Common variants at VRK2 and TCF4 conferring risk of schizophrenia

Stacy Steinberg; Simone de Jong; Ole A. Andreassen; Thomas Werge; Anders D. Børglum; Ole Mors; Preben B. Mortensen; Omar Gustafsson; Javier Costas; Olli P.H. Pietiläinen; Ditte Demontis; Sergi Papiol; Johanna Huttenlocher; Manuel Mattheisen; René Breuer; Evangelos Vassos; Ina Giegling; Gillian Fraser; Nicholas Walker; Annamari Tuulio-Henriksson; Jaana Suvisaari; Jouko Lönnqvist; Tiina Paunio; Ingrid Agartz; Ingrid Melle; Srdjan Djurovic; Eric Strengman; Gesche Jürgens; Birte Glenthøj; Lars Terenius; David M. Hougaard; Torben Ørntoft; Carsten Wiuf; Michael Didriksen; Mads V. Hollegaard; Merete Nordentoft; Ruud van Winkel; Gunter Kenis; Lilia Abramova; Vasily Kaleda; Manuel Arrojo; Julio Sanjuán; Celso Arango; Swetlana Sperling; Moritz Rossner; Michele Ribolsi; Valentina Magni; Alberto Siracusano; Claus Christiansen; Lambertus A. Kiemeney; Jan Veldink; Leonard van den Berg; Andres Ingason; Pierandrea Muglia; Robin Murray; Markus M. Nöthen; Engilbert Sigurdsson; Hannes Petursson; Unnur Thorsteinsdottir; Augustine Kong; I. Alex Rubino; Marc de Hert; János M. Réthelyi; István Bitter; Erik G. Jönsson; Vera Golimbet; Angel Carracedo; Hannelore Ehrenreich; Nick Craddock; Michael J. Owen; Michael C. O'Donovan; Mirella Ruggeri; Sarah Tosato; Leena Peltonen; Roel A. Ophoff; David A. Collier; David St Clair; Marcella Rietschel; Sven Cichon; Hreinn Stefansson; Dan Rujescu; Kari Stefansson

doi:10.1093/hmg/ddr325

Common variants at VRK2 and TCF4 conferring risk of schizophrenia

Stacy Steinberg, Simone de Jong, Ole A. Andreassen, Thomas Werge, Anders D. Børglum, Ole Mors, Preben B. Mortensen, Omar Gustafsson, Javier Costas, Olli P.H. Pietiläinen, Ditte Demontis, Sergi Papiol, Johanna Huttenlocher, Manuel Mattheisen, René Breuer, Evangelos Vassos, Ina Giegling, Gillian Fraser, Nicholas Walker, Annamari Tuulio-HenrikssonJaana Suvisaari, Jouko Lönnqvist, Tiina Paunio, Ingrid Agartz, Ingrid Melle, Srdjan Djurovic, Eric Strengman, Gesche Jürgens, Birte Glenthøj, Lars Terenius, David M. Hougaard, Torben Ørntoft, Carsten Wiuf, Michael Didriksen, Mads V. Hollegaard, Merete Nordentoft, Ruud van Winkel, Gunter Kenis, Lilia Abramova, Vasily Kaleda, Manuel Arrojo, Julio Sanjuán, Celso Arango, Swetlana Sperling, Moritz Rossner, Michele Ribolsi, Valentina Magni, Alberto Siracusano, Claus Christiansen, Lambertus A. Kiemeney, Jan Veldink, Leonard van den Berg, Andres Ingason, Pierandrea Muglia, Robin Murray, Markus M. Nöthen, Engilbert Sigurdsson, Hannes Petursson, Unnur Thorsteinsdottir, Augustine Kong, I. Alex Rubino, Marc de Hert, János M. Réthelyi, István Bitter, Erik G. Jönsson, Vera Golimbet, Angel Carracedo, Hannelore Ehrenreich, Nick Craddock, Michael J. Owen, Michael C. O'Donovan, Mirella Ruggeri, Sarah Tosato, Leena Peltonen, Roel A. Ophoff, David A. Collier, David St Clair, Marcella Rietschel, Sven Cichon, Hreinn Stefansson, Dan Rujescu, Kari Stefansson^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

157 Citations (Scopus)

Abstract

Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10^-9] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10^-9).

