A polygenic burden of rare disruptive mutations in schizophrenia

被引：990

作者：

Purcell, Shaun M. ^{[1
,2
,3
,4
,5
]}

Moran, Jennifer L. ^{[1
]}

Fromer, Menachem ^{[1
,2
,3
,4
]}

Ruderfer, Douglas ^{[2
,3
]}

Solovieff, Nadia ^{[4
]}

Roussos, Panos ^{[2
,3
]}

O'Dushlaine, Colm ^{[1
]}

Chambert, Kimberly ^{[1
]}

Bergen, Sarah E. ^{[1
,6
]}

Kahler, Anna ^{[6
]}

Duncan, Laramie ^{[1
,4
,5
]}

Stahl, Eli ^{[2
,3
]}

Genovese, Giulio ^{[1
]}

Fernandez, Esperanza ^{[7
,8
]}

Collins, Mark O. ^{[9
]}

Komiyama, Noboru H. ^{[9
]}

Choudhary, Jyoti S. ^{[9
]}

Magnusson, Patrik K. E. ^{[6
]}

Banks, Eric ^{[5
]}

Shakir, Khalid ^{[5
]}

Garimella, Kiran ^{[5
]}

Fennell, Tim ^{[5
]}

DePristo, Mark ^{[5
]}

Grant, Seth G. N. ^{[10
,11
]}

Haggarty, Stephen J. ^{[1
,4
,12
]}

Gabriel, Stacey ^{[5
]}

Scolnick, Edward M. ^{[1
]}

Lander, Eric S. ^{[5
]}

Hultman, Christina M. ^{[6
]}

Sullivan, Patrick F. ^{[13
,14
]}

McCarroll, Steven A. ^{[1
,5
,15
]}

Sklar, Pamela ^{[2
,3
,16
]}

机构：

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

[2] Icahn Sch Med Mt Sinai, Div Psychiat Genom, Dept Psychiat, New York, NY 10029 USA

[3] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA

[4] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA

[5] Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA 02142 USA

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

[7] Katholieke Univ Leuven, Ctr Human Genet, B-3000 Louvain, Belgium

[8] VIB Ctr Biol Dis, B-3000 Louvain, Belgium

[9] Wellcome Trust Sanger Inst, Prote Mass Spectrometry, Cambridge CB10 1SA, England

[10] Univ Edinburgh, Ctr Clin Brain Sci, Genes Cognit Programme, Edinburgh EH16 4SB, Midlothian, Scotland

[11] Univ Edinburgh, Ctr Neuroregenerat, Edinburgh EH16 4SB, Midlothian, Scotland

[12] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA

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

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

[15] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[16] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA

来源：

NATURE | 2014年 / 506卷 / 7487期

基金：

瑞典研究理事会; 英国医学研究理事会; 英国惠康基金; 美国国家卫生研究院;

关键词：

DE-NOVO MUTATIONS; MESSENGER-RNA; POSTSYNAPTIC DENSITY-95; INTELLECTUAL DISABILITY; ASSOCIATION ANALYSIS; PROTEIN; VARIANT; AUTISM; RISK; COMPLEX;

D O I：

10.1038/nature12975

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 common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.

引用

页码：185 / +

页数：17

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