Implication of a Rare Deletion at Distal 16p11.2 in Schizophrenia

被引：57

作者：

Guha, Saurav ^{[1
]}

Rees, Elliott ^{[2
,3
]}

Darvasi, Ariel ^{[4
]}

Ivanov, Dobril ^{[2
,3
]}

Ikeda, Masashi ^{[5
]}

Bergen, Sarah E. ^{[6
,7
,8
,9
]}

Magnusson, Patrik K. ^{[10
]}

Cormican, Paul ^{[11
]}

Morris, Derek ^{[11
]}

Gill, Michael ^{[11
]}

Cichon, Sven ^{[13
,14
,16
]}

Rosenfeld, Jeffrey A. ^{[17
]}

Lee, Annette ^{[18
]}

Gregersen, Peter K. ^{[18
]}

Kane, John M. ^{[1
,19
,20
]}

Malhotra, Anil K. ^{[1
,19
,20
]}

Rietschel, Marcella ^{[21
]}

Noethen, Markus M. ^{[13
,15
]}

Degenhardt, Franziska ^{[13
,14
]}

Priebe, Lutz ^{[13
,14
]}

Breuer, Rene ^{[21
]}

Strohmaier, Jana ^{[21
]}

Ruderfer, Douglas M. ^{[22
]}

Moran, Jennifer L. ^{[9
]}

Chambert, Kimberly D. ^{[9
]}

Sanders, Alan R. ^{[23
,24
]}

Shi, Jianxin ^{[25
]}

Kendler, Kenneth ^{[26
]}

Riley, Brien ^{[27
]}

O'Neill, Tony ^{[28
]}

Walsh, Dermot ^{[12
]}

Malhotra, Dheeraj ^{[29
]}

Corvin, Aiden ^{[11
]}

Purcell, Shaun ^{[6
,7
,8
,9
,22
]}

Sklar, Pamela ^{[22
]}

Iwata, Nakao ^{[5
]}

Hultman, Christina M. ^{[10
]}

Sullivan, Patrick F. ^{[30
,31
,32
]}

Sebat, Jonathan ^{[29
]}

McCarthy, Shane ^{[33
]}

Gejman, Pablo V. ^{[23
,24
]}

Levinson, Douglas F. ^{[34
]}

Owen, Michael J. ^{[2
,3
]}

O'Donovan, Michael C. ^{[2
,3
]}

Lencz, Todd ^{[1
,19
,20
]}

Kirov, George ^{[2
,3
]}

机构：

[1] Zucker Hillside Hosp, Div Psychiat Res, Glen Oaks, NY 11004 USA

[2] Cardiff Univ, Med Res Council, Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales

[3] Cardiff Univ, Neurosci & Mental Hlth Res Inst, Cardiff CF10 3AX, S Glam, Wales

[4] Hebrew Univ Jerusalem, Inst Life Sci, Dept Genet, IL-91904 Jerusalem, Israel

[5] Fujita Hlth Univ, Sch Med, Toyoake, Aichi 47011, Japan

[6] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA

[7] Harvard Univ, Sch Med, Boston, MA USA

[8] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[9] Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA USA

[10] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[11] Trinity Coll Dublin, Dept Psychiat, Dublin, Ireland

[12] Hlth Res Board, Dublin, Ireland

[13] Univ Bonn, Inst Human Genet, Bonn, Germany

[14] Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany

[15] Ctr Neurodegenerat Dis, Bonn, Germany

[16] Res Ctr Juelich, Inst Neurosci & Med, Julich, Germany

[17] Univ Med & Dent New Jersey, IST High Performance & Res Comp, Newark, NJ 07103 USA

[18] Feinstein Inst Med Res, Robert S Boas Ctr Human Genet & Genom, Manhasset, NY USA

[19] Feinstein Inst Med Res, Ctr Psychiat Neurosci, Manhasset, NY USA

[20] Hofstra Univ, Sch Med, Dept Psychiat, Long Isl City, NY USA

[21] Heidelberg Univ, Cent Inst Mental Hlth, Med Fac Mannheim, Mannheim, Germany

[22] Mt Sinai Sch Med, Dept Psychiat, Div Psychiat Genom, New York, NY USA

[23] NorthShore Univ, HealthSyst Res Inst, Dept Psychiat & Behav Sci, Evanston, IL USA

[24] Univ Chicago, Dept Psychiat & Behav Sci, Chicago, IL 60637 USA

[25] NCI, Bethesda, MD 20892 USA

[26] Virginia Commonwealth Univ, Sch Med, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23284 USA

[27] Virginia Commonwealth Univ, Sch Med, Dept Psychiat, Richmond, VA 23284 USA

[28] Queens Univ, Dept Psychiat, Belfast, North Ireland

[29] Univ Calif San Diego, Beyster Ctr Genom Psychiat Dis, La Jolla, CA 92093 USA

[30] Univ N Carolina, Dept Genet, Chapel Hill, NC USA

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

[32] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA

[33] Woodbury Genome Ctr, Cold Spring Harbor Lab, Stanley Inst Cognit Genom, Cold Spring on Hudson, NY USA

[34] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA

来源：

JAMA PSYCHIATRY | 2013年 / 70卷 / 03期

基金：

美国国家卫生研究院; 英国惠康基金; 英国医学研究理事会;

关键词：

COPY-NUMBER VARIATION; HIDDEN-MARKOV MODEL; DE-NOVO; GENE; MUTATIONS; PHENOTYPE; DISEASE; SH2B1; CNVS; MAP;

D O I：

10.1001/2013.jamapsychiatry.71

中图分类号：

R749 [精神病学];

学科分类号：

100205 ;

摘要：

Context: Large genomic copy number variations have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication. Objective: To detect novel copy number variations that increase the susceptibility to schizophrenia by using 2 ethnically homogeneous discovery cohorts and replication in large samples. Design: Genetic association study of microarray data. Setting: Samples of DNA were collected at 9 sites from different countries. Participants: Two discovery cohorts consisted of 790 cases with schizophrenia and schizoaffective disorder and 1347 controls of Ashkenazi Jewish descent and 662 parent-offspring trios from Bulgaria, of which the offspring had schizophrenia or schizoaffective disorder. Replication data sets consisted of 12 398 cases and 17 945 controls. Main Outcome Measures: Statistically increased rate of specific copy number variations in cases vs controls. Results: One novel locus was implicated: a deletion at distal 16p11.2, which does not overlap the proximal 16p11.2 locus previously reported in schizophrenia and autism. Deletions at this locus were found in 13 of 13 850 cases (0.094%) and 3 of 19 954 controls (0.015%) (odds ratio, 6.25 [95% CI, 1.78-21.93]; P=.001, Fisher exact test). Conclusions: Deletions at distal 16p11.2 have been previously implicated in developmental delay and obesity. The region contains 9 genes, several of which are implicated in neurological diseases, regulation of body weight, and glucose homeostasis. A telomeric extension of the deletion, observed in about half the cases but no controls, potentially implicates an additional 8 genes. Our findings add a new locus to the list of copy number variations that increase the risk for development of schizophrenia. JAMA Psychiatry. 2013; 70(3): 253-260. Published online January 16, 2013. doi:10.1001/2013.jamapsychiatry.71

引用

页码：253 / 260

页数：8

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