Original language	English
Article number	ddr325
Pages (from-to)	4076-4081
Number of pages	6
Journal	Human Molecular Genetics
Volume	20
Issue number	20
DOIs	https://doi.org/10.1093/hmg/ddr325
Publication status	Published - Oct 2011

Bibliographical note

Funding Information:
This work was supported by the European Union [grant numbers LSHM-CT-2006-037761 (Project SGENE), PIAP-GA-2008-218251 (Project PsychGene), HEALTH-F2-2009-223423 (Project PsychCNVs)]; the National Genome Research Network of the German Federal Ministry of Education and Research (BMBF) [grant numbers 01GS08144 (MooDS-Net), 01GS08147 (NGFNplus)]; the National Institute of Mental Health [R01 MH078075, and N01 MH900001, MH074027 to the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project]; the Centre of Excellence for Complex Disease Genetics of the Academy of Finland (grant numbers 213506, 129680); the Biocentrum Helsinki Foundation and Research Program for Molecular Medicine, Faculty of Medicine, University of Helsinki; the Stanley Medical Research Institute; the Danish Council for Strategic Research (grant number 2101-07-0059); H. Lundbeck A/S; the Research Council of Norway (grant number 163070/V50); the South-East Norway Health Authority (grant number 2004-123); the Medical Research Council; Ministerio de Sanidad y Consumo, Spain (grant number PI081522 to J.C.); Xunta de Galicia (grant number 08CSA005208PR to A.C.); the Swedish Research Council; the Wellcome Trust (grant number 083948/Z/07/Z as part of the Wellcome Trust Case Control Consortium 2); the Max Planck Society and Eli Lilly and Company (genotyping for CATIE and part of the TOP sample).

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Steinberg, S., de Jong, S., Andreassen, O. A., Werge, T., Børglum, A. D., Mors, O., Mortensen, P. B., Gustafsson, O., Costas, J., Pietiläinen, O. P. H., Demontis, D., Papiol, S., Huttenlocher, J., Mattheisen, M., Breuer, R., Vassos, E., Giegling, I., Fraser, G., Walker, N., ... Stefansson, K. (2011). Common variants at VRK2 and TCF4 conferring risk of schizophrenia. Human Molecular Genetics, 20(20), 4076-4081. [ddr325]. https://doi.org/10.1093/hmg/ddr325

@article{4da4e09d0aad43dcbeaa8b717f0d1c19,

title = "Common variants at VRK2 and TCF4 conferring risk of schizophrenia",

abstract = "Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10-9] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10-9).",

author = "Stacy Steinberg and {de Jong}, Simone and Andreassen, {Ole A.} and Thomas Werge and B{\o}rglum, {Anders D.} and Ole Mors and Mortensen, {Preben B.} and Omar Gustafsson and Javier Costas and Pietil{\"a}inen, {Olli P.H.} and Ditte Demontis and Sergi Papiol and Johanna Huttenlocher and Manuel Mattheisen and Ren{\'e} Breuer and Evangelos Vassos and Ina Giegling and Gillian Fraser and Nicholas Walker and Annamari Tuulio-Henriksson and Jaana Suvisaari and Jouko L{\"o}nnqvist and Tiina Paunio and Ingrid Agartz and Ingrid Melle and Srdjan Djurovic and Eric Strengman and Gesche J{\"u}rgens and Birte Glenth{\o}j and Lars Terenius and Hougaard, {David M.} and Torben {\O}rntoft and Carsten Wiuf and Michael Didriksen and Hollegaard, {Mads V.} and Merete Nordentoft and {van Winkel}, Ruud and Gunter Kenis and Lilia Abramova and Vasily Kaleda and Manuel Arrojo and Julio Sanju{\'a}n and Celso Arango and Swetlana Sperling and Moritz Rossner and Michele Ribolsi and Valentina Magni and Alberto Siracusano and Claus Christiansen and Kiemeney, {Lambertus A.} and Jan Veldink and {van den Berg}, Leonard and Andres Ingason and Pierandrea Muglia and Robin Murray and N{\"o}then, {Markus M.} and Engilbert Sigurdsson and Hannes Petursson and Unnur Thorsteinsdottir and Augustine Kong and Rubino, {I. Alex} and {de Hert}, Marc and R{\'e}thelyi, {J{\'a}nos M.} and Istv{\'a}n Bitter and J{\"o}nsson, {Erik G.} and Vera Golimbet and Angel Carracedo and Hannelore Ehrenreich and Nick Craddock and Owen, {Michael J.} and O'Donovan, {Michael C.} and Mirella Ruggeri and Sarah Tosato and Leena Peltonen and Ophoff, {Roel A.} and Collier, {David A.} and {St Clair}, David and Marcella Rietschel and Sven Cichon and Hreinn Stefansson and Dan Rujescu and Kari Stefansson",

