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 Pietiläinen; Ole Mors; Preben Bo Mortensen; Engilbert Sigurdsson; Omar Gustafsson; Mette Nyegaard; Annamari Tuulio-Henriksson; Andres Ingason; Thomas Hansen; Jaana Suvisaari; Jouko Lonnqvist; Tiina Paunio; Anders D Børglum; Annette Hartmann; Anders Fink-Jensen; Merete Nordentoft; David Hougaard; Bent Norgaard-Pedersen; Yvonne Böttcher; Jes Olesen; René Breuer; Hans-Jürgen Möller; Ina Giegling; Henrik B Rasmussen; Sally Timm; Manuel Mattheisen; István Bitter; János M Réthelyi; Brynja B Magnusdottir; Thordur Sigmundsson; Pall Olason; Gisli Masson; 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; Genetic Risk and Outcome in Psychosis (GROUP)

doi:http://dx.doi.org/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 Pietiläinen, Ole Mors, Preben Bo Mortensen, Engilbert Sigurdsson, Omar Gustafsson, Mette Nyegaard, Annamari Tuulio-Henriksson, Andres Ingason, Thomas Hansen, Jaana Suvisaari, Jouko Lonnqvist, Tiina Paunio, Anders D BørglumAnnette Hartmann, Anders Fink-Jensen, Merete Nordentoft, David Hougaard, Bent Norgaard-Pedersen, Yvonne Böttcher, Jes Olesen, René Breuer, Hans-Jürgen Möller, Ina Giegling, Henrik B Rasmussen, Sally Timm, Manuel Mattheisen, István Bitter, János M Réthelyi, Brynja B Magnusdottir, Thordur Sigmundsson, Pall Olason, Gisli Masson, 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, Genetic Risk and Outcome in Psychosis (GROUP)

1260 Citations (Scopus)

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. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. 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
Journal	Nature
Volume	460
Issue number	7256
Pages (from-to)	744-7
Number of pages	4
ISSN	0028-0836
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., Pietiläinen, 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., ... Genetic Risk and Outcome in Psychosis (GROUP) (2009). Common variants conferring risk of schizophrenia. Nature, 460(7256), 744-7. https://doi.org/10.1038/nature08186

Stefansson, H, Ophoff, RA, Steinberg, S, Andreassen, OA, Cichon, S, Rujescu, D, Werge, T, Pietiläinen, OPH, Mors, O, Mortensen, PB, Sigurdsson, E, Gustafsson, O, Nyegaard, M, Tuulio-Henriksson, A, Ingason, A, Hansen, T, Suvisaari, J, Lonnqvist, J, Paunio, T, Børglum, AD, Hartmann, A, Fink-Jensen, A, Nordentoft, M, Hougaard, D, Norgaard-Pedersen, B, Böttcher, Y, Olesen, J, Breuer, R, Möller, H-J, Giegling, I, Rasmussen, HB, Timm, S, Mattheisen, M, Bitter, I, Réthelyi, JM, Magnusdottir, BB, Sigmundsson, T, Olason, P, Masson, G, Gulcher, JR, Haraldsson, M, Fossdal, R, Thorgeirsson, TE, Thorsteinsdottir, U, Ruggeri, M, Tosato, S, Franke, B, Strengman, E, Kiemeney, LA, Melle, I & Genetic Risk and Outcome in Psychosis (GROUP) 2009, 'Common variants conferring risk of schizophrenia', Nature, vol. 460, no. 7256, pp. 744-7. https://doi.org/10.1038/nature08186

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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. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. 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 Pietil{\"a}inen, {Olli P H} and Ole Mors and Mortensen, {Preben Bo} 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 B{\o}rglum, {Anders D} and Annette Hartmann and Anders Fink-Jensen and Merete Nordentoft and David Hougaard and Bent Norgaard-Pedersen and Yvonne B{\"o}ttcher and Jes Olesen and Ren{\'e} Breuer and Hans-J{\"u}rgen M{\"o}ller and Ina Giegling and Rasmussen, {Henrik B} and Sally Timm and Manuel Mattheisen and Istv{\'a}n Bitter and R{\'e}thelyi, {J{\'a}nos M} and Magnusdottir, {Brynja B} and Thordur Sigmundsson and Pall Olason and Gisli Masson 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 Thomas Werge",

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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 - Pietiläinen, Olli P H

AU - Mors, Ole

AU - Mortensen, Preben Bo

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 - Børglum, Anders D

AU - Hartmann, Annette

AU - Fink-Jensen, Anders

AU - Nordentoft, Merete

AU - Hougaard, David

AU - Norgaard-Pedersen, Bent

AU - Böttcher, Yvonne

AU - Olesen, Jes

AU - Breuer, René

AU - Möller, Hans-Jürgen

AU - Giegling, Ina

AU - Rasmussen, Henrik B

AU - Timm, Sally

AU - Mattheisen, Manuel

AU - Bitter, István

AU - Réthelyi, János M

AU - Magnusdottir, Brynja B

AU - Sigmundsson, Thordur

AU - Olason, Pall

AU - Masson, 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 - Genetic Risk and Outcome in Psychosis (GROUP)

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. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. 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. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. 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 - http://dx.doi.org/10.1038/nature08186

DO - http://dx.doi.org/10.1038/nature08186

M3 - Journal article

SN - 0028-0836

VL - 460

SP - 744

EP - 747

JO - Nature

JF - Nature

IS - 7256

ER -

Common variants conferring risk of schizophrenia

Abstract

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