Common variants conferring risk of schizophrenia

Hreinn Stefansson; Roel A. Ophoff; Stacy Steinberg; Ole A. Andreassen; Sven Cichon; Dan Rujescu; Thomas Werge; Olli P. H. Pietilainen; Ole Mors; Preben B. Mortensen; Engilbert Sigurdsson; Omar Gustafsson; Mette Nyegaard; Annamari Tuulio-Henriksson; Andres Ingason; Thomas Hansen; Jaana Suvisaari; Jouko Lonnqvist; Tiina Paunio; Anders D. Borglum; Annette Hartmann; Anders Fink-Jensen; Merete Nordentoft; David Hougaard; Bent Norgaard-Pedersen; Yvonne Bottcher; Jes Olesen; Rene Breuer; Hans-Jurgen Moeller; Ina Giegling; Henrik B. Rasmussen; Sally Timm; Manuel Mattheisen; Istvan Bitter; Janos M. Rethelyi; Brynja B. Magnusdottir; Thordur Sigmundsson; Pall Olason; Gisli Mason; Jeffrey R. Gulcher; Magnus Haraldsson; Ragnheidur Fossdal; Thorgeir E. Thorgeirsson; Unnur Thorsteinsdottir; Mirella Ruggeri; Sarah Tosato; Barbara Franke; Eric Strengman; Lambertus A. Kiemeney; Ingrid Melle; Srdjan Djurovic; Lilia Abramova; Vasily Kaleda; Julio Sanjuan; Rosa de Frutos; Elvira Bramon; Evangelos Vassos; Gillian Fraser; Ulrich Ettinger; Marco Picchioni; Nicholas Walker; Timi Toulopoulou; Anna C. Need; Dongliang Ge; Joeng Lim Yoon; Kevin V. Shianna; Nelson B. Freimer; Rita M. Cantor; Robin Murray; Augustine Kong; Vera Golimbet; Angel Carracedo; Celso Arango; Javier Costas; Erik G. Joensson; Lars Terenius; Ingrid Agartz; Hannes Petursson; Markus M. Nothen; Marcella Rietschel; Paul M. Matthews; Pierandrea Muglia; Leena Peltonen; David St Clair; David B. Goldstein; Kari Stefansson; David A. Collier

doi:10.1038/nature08186

Common variants conferring risk of schizophrenia

Hreinn Stefansson, Roel A. Ophoff, Stacy Steinberg, Ole A. Andreassen, Sven Cichon, Dan Rujescu, Thomas Werge, Olli P. H. Pietilainen, Ole Mors, Preben B. Mortensen, Engilbert Sigurdsson, Omar Gustafsson, Mette Nyegaard, Annamari Tuulio-Henriksson, Andres Ingason, Thomas Hansen, Jaana Suvisaari, Jouko Lonnqvist, Tiina Paunio, Anders D. BorglumAnnette Hartmann, Anders Fink-Jensen, Merete Nordentoft, David Hougaard, Bent Norgaard-Pedersen, Yvonne Bottcher, Jes Olesen, Rene Breuer, Hans-Jurgen Moeller, Ina Giegling, Henrik B. Rasmussen, Sally Timm, Manuel Mattheisen, Istvan Bitter, Janos M. Rethelyi, Brynja B. Magnusdottir, Thordur Sigmundsson, Pall Olason, Gisli Mason, Jeffrey R. Gulcher, Magnus Haraldsson, Ragnheidur Fossdal, Thorgeir E. Thorgeirsson, Unnur Thorsteinsdottir, Mirella Ruggeri, Sarah Tosato, Barbara Franke, Eric Strengman, Lambertus A. Kiemeney, Ingrid Melle, Srdjan Djurovic, Lilia Abramova, Vasily Kaleda, Julio Sanjuan, Rosa de Frutos, Elvira Bramon, Evangelos Vassos, Gillian Fraser, Ulrich Ettinger, Marco Picchioni, Nicholas Walker, Timi Toulopoulou, Anna C. Need, Dongliang Ge, Joeng Lim Yoon, Kevin V. Shianna, Nelson B. Freimer, Rita M. Cantor, Robin Murray, Augustine Kong, Vera Golimbet, Angel Carracedo, Celso Arango, Javier Costas, Erik G. Joensson, Lars Terenius, Ingrid Agartz, Hannes Petursson, Markus M. Nothen, Marcella Rietschel, Paul M. Matthews, Pierandrea Muglia, Leena Peltonen, David St Clair, David B. Goldstein, Kari Stefansson, David A. Collier

