Disruption of the neurexin 1 gene is associated with schizophrenia

Dan Rujescu; Andres Ingason; Sven Cichon; Olli P. H. Pietilainen; Michael R. Barnes; Timothea Toulopoulou; Marco Picchioni; Evangelos Vassos; Ulrich Ettinger; Elvira Bramon; Robin Murray; Mirella Ruggeri; Sarah Tosato; Chiara Bonetto; Stacy Steinberg; Engilbert Sigurdsson; Thordur Sigmundsson; Hannes Petursson; Arnaldur Gylfason; Pall I. Olason; Gudmundur Hardarsson; Gudrun A. Jonsdottir; Omar Gustafsson; Ragnheidur Fossdal; Ina Giegling; Hans-Jurgen Moeller; Annette M. Hartmann; Per Hoffmann; Caroline Crombie; Gillian Fraser; Nicholas Walker; Jouko Lonnqvist; Jaana Suvisaari; Annamari Tuulio-Henriksson; Srdjan Djurovic; Ingrid Melle; Ole A. Andreassen; Thomas Hansen; Thomas Werge; Lambertus A. Kiemeney; Barbara Franke; Joris Veltman; Jacobine E. Buizer-Voskamp; Chiara Sabatti; Roel A. Ophoff; Marcella Rietschel; Markus M. Noehen; Kari Stefansson; Leena Peltonen; David St Clair; Hreinn Stefansson; David A. Collier

doi:10.1093/hmg/ddn351

Disruption of the neurexin 1 gene is associated with schizophrenia

Dan Rujescu, Andres Ingason, Sven Cichon, Olli P. H. Pietilainen, Michael R. Barnes, Timothea Toulopoulou, Marco Picchioni, Evangelos Vassos, Ulrich Ettinger, Elvira Bramon, Robin Murray, Mirella Ruggeri, Sarah Tosato, Chiara Bonetto, Stacy Steinberg, Engilbert Sigurdsson, Thordur Sigmundsson, Hannes Petursson, Arnaldur Gylfason, Pall I. OlasonGudmundur Hardarsson, Gudrun A. Jonsdottir, Omar Gustafsson, Ragnheidur Fossdal, Ina Giegling, Hans-Jurgen Moeller, Annette M. Hartmann, Per Hoffmann, Caroline Crombie, Gillian Fraser, Nicholas Walker, Jouko Lonnqvist, Jaana Suvisaari, Annamari Tuulio-Henriksson, Srdjan Djurovic, Ingrid Melle, Ole A. Andreassen, Thomas Hansen, Thomas Werge, Lambertus A. Kiemeney, Barbara Franke, Joris Veltman, Jacobine E. Buizer-Voskamp, Chiara Sabatti, Roel A. Ophoff, Marcella Rietschel, Markus M. Noehen, Kari Stefansson, Leena Peltonen, David St Clair, Hreinn Stefansson, David A. Collier

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Abstract

Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.

Original language	English
Article number	N/A
Pages (from-to)	988 - 996
Number of pages	9
Journal	Human Molecular Genetics
Volume	18
Issue number	5
DOIs	https://doi.org/10.1093/hmg/ddn351
Publication status	Published - 1 Mar 2009

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http://hmg.oxfordjournals.org/content/18/5/988.abstract

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Rujescu, D., Ingason, A., Cichon, S., Pietilainen, O. P. H., Barnes, M. R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., Tosato, S., Bonetto, C., Steinberg, S., Sigurdsson, E., Sigmundsson, T., Petursson, H., Gylfason, A., ... Collier, D. A. (2009). Disruption of the neurexin 1 gene is associated with schizophrenia. Human Molecular Genetics, 18(5), 988 - 996. Article N/A. https://doi.org/10.1093/hmg/ddn351

@article{d59924159c7a407fa4b90fc7521058b3,

title = "Disruption of the neurexin 1 gene is associated with schizophrenia",

abstract = "Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.",

author = "Dan Rujescu and Andres Ingason and Sven Cichon and Pietilainen, {Olli P. H.} and Barnes, {Michael R.} and Timothea Toulopoulou and Marco Picchioni and Evangelos Vassos and Ulrich Ettinger and Elvira Bramon and Robin Murray and Mirella Ruggeri and Sarah Tosato and Chiara Bonetto and Stacy Steinberg and Engilbert Sigurdsson and Thordur Sigmundsson and Hannes Petursson and Arnaldur Gylfason and Olason, {Pall I.} and Gudmundur Hardarsson and Jonsdottir, {Gudrun A.} and Omar Gustafsson and Ragnheidur Fossdal and Ina Giegling and Hans-Jurgen Moeller and Hartmann, {Annette M.} and Per Hoffmann and Caroline Crombie and Gillian Fraser and Nicholas Walker and Jouko Lonnqvist and Jaana Suvisaari and Annamari Tuulio-Henriksson and Srdjan Djurovic and Ingrid Melle and Andreassen, {Ole A.} and Thomas Hansen and Thomas Werge and Kiemeney, {Lambertus A.} and Barbara Franke and Joris Veltman and Buizer-Voskamp, {Jacobine E.} and Chiara Sabatti and Ophoff, {Roel A.} and Marcella Rietschel and Noehen, {Markus M.} and Kari Stefansson and Leena Peltonen and {St Clair}, David and Hreinn Stefansson and Collier, {David A.}",

