Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia

Tom Walsh; Jon M. McClellan; Shane E. McCarthy; Anjené M. Addington; Sarah B. Pierce; Greg M. Cooper; Alex S. Nord; Mary Kusenda; Dheeraj Malhotra; Abhishek Bhandari; Sunday M. Stray; Caitlin F. Rippey; Patricia Roccanova; Vlad Makarov; B. Lakshmi; Robert L. Findling; Linmarie Sikich; Thomas Stromberg; Barry Merriman; Nitin Gogtay; Philip Butler; Kristen Eckstrand; Laila Noory; Peter Gochman; Robert Long; Zugen Chen; Sean Davis; Carl Baker; Evan E. Eichler; Paul S. Meltzer; Stanley F. Nelson; Andrew B. Singleton; Ming K. Lee; Judith L. Rapoport; Mary Claire King; Jonathan Sebat

doi:10.1126/science.1155174

Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia

Tom Walsh, Jon M. McClellan, Shane E. McCarthy, Anjené M. Addington, Sarah B. Pierce, Greg M. Cooper, Alex S. Nord, Mary Kusenda, Dheeraj Malhotra, Abhishek Bhandari, Sunday M. Stray, Caitlin F. Rippey, Patricia Roccanova, Vlad Makarov, B. Lakshmi, Robert L. Findling, Linmarie Sikich, Thomas Stromberg, Barry Merriman, Nitin GogtayPhilip Butler, Kristen Eckstrand, Laila Noory, Peter Gochman, Robert Long, Zugen Chen, Sean Davis, Carl Baker, Evan E. Eichler, Paul S. Meltzer, Stanley F. Nelson, Andrew B. Singleton, Ming K. Lee, Judith L. Rapoport, Mary Claire King, Jonathan Sebat

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Abstract

Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.

Original language	English (US)
Pages (from-to)	539-543
Number of pages	5
Journal	Science
Volume	320
Issue number	5875
DOIs	https://doi.org/10.1126/science.1155174
State	Published - Apr 25 2008
Externally published	Yes

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Walsh, T., McClellan, J. M., McCarthy, S. E., Addington, A. M., Pierce, S. B., Cooper, G. M., Nord, A. S., Kusenda, M., Malhotra, D., Bhandari, A., Stray, S. M., Rippey, C. F., Roccanova, P., Makarov, V., Lakshmi, B., Findling, R. L., Sikich, L., Stromberg, T., Merriman, B., ... Sebat, J. (2008). Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science, 320(5875), 539-543. https://doi.org/10.1126/science.1155174

Walsh, T, McClellan, JM, McCarthy, SE, Addington, AM, Pierce, SB, Cooper, GM, Nord, AS, Kusenda, M, Malhotra, D, Bhandari, A, Stray, SM, Rippey, CF, Roccanova, P, Makarov, V, Lakshmi, B, Findling, RL, Sikich, L, Stromberg, T, Merriman, B, Gogtay, N, Butler, P, Eckstrand, K, Noory, L, Gochman, P, Long, R, Chen, Z, Davis, S, Baker, C, Eichler, EE, Meltzer, PS, Nelson, SF, Singleton, AB, Lee, MK, Rapoport, JL, King, MC & Sebat, J 2008, 'Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia', Science, vol. 320, no. 5875, pp. 539-543. https://doi.org/10.1126/science.1155174

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title = "Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia",

abstract = "Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.",

author = "Tom Walsh and McClellan, {Jon M.} and McCarthy, {Shane E.} and Addington, {Anjen{\'e} M.} and Pierce, {Sarah B.} and Cooper, {Greg M.} and Nord, {Alex S.} and Mary Kusenda and Dheeraj Malhotra and Abhishek Bhandari and Stray, {Sunday M.} and Rippey, {Caitlin F.} and Patricia Roccanova and Vlad Makarov and B. Lakshmi and Findling, {Robert L.} and Linmarie Sikich and Thomas Stromberg and Barry Merriman and Nitin Gogtay and Philip Butler and Kristen Eckstrand and Laila Noory and Peter Gochman and Robert Long and Zugen Chen and Sean Davis and Carl Baker and Eichler, {Evan E.} and Meltzer, {Paul S.} and Nelson, {Stanley F.} and Singleton, {Andrew B.} and Lee, {Ming K.} and Rapoport, {Judith L.} and King, {Mary Claire} and Jonathan Sebat",

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AU - Nord, Alex S.

AU - Kusenda, Mary

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AU - Bhandari, Abhishek

AU - Stray, Sunday M.

AU - Rippey, Caitlin F.

AU - Roccanova, Patricia

AU - Makarov, Vlad

AU - Lakshmi, B.

AU - Findling, Robert L.

AU - Sikich, Linmarie

AU - Stromberg, Thomas

AU - Merriman, Barry

AU - Gogtay, Nitin

AU - Butler, Philip

AU - Eckstrand, Kristen

AU - Noory, Laila

AU - Gochman, Peter

AU - Long, Robert

AU - Chen, Zugen

AU - Davis, Sean

AU - Baker, Carl

AU - Eichler, Evan E.

AU - Meltzer, Paul S.

AU - Nelson, Stanley F.

AU - Singleton, Andrew B.

AU - Lee, Ming K.

AU - Rapoport, Judith L.

AU - King, Mary Claire

AU - Sebat, Jonathan

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Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia

Abstract

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