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

M Rietschel; M Mattheisen; F Degenhardt; René S Kahn; Don H Linszen; Jim van Os; Durk Wiersma; Richard Bruggeman; Wiepke Cahn; Lieuwe de Haan; Lydia Krabbendam; Inez Myin-Germeys; T W Mühleisen; P Kirsch; C Esslinger; S Herms; Ditte Demontis; M Steffens; J Strohmaier; B Haenisch; R Breuer; P M Czerski; I Giegling; E Strengman; C Schmael; Ole Mors; P B Mortensen; D M Hougaard; T Orntoft; P Kapelski; L Priebe; F B Basmanav; A J Forstner; Pablo Francisco F. 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; Robert Cantor; S Erk; T G Schulze; Hreinn Stefansson; Stacy Steinberg; Omar Gustafsson; Engilbert Sigurdsson; Hannes Petursson; Augustine Kong; Kari Stefansson; Olli P H Pietiläinen; Annamari Tuulio-Henriksson; Tiina Paunio; Jouko Lonnqvist; Jaana Suvisaari; Leena Peltonen; Mirella Ruggeri; Sarah Tosato; Muriel Walshe; Robin Murray; David A Collier; David St Clair; T. Hansen; A. Ingason; Klaus D Jakobsen; L. Duong; T. Werge; Ingrid Melle; Ole A Andreassen; Srdjan Djurovic; István Bitter; János M Réthelyi; Lilia Abramova; Vasily Kaleda; Vera Golimbet; Erik G Jönsson; L. Terenius; Ingrid Agartz; Ruud van Winkel; Gunter Kenis; Marc De Hert; Jan Veldink; Carsten Wiuf; Michael Didriksen; N Craddock; M J Owen; M C O'Donovan; Anders 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, René S Kahn, Don H Linszen, Jim van Os, Durk Wiersma, Richard Bruggeman, Wiepke Cahn, Lieuwe de Haan, Lydia Krabbendam, Inez Myin-Germeys, T W Mühleisen, P Kirsch, C Esslinger, S Herms, Ditte Demontis, M Steffens, J Strohmaier, B HaenischR Breuer, P M Czerski, I Giegling, E Strengman, C Schmael, Ole Mors, P B Mortensen, D M Hougaard, T Orntoft, P Kapelski, L Priebe, F B Basmanav, A J Forstner, Pablo Francisco F. 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, Robert Cantor, S Erk, T G Schulze, Hreinn Stefansson, Stacy Steinberg, Omar Gustafsson, Engilbert Sigurdsson, Hannes Petursson, Augustine Kong, Kari Stefansson, Olli P H Pietiläinen, Annamari Tuulio-Henriksson, Tiina Paunio, Jouko Lonnqvist, Jaana Suvisaari, Leena Peltonen, Mirella Ruggeri, Sarah Tosato, Muriel Walshe, Robin Murray, David A Collier, David St Clair, T. Hansen, A. Ingason, Klaus D Jakobsen, L. Duong, T. Werge, Ingrid Melle, Ole A Andreassen, Srdjan Djurovic, István Bitter, János M Réthelyi, Lilia Abramova, Vasily Kaleda, Vera Golimbet, Erik G Jönsson, L. Terenius, Ingrid Agartz, Ruud van Winkel, Gunter Kenis, Marc De Hert, Jan Veldink, Carsten Wiuf, Michael Didriksen, N Craddock, M J Owen, M C O'Donovan, Anders Børglum, D Rujescu, H Walter, A Meyer-Lindenberg, M M Nöthen, R A Ophoff, S Cichon

82 Citations (Scopus)

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 (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.

Original language	English
Journal	Molecular Psychiatry
Volume	17
Issue number	9
Pages (from-to)	906-917
Number of pages	12
ISSN	1359-4184
DOIs	https://doi.org/10.1038/mp.2011.80
Publication status	Published - Sept 2012
Externally published	Yes

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Rietschel, M., Mattheisen, M., Degenhardt, F., Kahn, R. S., Linszen, D. H., Os, J. V., Wiersma, D., Bruggeman, R., Cahn, W., de Haan, L., Krabbendam, L., Myin-Germeys, I., Mühleisen, T. W., Kirsch, P., Esslinger, C., Herms, S., Demontis, D., Steffens, M., Strohmaier, J., ... 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, Kahn, RS, Linszen, DH, Os, JV, Wiersma, D, Bruggeman, R, Cahn, W, de Haan, L, Krabbendam, L, Myin-Germeys, I, 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, PFF, Meier, S, Nikitopoulos, J, Moebus, S, Alexander, M, Mössner, R, Wichmann, H-E, Schreiber, S, Rivandeneira, F, Hofman, A, Uitterlinden, AG, Wienker, TF, Schumacher, J, Hauser, J, Maier, W, Cantor, R, Erk, S, Schulze, TG, Stefansson, H, Steinberg, S, Gustafsson, O, Sigurdsson, E, Petursson, H, Kong, A, Stefansson, K, Pietiläinen, OPH, Tuulio-Henriksson, A, Paunio, T, Lonnqvist, J, Suvisaari, J, Peltonen, L, Ruggeri, M, Tosato, S, Walshe, M, Murray, R, Collier, DA, Clair, DS, Hansen, T, Ingason, A, Jakobsen, KD, Duong, L, Werge, T, Melle, I, Andreassen, OA, Djurovic, S, Bitter, I, Réthelyi, JM, Abramova, L, Kaleda, V, Golimbet, V, Jönsson, EG, Terenius, L, Agartz, I, Winkel, RV, Kenis, G, Hert, MD, Veldink, J, Wiuf, C, Didriksen, M, Craddock, N, Owen, MJ, O'Donovan, MC, Børglum, A, 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 (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.",