note = "Funding Information: This work was supported by the European Union [grant numbers LSHM-CT-2006-037761 (Project SGENE), PIAP-GA-2008-218251 (Project PsychGene), HEALTH-F2-2009-223423 (Project PsychCNVs)]; the National Genome Research Network of the German Federal Ministry of Education and Research (BMBF) [grant numbers 01GS08144 (MooDS-Net), 01GS08147 (NGFNplus)]; the National Institute of Mental Health [R01 MH078075, and N01 MH900001, MH074027 to the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project]; the Centre of Excellence for Complex Disease Genetics of the Academy of Finland (grant numbers 213506, 129680); the Biocentrum Helsinki Foundation and Research Program for Molecular Medicine, Faculty of Medicine, University of Helsinki; the Stanley Medical Research Institute; the Danish Council for Strategic Research (grant number 2101-07-0059); H. Lundbeck A/S; the Research Council of Norway (grant number 163070/V50); the South-East Norway Health Authority (grant number 2004-123); the Medical Research Council; Ministerio de Sanidad y Consumo, Spain (grant number PI081522 to J.C.); Xunta de Galicia (grant number 08CSA005208PR to A.C.); the Swedish Research Council; the Wellcome Trust (grant number 083948/Z/07/Z as part of the Wellcome Trust Case Control Consortium 2); the Max Planck Society and Eli Lilly and Company (genotyping for CATIE and part of the TOP sample).",

year = "2011",

month = oct,

doi = "10.1093/hmg/ddr325",

language = "English",

volume = "20",

pages = "4076--4081",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "20",

}

Steinberg, S, de Jong, S, Andreassen, OA, Werge, T, Børglum, AD, Mors, O, Mortensen, PB, Gustafsson, O, Costas, J, Pietiläinen, OPH, Demontis, D, Papiol, S, Huttenlocher, J, Mattheisen, M, Breuer, R, Vassos, E, Giegling, I, Fraser, G, Walker, N, Tuulio-Henriksson, A, Suvisaari, J, Lönnqvist, J, Paunio, T, Agartz, I, Melle, I, Djurovic, S, Strengman, E, Jürgens, G, Glenthøj, B, Terenius, L, Hougaard, DM, Ørntoft, T, Wiuf, C, Didriksen, M, Hollegaard, MV, Nordentoft, M, van Winkel, R, Kenis, G, Abramova, L, Kaleda, V, Arrojo, M, Sanjuán, J, Arango, C, Sperling, S, Rossner, M, Ribolsi, M, Magni, V, Siracusano, A, Christiansen, C, Kiemeney, LA, Veldink, J, van den Berg, L, Ingason, A, Muglia, P, Murray, R, Nöthen, MM, Sigurdsson, E, Petursson, H, Thorsteinsdottir, U, Kong, A, Rubino, IA, de Hert, M, Réthelyi, JM, Bitter, I, Jönsson, EG, Golimbet, V, Carracedo, A, Ehrenreich, H, Craddock, N, Owen, MJ, O'Donovan, MC, Ruggeri, M, Tosato, S, Peltonen, L, Ophoff, RA, Collier, DA, St Clair, D, Rietschel, M, Cichon, S, Stefansson, H, Rujescu, D & Stefansson, K 2011, 'Common variants at VRK2 and TCF4 conferring risk of schizophrenia', Human Molecular Genetics, vol. 20, no. 20, ddr325, pp. 4076-4081. https://doi.org/10.1093/hmg/ddr325

TY - JOUR

T1 - Common variants at VRK2 and TCF4 conferring risk of schizophrenia

AU - Steinberg, Stacy

AU - de Jong, Simone

AU - Andreassen, Ole A.

AU - Werge, Thomas

AU - Børglum, Anders D.

AU - Mors, Ole

AU - Mortensen, Preben B.

AU - Gustafsson, Omar

AU - Costas, Javier

AU - Pietiläinen, Olli P.H.