year = "2009",

month = mar,

day = "1",

doi = "10.1093/hmg/ddn351",

language = "English",

volume = "18",

pages = "988 -- 996",

journal = "Human Molecular Genetics",

issn = "1460-2083",

publisher = "Oxford University Press",

number = "5",

}

Rujescu, D, Ingason, A, Cichon, S, Pietilainen, OPH, Barnes, MR, Toulopoulou, T , Picchioni, M , Vassos, E, Ettinger, U, Bramon, E , Murray, R, Ruggeri, M, Tosato, S, Bonetto, C, Steinberg, S, Sigurdsson, E, Sigmundsson, T, Petursson, H, Gylfason, A, Olason, PI, Hardarsson, G, Jonsdottir, GA, Gustafsson, O, Fossdal, R, Giegling, I, Moeller, H-J, Hartmann, AM, Hoffmann, P, Crombie, C, Fraser, G, Walker, N, Lonnqvist, J, Suvisaari, J, Tuulio-Henriksson, A, Djurovic, S, Melle, I, Andreassen, OA, Hansen, T, Werge, T, Kiemeney, LA, Franke, B, Veltman, J, Buizer-Voskamp, JE, Sabatti, C, Ophoff, RA, Rietschel, M, Noehen, MM, Stefansson, K, Peltonen, L, St Clair, D, Stefansson, H & Collier, DA 2009, 'Disruption of the neurexin 1 gene is associated with schizophrenia', Human Molecular Genetics, vol. 18, no. 5, N/A, pp. 988 - 996. https://doi.org/10.1093/hmg/ddn351

TY - JOUR

T1 - Disruption of the neurexin 1 gene is associated with schizophrenia

AU - Rujescu, Dan

AU - Ingason, Andres

AU - Cichon, Sven

AU - Pietilainen, Olli P. H.

AU - Barnes, Michael R.

AU - Toulopoulou, Timothea

AU - Picchioni, Marco

AU - Vassos, Evangelos

AU - Ettinger, Ulrich

AU - Bramon, Elvira

AU - Murray, Robin

AU - Ruggeri, Mirella

AU - Tosato, Sarah

AU - Bonetto, Chiara

AU - Steinberg, Stacy

AU - Sigurdsson, Engilbert

AU - Sigmundsson, Thordur

AU - Petursson, Hannes

AU - Gylfason, Arnaldur

AU - Olason, Pall I.

AU - Hardarsson, Gudmundur

AU - Jonsdottir, Gudrun A.

AU - Gustafsson, Omar

AU - Fossdal, Ragnheidur

AU - Giegling, Ina

AU - Moeller, Hans-Jurgen

AU - Hartmann, Annette M.

AU - Hoffmann, Per

AU - Crombie, Caroline

AU - Fraser, Gillian

AU - Walker, Nicholas

AU - Lonnqvist, Jouko

AU - Suvisaari, Jaana

AU - Tuulio-Henriksson, Annamari

AU - Djurovic, Srdjan

AU - Melle, Ingrid

AU - Andreassen, Ole A.

AU - Hansen, Thomas

AU - Werge, Thomas

AU - Kiemeney, Lambertus A.

AU - Franke, Barbara

AU - Veltman, Joris

AU - Buizer-Voskamp, Jacobine E.

AU - Sabatti, Chiara

AU - Ophoff, Roel A.

AU - Rietschel, Marcella

AU - Noehen, Markus M.

AU - Stefansson, Kari

AU - Peltonen, Leena

AU - St Clair, David

AU - Stefansson, Hreinn

AU - Collier, David A.

PY - 2009/3/1

Y1 - 2009/3/1

N2 - Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.

AB - Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.

U2 - 10.1093/hmg/ddn351

DO - 10.1093/hmg/ddn351

M3 - Article

SN - 1460-2083

VL - 18

SP - 988

EP - 996

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 5

M1 - N/A

ER -

Disruption of the neurexin 1 gene is associated with schizophrenia

Abstract

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