author = "M Rietschel and M Mattheisen and F Degenhardt and Kahn, {Ren{\'e} S} and Linszen, {Don H} and Os, {Jim van} and Durk Wiersma and Richard Bruggeman and Wiepke Cahn and {de Haan}, Lieuwe and Lydia Krabbendam and Inez Myin-Germeys and M{\"u}hleisen, {T W} and P Kirsch and C Esslinger and S Herms and Ditte 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 Ole 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 Hoffmann, {Pablo Francisco F.} and S Meier and J Nikitopoulos and S Moebus and M Alexander and R M{\"o}ssner and H-E Wichmann 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 Robert Cantor and S Erk and Schulze, {T G} and Hreinn Stefansson and Stacy Steinberg and Omar Gustafsson and Engilbert Sigurdsson and Hannes Petursson and Augustine Kong and Kari Stefansson and Pietil{\"a}inen, {Olli P H} and Annamari Tuulio-Henriksson and Tiina Paunio and Jouko Lonnqvist and Jaana Suvisaari and Leena Peltonen and Mirella Ruggeri and Sarah Tosato and Muriel Walshe and Robin Murray and Collier, {David A} and Clair, {David St} and T. Hansen and A. Ingason and Jakobsen, {Klaus D} and L. Duong and T. Werge and Ingrid Melle and Andreassen, {Ole A} and Srdjan Djurovic and Istv{\'a}n Bitter and R{\'e}thelyi, {J{\'a}nos M} and Lilia Abramova and Vasily Kaleda and Vera Golimbet and J{\"o}nsson, {Erik G} and L. Terenius and Ingrid Agartz and Winkel, {Ruud van} and Gunter Kenis and Hert, {Marc De} and Jan Veldink and Carsten Wiuf and Michael Didriksen and N Craddock and Owen, {M J} and O'Donovan, {M C} and Anders B{\o}rglum and D Rujescu and H Walter and A Meyer-Lindenberg and N{\"o}then, {M M} and Ophoff, {R A} and S Cichon",

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 - Kahn, René S

AU - Linszen, Don H

AU - Os, Jim van

AU - Wiersma, Durk

AU - Bruggeman, Richard

AU - Cahn, Wiepke

AU - de Haan, Lieuwe

AU - Krabbendam, Lydia

AU - Myin-Germeys, Inez

AU - Mühleisen, T W

AU - Kirsch, P

AU - Esslinger, C

AU - Herms, S

AU - Demontis, Ditte

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, Ole

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, Pablo Francisco F.

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, Robert

AU - Erk, S

AU - Schulze, T G

AU - Stefansson, Hreinn

AU - Steinberg, Stacy

AU - Gustafsson, Omar

AU - Sigurdsson, Engilbert

AU - Petursson, Hannes

AU - Kong, Augustine

AU - Stefansson, Kari

AU - Pietiläinen, Olli P H

AU - Tuulio-Henriksson, Annamari

AU - Paunio, Tiina

AU - Lonnqvist, Jouko

AU - Suvisaari, Jaana

AU - Peltonen, Leena

AU - Ruggeri, Mirella

AU - Tosato, Sarah

AU - Walshe, Muriel

AU - Murray, Robin

AU - Collier, David A

AU - Clair, David St

AU - Hansen, T.

AU - Ingason, A.

AU - Jakobsen, Klaus D

AU - Duong, L.

AU - Werge, T.

AU - Melle, Ingrid

AU - Andreassen, Ole A

AU - Djurovic, Srdjan

AU - Bitter, István

AU - Réthelyi, János M

AU - Abramova, Lilia

AU - Kaleda, Vasily

AU - Golimbet, Vera

AU - Jönsson, Erik G

AU - Terenius, L.

AU - Agartz, Ingrid

AU - Winkel, Ruud van

AU - Kenis, Gunter

AU - Hert, Marc De

AU - Veldink, Jan

AU - Wiuf, Carsten

AU - Didriksen, Michael

AU - Craddock, N

AU - Owen, M J

AU - O'Donovan, M C

AU - Børglum, Anders

AU - Rujescu, D

AU - Walter, H

AU - Meyer-Lindenberg, A

AU - Nöthen, M M

AU - Ophoff, R A

AU - Cichon, S

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.

U2 - 10.1038/mp.2011.80

DO - 10.1038/mp.2011.80

M3 - Journal article

C2 - 21747397

SN - 1359-4184

VL - 17

SP - 906

EP - 917

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 9

ER -

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

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