Rare chromosomal deletions and duplications increase risk of schizophrenia

被引：1116

作者：

Stone, Jennifer L. ^{[1
,2
,3
,4
]}

O'Donovan, Michael C. ^{[5
]}

Gurling, Hugh ^{[6
]}

Kirov, George K. ^{[5
]}

Blackwood, Douglas H. R. ^{[7
]}

Corvin, Aiden ^{[8
,9
]}

Craddock, Nick J. ^{[5
]}

Gill, Michael ^{[8
,9
]}

Hultman, Christina M. ^{[10
,11
]}

Lichtenstein, Paul ^{[10
]}

McQuillin, Andrew ^{[6
]}

Pato, Carlos N. ^{[12
]}

Ruderfer, Douglas M. ^{[1
,2
,3
,4
]}

Owen, Michael J. ^{[5
]}

St Clair, David ^{[13
]}

Sullivan, Patrick F. ^{[14
,15
,16
]}

Sklar, Pamela ^{[1
,2
,3
,4
]}

Purcell, Shaun M. ^{[1
,2
,3
,4
]}

Scolnick, E. M. ^{[3
]}

Holmans, P. A. ^{[5
]}

Georgieva, L. ^{[5
]}

Nikolov, I. ^{[5
]}

Norton, N. ^{[5
]}

Williams, H. ^{[5
]}

Williams, N. M. ^{[5
]}

Toncheva, D. ^{[18
]}

Milanova, V. ^{[19
]}

Thelander, E. F. ^{[10
]}

Morris, D. W. ^{[8
,9
]}

O'Dushlaine, C. T. ^{[8
,9
]}

Kenny, E. ^{[8
,9
]}

Waddington, J. L. ^{[20
]}

Choudhury, K. ^{[6
]}

Datta, S. ^{[6
]}

Pimm, J. ^{[6
]}

Thirumalai, S. ^{[21
]}

Puri, V. ^{[6
]}

Krasucki, R. ^{[6
]}

Lawrence, J. ^{[6
]}

Quested, D. ^{[22
]}

Bass, N. ^{[6
]}

Curtis, D. ^{[23
]}

Crombie, C. ^{[24
]}

Fraser, G. ^{[24
]}

Kwan, S. L. ^{[13
]}

Muir, W. J. ^{[7
]}

McGhee, K. A. ^{[7
]}

Pickard, B. ^{[7
]}

Malloy, P. ^{[7
]}

Maclean, A. W. ^{[7
]}

机构：

[1] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA

[2] Harvard Univ, Sch Med, Boston, MA 02114 USA

[3] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[4] Massachusetts Gen Hosp, Ctr Human Genet Res, Cambridge, MA 02142 USA

[5] Cardiff Univ, Sch Med, Dept Med Psychol, Sch Med, Cardiff C14 4XN, Wales

[6] UCL, Sch Med, Mol Psychiat Lab, Dept Mental Hlth Sci,Windeyer Inst Med Sci, London W1T 4JF, England

[7] Univ Edinburgh, Div Psychiat, Sch Mol & Clin Med, Edinburgh EH10 5HF, Midlothian, Scotland

[8] Univ Dublin Trinity Coll, Neuropsychiat Genet Res Grp, Dept Psychiat, Dublin 2, Ireland

[9] Univ Dublin Trinity Coll, Neuropsychiat Genet Res Grp, Inst Mol Med, Dublin 2, Ireland

[10] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden

[11] Uppsala Univ, Dept Neurosci Psychiat, SE-75017 Uppsala, Sweden

[12] Univ So Calif, Ctr Genom Psychiat, Los Angeles, CA 90033 USA

[13] Univ Aberdeen, Inst Med Sci, Aberdeen AB25 2ZD, Scotland

[14] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

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

[16] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA

[17] Queensland Inst Med Res, Brisbane, Qld 4006, Australia

[18] Univ Hosp Maichin Dom, Dept Med Genet, Sofia 1431, Bulgaria

[19] Alexander Univ Hosp, Dept Psychiat, Psychiat Clin 1, Sofia 1431, Bulgaria

[20] Royal Coll Surgeons Ireland, Molec & Cellular Therapeut & RCSI res Inst, Dublin 2, Ireland

[21] W Berkshire NHS Trust, Reading RG3 5LR, Berks, England

[22] W London Mental Hlth Trust, Hammersmith & Fulham Mental Hlth Unit, London W6 8RF, England

[23] Royal London Hosp, Univ London & E London & City Mental Hlth Trust, Quenn Mary Coll, London E1 1BB, England

[24] Univ Aberdeen, Dept Mental Hlth, Aberdeen AB25 2ZD, Scotland

[25] SUNY, Upstate Med Ctr, Syracuse, NY 13210 USA

[26] Washington VA Med Ctr, Washington, DC 20422 USA

[27] Georgetown Univ, Sch Med, Dept Psychiat, Washington, DC 20057 USA

[28] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA 23298 USA

[29] Dept Psychiat, P-9500310 Sao Miguel, Portugal

来源：

NATURE | 2008年 / 455卷 / 7210期

基金：

爱尔兰科学基金会; 英国惠康基金; 英国医学研究理事会;

关键词：

D O I：

10.1038/nature07239

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 severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73 - 90% ( ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants ( CNVs) have been identified in individual patients with schizophrenia(2-7) and also in neurodevelopmental disorders(8-11), but large- scale genome- wide surveys have not been performed. Here we report a genome- wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high- density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15- fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single- occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo- cardio- facial syndrome, which includes psychotic symptoms in 30% of patients(12). Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome- wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome- wide and at specific loci.

引用

页码：237 / 241

页数：5

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