Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia

被引：329

作者：

Genovese, Giulio ^{[1
,2
,3
]}

Fromer, Menachem ^{[4
,5
]}

Stahl, Eli A. ^{[4
,5
]}

Ruderfer, Douglas M. ^{[4
,5
]}

Chambert, Kimberly ^{[1
]}

Landen, Mikael ^{[6
]}

Moran, Jennifer L. ^{[1
]}

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

Sklar, Pamela ^{[4
,5
]}

Sullivan, Patrick F. ^{[7
,8
,9
]}

Hultman, Christina M. ^{[9
]}

McCarroll, Steven A. ^{[1
,2
,3
]}

机构：

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

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

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

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

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

[6] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci Physiol, Dept Psychiat & Neurochem, Gothenburg, Sweden

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

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

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

来源：

NATURE NEUROSCIENCE | 2016年 / 19卷 / 11期

关键词：

AUTISM SPECTRUM DISORDERS; OF-FUNCTION VARIANTS; DE-NOVO; BRAIN-DEVELOPMENT; BIPOLAR DISORDER; GENES; MUTATIONS; ASSOCIATION; TRANSLOCATION; HERITABILITY;

D O I：

10.1038/nn.4402

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

By analyzing the exomes of 12,332 unrelated Swedish individuals, including 4,877 individuals affected with schizophrenia, in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant among individuals with schizophrenia than among controls (P = 1.3 x 10(-10)). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this elevation arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.

引用

页码：1433 / 1441

页数：9

共 49 条

[1] Characterization of the proteome, diseases and evolution of the human postsynaptic density [J].

Bayes, Alex ;

van de Lagemaat, Louie N. ;

Collins, Mark O. ;

Croning, Mike D. R. ;

Whittle, Ian R. ;

Choudhary, Jyoti S. ;

Grant, Seth G. N. .

NATURE NEUROSCIENCE, 2011, 14 (01) :19-21

[2] Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites [J].

Betel, Doron ;

Koppal, Anjali ;

Agius, Phaedra ;

Sander, Chris ;

Leslie, Christina .

GENOME BIOLOGY, 2010, 11 (08)

[3] A systematic review and meta-analysis of the fertility of patients with schizophrenia and their unaffected relatives [J].

Bundy, H. ;

Stahl, D. ;

MacCabe, J. H. .

ACTA PSYCHIATRICA SCANDINAVICA, 2011, 123 (02) :98-106

[4] A transcriptome database for astrocytes, neurons, and oligodendrocytes: A new resource for understanding brain development and function [J].

Cahoy, John D. ;

Emery, Ben ;

Kaushal, Amit ;

Foo, Lynette C. ;

Zamanian, Jennifer L. ;

Christopherson, Karen S. ;

Xing, Yi ;

Lubischer, Jane L. ;

Krieg, Paul A. ;

Krupenko, Sergey A. ;

Thompson, Wesley J. ;

Barres, Ben A. .

JOURNAL OF NEUROSCIENCE, 2008, 28 (01) :264-278

[5] FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism [J].

Darnell, Jennifer C. ;

Van Driesche, Sarah J. ;

Zhang, Chaolin ;

Hung, Ka Ying Sharon ;

Mele, Aldo ;

Fraser, Claire E. ;

Stone, Elizabeth F. ;

Chen, Cynthia ;

Fak, John J. ;

Chi, Sung Wook ;

Licatalosi, Donny D. ;

Richter, Joel D. ;

Darnell, Robert B. .

CELL, 2011, 146 (02) :247-261

[6] Synaptic, transcriptional and chromatin genes disrupted in autism [J].

De Rubeis, Silvia ;

He, Xin ;

Goldberg, Arthur P. ;

Poultney, Christopher S. ;

Samocha, Kaitlin ;

Cicek, A. Ercument ;

Kou, Yan ;

Liu, Li ;

Fromer, Menachem ;

Walker, Susan ;

Singh, Tarjinder ;

Klei, Lambertus ;

Kosmicki, Jack ;

Fu, Shih-Chen ;

Aleksic, Branko ;

Biscaldi, Monica ;

Bolton, Patrick F. ;

Brownfeld, Jessica M. ;

Cai, Jinlu ;

Campbell, Nicholas G. ;

Carracedo, Angel ;

Chahrour, Maria H. ;

Chiocchetti, Andreas G. ;

Coon, Hilary ;