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Abstract

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders(1-3). The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized(4). Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Original language	English
Pages (from-to)	744 - 747
Number of pages	4
Journal	NATURE
Volume	460
Issue number	7256
DOIs	https://doi.org/10.1038/nature08186
Publication status	Published - 6 Aug 2009

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Stefansson, H., Ophoff, R. A., Steinberg, S., Andreassen, O. A., Cichon, S., Rujescu, D., Werge, T., Pietilainen, O. P. H., Mors, O., Mortensen, P. B., Sigurdsson, E., Gustafsson, O., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Suvisaari, J., Lonnqvist, J., Paunio, T., ... Collier, D. A. (2009). Common variants conferring risk of schizophrenia. NATURE, 460(7256), 744 - 747. https://doi.org/10.1038/nature08186

@article{a8d3b7c92b5d491d9f5088112e10c3e0,

title = "Common variants conferring risk of schizophrenia",

abstract = "Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders(1-3). The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized(4). Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.",

author = "Hreinn Stefansson and Ophoff, {Roel A.} and Stacy Steinberg and Andreassen, {Ole A.} and Sven Cichon and Dan Rujescu and Thomas Werge and Pietilainen, {Olli P. H.} and Ole Mors and Mortensen, {Preben B.} and Engilbert Sigurdsson and Omar Gustafsson and Mette Nyegaard and Annamari Tuulio-Henriksson and Andres Ingason and Thomas Hansen and Jaana Suvisaari and Jouko Lonnqvist and Tiina Paunio and Borglum, {Anders D.} and Annette Hartmann and Anders Fink-Jensen and Merete Nordentoft and David Hougaard and Bent Norgaard-Pedersen and Yvonne Bottcher and Jes Olesen and Rene Breuer and Hans-Jurgen Moeller and Ina Giegling and Rasmussen, {Henrik B.} and Sally Timm and Manuel Mattheisen and Istvan Bitter and Rethelyi, {Janos M.} and Magnusdottir, {Brynja B.} and Thordur Sigmundsson and Pall Olason and Gisli Mason and Gulcher, {Jeffrey R.} and Magnus Haraldsson and Ragnheidur Fossdal and Thorgeirsson, {Thorgeir E.} and Unnur Thorsteinsdottir and Mirella Ruggeri and Sarah Tosato and Barbara Franke and Eric Strengman and Kiemeney, {Lambertus A.} and Ingrid Melle and Srdjan Djurovic and Lilia Abramova and Vasily Kaleda and Julio Sanjuan and {de Frutos}, Rosa and Elvira Bramon and Evangelos Vassos and Gillian Fraser and Ulrich Ettinger and Marco Picchioni and Nicholas Walker and Timi Toulopoulou and Need, {Anna C.} and Dongliang Ge and Yoon, {Joeng Lim} and Shianna, {Kevin V.} and Freimer, {Nelson B.} and Cantor, {Rita M.} and Robin Murray and Augustine Kong and Vera Golimbet and Angel Carracedo and Celso Arango and Javier Costas and Joensson, {Erik G.} and Lars Terenius and Ingrid Agartz and Hannes Petursson and Nothen, {Markus M.} and Marcella Rietschel and Matthews, {Paul M.} and Pierandrea Muglia and Leena Peltonen and {St Clair}, David and Goldstein, {David B.} and Kari Stefansson and Collier, {David A.}",

year = "2009",

month = aug,

day = "6",

doi = "10.1038/nature08186",

language = "English",

volume = "460",

pages = "744 -- 747",

journal = "NATURE",

issn = "1476-4687",

publisher = "Nature Publishing Group",

number = "7256",

}

Stefansson, H, Ophoff, RA, Steinberg, S, Andreassen, OA, Cichon, S, Rujescu, D, Werge, T, Pietilainen, OPH, Mors, O, Mortensen, PB, Sigurdsson, E, Gustafsson, O, Nyegaard, M, Tuulio-Henriksson, A, Ingason, A, Hansen, T, Suvisaari, J, Lonnqvist, J, Paunio, T, Borglum, AD, Hartmann, A, Fink-Jensen, A, Nordentoft, M, Hougaard, D, Norgaard-Pedersen, B, Bottcher, Y, Olesen, J, Breuer, R, Moeller, H-J, Giegling, I, Rasmussen, HB, Timm, S, Mattheisen, M, Bitter, I, Rethelyi, JM, Magnusdottir, BB, Sigmundsson, T, Olason, P, Mason, G, Gulcher, JR, Haraldsson, M, Fossdal, R, Thorgeirsson, TE, Thorsteinsdottir, U, Ruggeri, M, Tosato, S, Franke, B, Strengman, E, Kiemeney, LA, Melle, I, Djurovic, S, Abramova, L, Kaleda, V, Sanjuan, J, de Frutos, R, Bramon, E , Vassos, E, Fraser, G, Ettinger, U, Picchioni, M, Walker, N, Toulopoulou, T, Need, AC, Ge, D, Yoon, JL, Shianna, KV, Freimer, NB, Cantor, RM, Murray, R, Kong, A, Golimbet, V, Carracedo, A, Arango, C, Costas, J, Joensson, EG, Terenius, L, Agartz, I, Petursson, H, Nothen, MM, Rietschel, M, Matthews, PM, Muglia, P, Peltonen, L, St Clair, D, Goldstein, DB, Stefansson, K & Collier, DA 2009, 'Common variants conferring risk of schizophrenia', NATURE, vol. 460, no. 7256, pp. 744 - 747. https://doi.org/10.1038/nature08186

