Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia

被引：1289

作者：

Walsh, Tom ^{[2
]}

McClellan, Jon M. ^{[1
]}

McCarthy, Shane E. ^{[3
]}

Addington, Anjene M. ^{[4
]}

Pierce, Sarah B. ^{[2
]}

Cooper, Greg M. ^{[5
]}

Nord, Alex S. ^{[5
]}

Kusenda, Mary ^{[3
,6
]}

Malhotra, Dheeraj ^{[3
]}

Bhandari, Abhishek ^{[3
]}

Stray, Sunday M. ^{[2
]}

Rippey, Caitlin F. ^{[5
]}

Roccanova, Patricia ^{[3
]}

Makarov, Vlad ^{[3
]}

Lakshmi, B. ^{[3
]}

Findling, Robert L. ^{[7
]}

Sikich, Linmarie ^{[8
]}

Stromberg, Thomas ^{[4
]}

Merriman, Barry ^{[9
]}

Gogtay, Nitin ^{[4
]}

Butler, Philip ^{[4
]}

Eckstrand, Kristen ^{[4
]}

Noory, Laila ^{[4
]}

Gochman, Peter ^{[4
]}

Long, Robert ^{[4
]}

Chen, Zugen ^{[9
]}

Davis, Sean ^{[10
]}

Baker, Carl ^{[5
]}

Eichler, Evan E. ^{[5
]}

Meltzer, Paul S. ^{[10
]}

Nelson, Stanley F. ^{[9
]}

Singleton, Andrew B. ^{[11
]}

Lee, Ming K. ^{[2
]}

Rapoport, Judith L. ^{[4
]}

King, Mary-Claire ^{[2
,5
]}

Sebat, Jonathan ^{[3
]}

机构：

[1] Univ Washington, Dept Psychiat, Seattle, WA 98195 USA

[2] Univ Washington, Dept Med, Seattle, WA 98195 USA

[3] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[4] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA

[5] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[6] SUNY Stony Brook, Grad Program Genet, Stony Brook, NY 11794 USA

[7] Case Med Ctr, Dept Psychiat, Cleveland, OH 44106 USA

[8] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA

[9] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA

[10] NCI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA

[11] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

来源：

SCIENCE | 2008年 / 320卷 / 5875期

关键词：

D O I：

10.1126/science.1155174

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：539 / 543

页数：5

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