Strong synaptic transmission impact by copy number variations in schizophrenia

被引：161

作者：

Glessner, Joseph T. ^{[1
]}

Reilly, Muredach P. ^{[2
]}

Kim, Cecilia E. ^{[1
]}

Takahashi, Nagahide ^{[3
,4
]}

Albano, Anthony ^{[1
]}

Hou, Cuiping ^{[1
]}

Bradfield, Jonathan P. ^{[1
]}

Zhang, Haitao ^{[1
]}

Sleiman, Patrick M. A. ^{[1
]}

Flory, James H. ^{[1
]}

Imielinski, Marcin ^{[1
]}

Frackelton, Edward C. ^{[1
]}

Chiavacci, Rosetta ^{[1
]}

Thomas, Kelly A. ^{[1
]}

Garris, Maria ^{[1
]}

Otieno, Frederick G. ^{[1
]}

Davidson, Michael ^{[5
]}

Weiser, Mark ^{[5
]}

Reichenberg, Abraham ^{[6
]}

Davis, Kenneth L. ^{[3
,4
]}

Friedman, Joseph I. ^{[3
,4
]}

Cappola, Thomas P. ^{[2
]}

Margulies, Kenneth B. ^{[2
]}

Rader, Daniel J. ^{[2
]}

Grant, Struan F. A. ^{[1
,7
,8
]}

Buxbaum, Joseph D. ^{[3
,4
]}

Gur, Raquel E. ^{[9
]}

Hakonarson, Hakon ^{[1
,7
,8
]}

机构：

[1] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[2] Univ Penn, Sch Med, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA

[3] Mt Sinai Sch Med, Conte Ctr Neurosci Mental Disorders, New York, NY 10029 USA

[4] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA

[5] Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel

[6] Kings Coll London, Mt Sinai & Inst Psychiat, London SE5 8AF, England

[7] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA

[8] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA

[9] Univ Penn, Dept Psychiat, Div Neuropsychiat, Schizophrenia Ctr, Philadelphia, PA 19104 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2010年 / 107卷 / 23期

基金：

美国国家卫生研究院;

关键词：

genetics; genomics; neurobiology; GENOME-WIDE ASSOCIATION; RARE STRUCTURAL VARIANTS; MITOCHONDRIAL DYSFUNCTION; EUROPEAN-ANCESTRY; BIPOLAR-DISORDER; GENE; AUTISM; BRAIN; MICRODELETIONS; IDENTIFICATION;

D O I：

10.1073/pnas.1000274107

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 psychiatric disorder with onset in late adolescence and unclear etiology characterized by both positive and negative symptoms, as well as cognitive deficits. To identify copy number variations (CNVs) that increase the risk of schizophrenia, we performed a whole-genome CNV analysis on a cohort of 977 schizophrenia cases and 2,000 healthy adults of European ancestry who were genotyped with 1.7 million probes. Positive findings were evaluated in an independent cohort of 758 schizophrenia cases and 1,485 controls. The Gene Ontology synaptic transmission family of genes was notably enriched for CNVs in the cases (P = 1.5 x 10(-7)). Among these, CACNA1B and DOC2A, both calcium-signaling genes responsible for neuronal excitation, were deleted in 16 cases and duplicated in 10 cases, respectively. In addition, RET and RIT2, both ras-related genes important for neural crest development, were significantly affected by CNVs. RET deletion was exclusive to seven cases, and RIT2 deletions were overrepresented common variant CNVs in the schizophrenia cases. Our results suggest that novel variations involving the processes of synaptic transmission contribute to the genetic susceptibility of schizophrenia.

引用

页码：10584 / 10589

页数：6

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