TY - JOUR

T1 - Common variants conferring risk of schizophrenia

AU - Stefansson, Hreinn

AU - Ophoff, Roel A.

AU - Steinberg, Stacy

AU - Andreassen, Ole A.

AU - Cichon, Sven

AU - Rujescu, Dan

AU - Werge, Thomas

AU - Pietilainen, Olli P. H.

AU - Mors, Ole

AU - Mortensen, Preben B.

AU - Sigurdsson, Engilbert

AU - Gustafsson, Omar

AU - Nyegaard, Mette

AU - Tuulio-Henriksson, Annamari

AU - Ingason, Andres

AU - Hansen, Thomas

AU - Suvisaari, Jaana

AU - Lonnqvist, Jouko

AU - Paunio, Tiina

AU - Borglum, Anders D.

AU - Hartmann, Annette

AU - Fink-Jensen, Anders

AU - Nordentoft, Merete

AU - Hougaard, David

AU - Norgaard-Pedersen, Bent

AU - Bottcher, Yvonne

AU - Olesen, Jes

AU - Breuer, Rene

AU - Moeller, Hans-Jurgen

AU - Giegling, Ina

AU - Rasmussen, Henrik B.

AU - Timm, Sally

AU - Mattheisen, Manuel

AU - Bitter, Istvan

AU - Rethelyi, Janos M.

AU - Magnusdottir, Brynja B.

AU - Sigmundsson, Thordur

AU - Olason, Pall

AU - Mason, Gisli

AU - Gulcher, Jeffrey R.

AU - Haraldsson, Magnus

AU - Fossdal, Ragnheidur

AU - Thorgeirsson, Thorgeir E.

AU - Thorsteinsdottir, Unnur

AU - Ruggeri, Mirella

AU - Tosato, Sarah

AU - Franke, Barbara

AU - Strengman, Eric

AU - Kiemeney, Lambertus A.

AU - Melle, Ingrid

AU - Djurovic, Srdjan

AU - Abramova, Lilia

AU - Kaleda, Vasily

AU - Sanjuan, Julio

AU - de Frutos, Rosa

AU - Bramon, Elvira

AU - Vassos, Evangelos

AU - Fraser, Gillian

AU - Ettinger, Ulrich

AU - Picchioni, Marco

AU - Walker, Nicholas

AU - Toulopoulou, Timi

AU - Need, Anna C.

AU - Ge, Dongliang

AU - Yoon, Joeng Lim

AU - Shianna, Kevin V.

AU - Freimer, Nelson B.

AU - Cantor, Rita M.

AU - Murray, Robin

AU - Kong, Augustine

AU - Golimbet, Vera

AU - Carracedo, Angel

AU - Arango, Celso

AU - Costas, Javier

AU - Joensson, Erik G.

AU - Terenius, Lars

AU - Agartz, Ingrid

AU - Petursson, Hannes

AU - Nothen, Markus M.

AU - Rietschel, Marcella

AU - Matthews, Paul M.

AU - Muglia, Pierandrea

AU - Peltonen, Leena

AU - St Clair, David

AU - Goldstein, David B.

AU - Stefansson, Kari

AU - Collier, David A.

PY - 2009/8/6

Y1 - 2009/8/6

N2 - Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders(1-3). The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized(4). Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

AB - Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders(1-3). The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized(4). Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

U2 - 10.1038/nature08186

DO - 10.1038/nature08186

M3 - Article

SN - 1476-4687

VL - 460

SP - 744

EP - 747

JO - NATURE

JF - NATURE

IS - 7256

ER -

Common variants conferring risk of schizophrenia

Abstract

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