Disruption of the neurexin 1 gene is associated with schizophrenia

Dan Rujescu; Andres Ingason; Sven Cichon; Olli P H Pietiläinen; 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-Jürgen Möller; 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 Nöthen; Kari Stefansson; Leena Peltonen; David St Clair; GROUP Investigators

doi:10.1093/hmg/ddn351

Disruption of the neurexin 1 gene is associated with schizophrenia

Dan Rujescu, Andres Ingason, Sven Cichon, Olli P H Pietiläinen, 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-Jürgen Möller, 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 Nöthen, Kari Stefansson, Leena Peltonen, David St Clair, GROUP Investigators

Research output: Contribution to journal › Article

350 Citations (Scopus)

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
Pages (from-to)	988-996
Number of pages	9
Journal	Human Molecular Genetics
Volume	18
Issue number	5
Early online date	22 Oct 2008
DOIs	https://doi.org/10.1093/hmg/ddn351
Publication status	Published - 2009

Keywords

adolescent
adult
case-control studies
European continental ancestry group
exons
female
gene deletion
gene dosage
gene duplication
gene silencing
genetic predisposition to disease
humans
male
nerve tissue proteins
schizophrenia
young adult

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Rujescu, D., Ingason, A., Cichon, S., Pietiläinen, 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., ... GROUP Investigators (2009). Disruption of the neurexin 1 gene is associated with schizophrenia. Human Molecular Genetics, 18(5), 988-996. https://doi.org/10.1093/hmg/ddn351

Disruption of the neurexin 1 gene is associated with schizophrenia. / Rujescu, Dan; Ingason, Andres; Cichon, Sven; Pietiläinen, Olli P H; Barnes, Michael R. ; Toulopoulou, Timothea; Picchioni, Marco; Vassos, Evangelos; Ettinger, Ulrich; Bramon, Elvira; Murray, Robin; Ruggeri, Mirella; Tosato, Sarah; Bonetto, Chiara; Steinberg, Stacy; Sigurdsson, Engilbert; Sigmundsson, Thordur; Petursson, Hannes; Gylfason, Arnaldur; Olason, Pall I; Hardarsson, Gudmundur; Jonsdottir, Gudrun A; Gustafsson, Omar; Fossdal, Ragnheidur; Giegling, Ina; Möller, Hans-Jürgen; Hartmann, Annette M; Hoffmann, Per; Crombie, Caroline; Fraser, Gillian; Walker, Nicholas; Lonnqvist, Jouko; Suvisaari, Jaana; Tuulio-Henriksson, Annamari; Djurovic, Srdjan; Melle, Ingrid; Andreassen, Ole A; Hansen, Thomas; Werge, Thomas; Kiemeney, Lambertus A; Franke, Barbara; Veltman, Joris; Buizer-Voskamp, Jacobine E; Sabatti, Chiara; Ophoff, Roel A; Rietschel, Marcella; Nöthen, Markus M; Stefansson, Kari; Peltonen, Leena; St Clair, David; GROUP Investigators.

In: Human Molecular Genetics, Vol. 18, No. 5, 2009, p. 988-996.

Research output: Contribution to journal › Article

Rujescu, D, Ingason, A, Cichon, S, Pietiläinen, 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, Möller, 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, Nöthen, MM, Stefansson, K, Peltonen, L, St Clair, D & GROUP Investigators 2009, 'Disruption of the neurexin 1 gene is associated with schizophrenia', Human Molecular Genetics, vol. 18, no. 5, pp. 988-996. https://doi.org/10.1093/hmg/ddn351

Rujescu, Dan ; Ingason, Andres ; Cichon, Sven ; Pietiläinen, Olli P H ; Barnes, Michael R. ; Toulopoulou, Timothea ; Picchioni, Marco ; Vassos, Evangelos ; Ettinger, Ulrich ; Bramon, Elvira ; Murray, Robin ; Ruggeri, Mirella ; Tosato, Sarah ; Bonetto, Chiara ; Steinberg, Stacy ; Sigurdsson, Engilbert ; Sigmundsson, Thordur ; Petursson, Hannes ; Gylfason, Arnaldur ; Olason, Pall I ; Hardarsson, Gudmundur ; Jonsdottir, Gudrun A ; Gustafsson, Omar ; Fossdal, Ragnheidur ; Giegling, Ina ; Möller, Hans-Jürgen ; Hartmann, Annette M ; Hoffmann, Per ; Crombie, Caroline ; Fraser, Gillian ; Walker, Nicholas ; Lonnqvist, Jouko ; Suvisaari, Jaana ; Tuulio-Henriksson, Annamari ; Djurovic, Srdjan ; Melle, Ingrid ; Andreassen, Ole A ; Hansen, Thomas ; Werge, Thomas ; Kiemeney, Lambertus A ; Franke, Barbara ; Veltman, Joris ; Buizer-Voskamp, Jacobine E ; Sabatti, Chiara ; Ophoff, Roel A ; Rietschel, Marcella ; Nöthen, Markus M ; Stefansson, Kari ; Peltonen, Leena ; St Clair, David ; GROUP Investigators. / Disruption of the neurexin 1 gene is associated with schizophrenia. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 5. pp. 988-996.

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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.",

keywords = "adolescent, adult, case-control studies, European continental ancestry group, exons, female, gene deletion, gene dosage, gene duplication, gene silencing, genetic predisposition to disease, humans, male, nerve tissue proteins, schizophrenia, young adult",

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AU - Ingason, Andres

AU - Cichon, Sven

AU - Pietiläinen, 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 - Möller, Hans-Jürgen

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

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AU - Andreassen, Ole A

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AU - Buizer-Voskamp, Jacobine E

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AU - Ophoff, Roel A

AU - Rietschel, Marcella

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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.

KW - adolescent

KW - adult

KW - case-control studies

KW - European continental ancestry group

KW - exons

KW - female

KW - gene deletion

KW - gene dosage

KW - gene duplication

KW - gene silencing

KW - genetic predisposition to disease

KW - humans

KW - male

KW - nerve tissue proteins

KW - schizophrenia

KW - young adult

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DO - 10.1093/hmg/ddn351

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JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

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