Crawford, Emily L. ;

Crooks, Lucy ;

Curran, Sarah R. ;

Dawson, Geraldine ;

Duketis, Eftichia ;

Fernandez, Bridget A. ;

Gallagher, Louise ;

Geller, Evan ;

Guter, Stephen J. ;

Hill, R. Sean ;

Ionita-Laza, Iuliana ;

Gonzalez, Patricia Jimenez ;

Kilpinen, Helena ;

Klauck, Sabine M. ;

Kolevzon, Alexander ;

Lee, Irene ;

Lei, Jing ;

Lehtimaeki, Terho ;

Lin, Chiao-Feng ;

Ma'ayan, Avi ;

Marshall, Christian R. ;

McInnes, Alison L. ;

Neale, Benjamin ;

Owen, Michael J. ;

Ozaki, Norio ;

Parellada, Mara .

NATURE, 2014, 515 (7526) :209-+

[7] Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics [J].

Fagerberg, Linn ;

Hallstrom, Bjorn M. ;

Oksvold, Per ;

Kampf, Caroline ;

Djureinovic, Dijana ;

Odeberg, Jacob ;

Habuka, Masato ;

Tahmasebpoor, Simin ;

Danielsson, Angelika ;

Edlund, Karolina ;

Asplund, Anna ;

Sjostedt, Evelina ;

Lundberg, Emma ;

Szigyarto, Cristina Al-Khalili ;

Skogs, Marie ;

Takanen, Jenny Ottosson ;

Berling, Holger ;

Tegel, Hanna ;

Mulder, Jan ;

Nilsson, Peter ;

Schwenk, Jochen M. ;

Lindskog, Cecilia ;

Danielsson, Frida ;

Mardinoglu, Adil ;

Sivertsson, Asa ;

von Feilitzen, Kalle ;

Forsberg, Mattias ;

Zwahlen, Martin ;

Olsson, IngMarie ;

Navani, Sanjay ;

Huss, Mikael ;

Nielsen, Jens ;

Ponten, Fredrik ;

Uhlen, Mathias .

MOLECULAR & CELLULAR PROTEOMICS, 2014, 13 (02) :397-406

[8] Partitioning heritability by functional annotation using genome-wide association summary statistics [J].

Finucane, Hilary K. ;

Bulik-Sullivan, Brendan ;

Gusev, Alexander ;

Trynka, Gosia ;

Reshef, Yakir ;

Loh, Po-Ru ;

Anttila, Verneri ;

Xu, Han ;

Zang, Chongzhi ;

Farh, Kyle ;

Ripke, Stephan ;

Day, Felix R. ;

Purcell, Shaun ;

Stahl, Eli ;

Lindstrom, Sara ;

Perry, John R. B. ;

Okada, Yukinori ;

Raychaudhuri, Soumya ;

Daly, Mark J. ;

Patterson, Nick ;

Neale, Benjamin M. ;

Price, Alkes L. .

NATURE GENETICS, 2015, 47 (11) :1228-+

[9] De novo mutations in schizophrenia implicate synaptic networks [J].

Fromer, Menachem ;

Pocklington, Andrew J. ;

Kavanagh, David H. ;

Williams, Hywel J. ;

Dwyer, Sarah ;

Gormley, Padhraig ;

Georgieva, Lyudmila ;

Rees, Elliott ;

Palta, Priit ;

Ruderfer, Douglas M. ;

Carrera, Noa ;

Humphreys, Isla ;

Johnson, Jessica S. ;

Roussos, Panos ;

Barker, Douglas D. ;

Banks, Eric ;

Milanova, Vihra ;

Grant, Seth G. ;

Hannon, Eilis ;

Rose, Samuel A. ;

Chambert, Kimberly ;

Mahajan, Milind ;

Scolnick, Edward M. ;

Moran, Jennifer L. ;

Kirov, George ;

Palotie, Aarno ;

McCarroll, Steven A. ;

Holmans, Peter ;

Sklar, Pamela ;

Owen, Michael J. ;

Purcell, Shaun M. ;

O'Donovan, Michael C. .

NATURE, 2014, 506 (7487) :179-+

[10] The genetic landscape of intellectual disability arising from chromosome X [J].

Gecz, Jozef ;

Shoubridge, Cheryl ;

Corbett, Mark .

TRENDS IN GENETICS, 2009, 25 (07) :308-316

← 1 2 3 4 5 →