AU - Demontis, Ditte

AU - Papiol, Sergi

AU - Huttenlocher, Johanna

AU - Mattheisen, Manuel

AU - Breuer, René

AU - Vassos, Evangelos

AU - Giegling, Ina

AU - Fraser, Gillian

AU - Walker, Nicholas

AU - Tuulio-Henriksson, Annamari

AU - Suvisaari, Jaana

AU - Lönnqvist, Jouko

AU - Paunio, Tiina

AU - Agartz, Ingrid

AU - Melle, Ingrid

AU - Djurovic, Srdjan

AU - Strengman, Eric

AU - Jürgens, Gesche

AU - Glenthøj, Birte

AU - Terenius, Lars

AU - Hougaard, David M.

AU - Ørntoft, Torben

AU - Wiuf, Carsten

AU - Didriksen, Michael

AU - Hollegaard, Mads V.

AU - Nordentoft, Merete

AU - van Winkel, Ruud

AU - Kenis, Gunter

AU - Abramova, Lilia

AU - Kaleda, Vasily

AU - Arrojo, Manuel

AU - Sanjuán, Julio

AU - Arango, Celso

AU - Sperling, Swetlana

AU - Rossner, Moritz

AU - Ribolsi, Michele

AU - Magni, Valentina

AU - Siracusano, Alberto

AU - Christiansen, Claus

AU - Kiemeney, Lambertus A.

AU - Veldink, Jan

AU - van den Berg, Leonard

AU - Ingason, Andres

AU - Muglia, Pierandrea

AU - Murray, Robin

AU - Nöthen, Markus M.

AU - Sigurdsson, Engilbert

AU - Petursson, Hannes

AU - Thorsteinsdottir, Unnur

AU - Kong, Augustine

AU - Rubino, I. Alex

AU - de Hert, Marc

AU - Réthelyi, János M.

AU - Bitter, István

AU - Jönsson, Erik G.

AU - Golimbet, Vera

AU - Carracedo, Angel

AU - Ehrenreich, Hannelore

AU - Craddock, Nick

AU - Owen, Michael J.

AU - O'Donovan, Michael C.

AU - Ruggeri, Mirella

AU - Tosato, Sarah

AU - Peltonen, Leena

AU - Ophoff, Roel A.

AU - Collier, David A.

AU - St Clair, David

AU - Rietschel, Marcella

AU - Cichon, Sven

AU - Stefansson, Hreinn

AU - Rujescu, Dan

AU - Stefansson, Kari

N1 - Funding Information: This work was supported by the European Union [grant numbers LSHM-CT-2006-037761 (Project SGENE), PIAP-GA-2008-218251 (Project PsychGene), HEALTH-F2-2009-223423 (Project PsychCNVs)]; the National Genome Research Network of the German Federal Ministry of Education and Research (BMBF) [grant numbers 01GS08144 (MooDS-Net), 01GS08147 (NGFNplus)]; the National Institute of Mental Health [R01 MH078075, and N01 MH900001, MH074027 to the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project]; the Centre of Excellence for Complex Disease Genetics of the Academy of Finland (grant numbers 213506, 129680); the Biocentrum Helsinki Foundation and Research Program for Molecular Medicine, Faculty of Medicine, University of Helsinki; the Stanley Medical Research Institute; the Danish Council for Strategic Research (grant number 2101-07-0059); H. Lundbeck A/S; the Research Council of Norway (grant number 163070/V50); the South-East Norway Health Authority (grant number 2004-123); the Medical Research Council; Ministerio de Sanidad y Consumo, Spain (grant number PI081522 to J.C.); Xunta de Galicia (grant number 08CSA005208PR to A.C.); the Swedish Research Council; the Wellcome Trust (grant number 083948/Z/07/Z as part of the Wellcome Trust Case Control Consortium 2); the Max Planck Society and Eli Lilly and Company (genotyping for CATIE and part of the TOP sample).

PY - 2011/10

Y1 - 2011/10

N2 - Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10-9] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10-9).

AB - Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10-9] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10-9).

UR - http://www.scopus.com/inward/record.url?scp=80053159517&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddr325

DO - 10.1093/hmg/ddr325

M3 - Article

C2 - 21791550

AN - SCOPUS:80053159517

SN - 0964-6906

VL - 20

SP - 4076

EP - 4081

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 20

M1 - ddr325

ER -

Common variants at VRK2 and TCF4 conferring risk of schizophrenia

Abstract

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