Rietschel, M, Mattheisen, M, Degenhardt, F, Mühleisen, TW, Kirsch, P, Esslinger, C, Herms, S, Demontis, D, Steffens, M, Strohmaier, J, Haenisch, B, Breuer, R, Czerski, PM, Giegling, I, Strengman, E, Schmael, C, Mors, O, Mortensen, PB, Hougaard, DM, Orntoft, T, Kapelski, P, Priebe, L, Basmanav, FB, Forstner, AJ, Hoffmann, P, Meier, S, Nikitopoulos, J, Moebus, S, Alexander, M, Mössner, R, Wichmann, HE, Schreiber, S, Rivandeneira, F, Hofman, A, Uitterlinden, AG, Wienker, TF, Schumacher, J, Hauser, J, Maier, W, Cantor, RM, Erk, S, Schulze, TG, Craddock, N, Owen, MJ, O'Donovan, MC, Børglum, AD, Rujescu, D, Walter, H, Meyer-Lindenberg, A, Nöthen, MM, Ophoff, RA & Cichon, S 2012, 'Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe', Molecular Psychiatry, vol. 17, no. 9, pp. 906-917. https://doi.org/10.1038/mp.2011.80

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

abstract = "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.",

author = "M. Rietschel and M. Mattheisen and F. Degenhardt and M{\"u}hleisen, {T. W.} and P. Kirsch and C. Esslinger and S. Herms and D. Demontis and M. Steffens and J. Strohmaier and B. Haenisch and R. Breuer and Czerski, {P. M.} and I. Giegling and E. Strengman and C. Schmael and O. Mors and Mortensen, {P. B.} and Hougaard, {D. M.} and T. Orntoft and P. Kapelski and L. Priebe and Basmanav, {F. B.} and Forstner, {A. J.} and P. Hoffmann and S. Meier and J. Nikitopoulos and S. Moebus and M. Alexander and R. M{\"o}ssner and Wichmann, {H. E.} and S. Schreiber and F. Rivandeneira and A. Hofman and Uitterlinden, {A. G.} and Wienker, {T. F.} and J. Schumacher and J. Hauser and W. Maier and Cantor, {R. M.} and S. Erk and Schulze, {T. G.} and N. Craddock and Owen, {M. J.} and O'Donovan, {M. C.} and B{\o}rglum, {A. D.} and D. Rujescu and H. Walter and A. Meyer-Lindenberg and N{\"o}then, {M. M.} and Ophoff, {R. A.} and S. Cichon",

note = "Funding Information: We are grateful to all of the patients who contributed to this study. We also thank the probands from the community-based cohorts of PopGen, KORA, the Heinz Nixdorf Recall (HNR) study, the Rotterdam Elderly Study, as well as the Munich controls. This study was supported by the German Federal Ministry of Education and Research (BMBF), within the context of the National Genome Research Network plus (NGFNplus) and the MooDS-Net (grant 01GS08144 to SC and MMN, grant 01GS08147 to MR). MMN also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. Further funding came from the European Union Seventh Framework Programme (FP7/2007–2011) under grant agreement no. 242257 (ADAMS). The Heinz Nixdorf Recall cohort was established with the support of the Heinz Nixdorf Foundation (Dr G Schmidt, Chairman). This study was also supported by The Polish Ministry of Science and Higher Education (grant N N402 244035 to PMC), The Danish Council for Strategic Research (grant no. 2101–07-0059), H Lundbeck A/S, the Faculty of Health Sciences, Aarhus University and the Stanley Medical Research Institute. Genotyp-ing of the Dutch samples from Utrecht was sponsored by NIMH funding, R01 MH078075.",

year = "2012",

month = sep,

doi = "10.1038/mp.2011.80",

language = "English",

volume = "17",

pages = "906--917",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "9",

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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, M.

AU - Degenhardt, F.

AU - Mühleisen, T. W.

AU - Kirsch, P.

AU - Esslinger, C.

AU - Herms, S.

AU - Demontis, D.

AU - Steffens, M.

AU - Strohmaier, J.

AU - Haenisch, B.

AU - Breuer, R.

AU - Czerski, P. M.

AU - Giegling, I.

AU - Strengman, E.

AU - Schmael, C.

AU - Mors, O.

AU - Mortensen, P. B.

AU - Hougaard, D. M.

AU - Orntoft, T.

AU - Kapelski, P.

AU - Priebe, L.

AU - Basmanav, F. B.

AU - Forstner, A. J.

AU - Hoffmann, P.

AU - Meier, S.

AU - Nikitopoulos, J.

AU - Moebus, S.

AU - Alexander, M.

AU - Mössner, R.

AU - Wichmann, H. E.

AU - Schreiber, S.

AU - Rivandeneira, F.

AU - Hofman, A.

AU - Uitterlinden, A. G.

AU - Wienker, T. F.

AU - Schumacher, J.

AU - Hauser, J.

AU - Maier, W.

AU - Cantor, R. M.

AU - Erk, S.

AU - Schulze, T. G.

AU - Craddock, N.

AU - Owen, M. J.

AU - O'Donovan, M. C.

AU - Børglum, A. D.

AU - Rujescu, D.

AU - Walter, H.

AU - Meyer-Lindenberg, A.

AU - Nöthen, M. M.

AU - Ophoff, R. A.

AU - Cichon, S.

N1 - Funding Information: We are grateful to all of the patients who contributed to this study. We also thank the probands from the community-based cohorts of PopGen, KORA, the Heinz Nixdorf Recall (HNR) study, the Rotterdam Elderly Study, as well as the Munich controls. This study was supported by the German Federal Ministry of Education and Research (BMBF), within the context of the National Genome Research Network plus (NGFNplus) and the MooDS-Net (grant 01GS08144 to SC and MMN, grant 01GS08147 to MR). MMN also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. Further funding came from the European Union Seventh Framework Programme (FP7/2007–2011) under grant agreement no. 242257 (ADAMS). The Heinz Nixdorf Recall cohort was established with the support of the Heinz Nixdorf Foundation (Dr G Schmidt, Chairman). This study was also supported by The Polish Ministry of Science and Higher Education (grant N N402 244035 to PMC), The Danish Council for Strategic Research (grant no. 2101–07-0059), H Lundbeck A/S, the Faculty of Health Sciences, Aarhus University and the Stanley Medical Research Institute. Genotyp-ing of the Dutch samples from Utrecht was sponsored by NIMH funding, R01 MH078075.

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 (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.

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 (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.

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

UN SDGs

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