一项对41321名受试者的全基因组研究：拷贝数变异对精神分裂症的影响
Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.
作者信息
Marshall Christian R, Howrigan Daniel P, Merico Daniele, Thiruvahindrapuram Bhooma, Wu Wenting, Greer Douglas S, Antaki Danny, Shetty Aniket, Holmans Peter A, Pinto Dalila, Gujral Madhusudan, Brandler William M, Malhotra Dheeraj, Wang Zhouzhi, Fajarado Karin V Fuentes, Maile Michelle S, Ripke Stephan, Agartz Ingrid, Albus Margot, Alexander Madeline, Amin Farooq, Atkins Joshua, Bacanu Silviu A, Belliveau Richard A, Bergen Sarah E, Bertalan Marcelo, Bevilacqua Elizabeth, Bigdeli Tim B, Black Donald W, Bruggeman Richard, Buccola Nancy G, Buckner Randy L, Bulik-Sullivan Brendan, Byerley William, Cahn Wiepke, Cai Guiqing, Cairns Murray J, Campion Dominique, Cantor Rita M, Carr Vaughan J, Carrera Noa, Catts Stanley V, Chambert Kimberley D, Cheng Wei, Cloninger C Robert, Cohen David, Cormican Paul, Craddock Nick, Crespo-Facorro Benedicto, Crowley James J, Curtis David, Davidson Michael, Davis Kenneth L, Degenhardt Franziska, Del Favero Jurgen, DeLisi Lynn E, Dikeos Dimitris, Dinan Timothy, Djurovic Srdjan, Donohoe Gary, Drapeau Elodie, Duan Jubao, Dudbridge Frank, Eichhammer Peter, Eriksson Johan, Escott-Price Valentina, Essioux Laurent, Fanous Ayman H, Farh Kai-How, Farrell Martilias S, Frank Josef, Franke Lude, Freedman Robert, Freimer Nelson B, Friedman Joseph I, Forstner Andreas J, Fromer Menachem, Genovese Giulio, Georgieva Lyudmila, Gershon Elliot S, Giegling Ina, Giusti-Rodríguez Paola, Godard Stephanie, Goldstein Jacqueline I, Gratten Jacob, de Haan Lieuwe, Hamshere Marian L, Hansen Mark, Hansen Thomas, Haroutunian Vahram, Hartmann Annette M, Henskens Frans A, Herms Stefan, Hirschhorn Joel N, Hoffmann Per, Hofman Andrea, Huang Hailiang, Ikeda Masashi, Joa Inge, Kähler Anna K, Kahn René S, Kalaydjieva Luba, Karjalainen Juha, Kavanagh David, Keller Matthew C, Kelly Brian J, Kennedy James L, Kim Yunjung, Knowles James A, Konte Bettina, Laurent Claudine, Lee Phil, Lee S Hong, Legge Sophie E, Lerer Bernard, Levy Deborah L, Liang Kung-Yee, Lieberman Jeffrey, Lönnqvist Jouko, Loughland Carmel M, Magnusson Patrik K E, Maher Brion S, Maier Wolfgang, Mallet Jacques, Mattheisen Manuel, Mattingsdal Morten, McCarley Robert W, McDonald Colm, McIntosh Andrew M, Meier Sandra, Meijer Carin J, Melle Ingrid, Mesholam-Gately Raquelle I, Metspalu Andres, Michie Patricia T, Milani Lili, Milanova Vihra, Mokrab Younes, Morris Derek W, Müller-Myhsok Bertram, Murphy Kieran C, Murray Robin M, Myin-Germeys Inez, Nenadic Igor, Nertney Deborah A, Nestadt Gerald, Nicodemus Kristin K, Nisenbaum Laura, Nordin Annelie, O'Callaghan Eadbhard, O'Dushlaine Colm, Oh Sang-Yun, Olincy Ann, Olsen Line, O'Neill F Anthony, Van Os Jim, Pantelis Christos, Papadimitriou George N, Parkhomenko Elena, Pato Michele T, Paunio Tiina, Perkins Diana O, Pers Tune H, Pietiläinen Olli, Pimm Jonathan, Pocklington Andrew J, Powell John, Price Alkes, Pulver Ann E, Purcell Shaun M, Quested Digby, Rasmussen Henrik B, Reichenberg Abraham, Reimers Mark A, Richards Alexander L, Roffman Joshua L, Roussos Panos, Ruderfer Douglas M, Salomaa Veikko, Sanders Alan R, Savitz Adam, Schall Ulrich, Schulze Thomas G, Schwab Sibylle G, Scolnick Edward M, Scott Rodney J, Seidman Larry J, Shi Jianxin, Silverman Jeremy M, Smoller Jordan W, Söderman Erik, Spencer Chris C A, Stahl Eli A, Strengman Eric, Strohmaier Jana, Stroup T Scott, Suvisaari Jaana, Svrakic Dragan M, Szatkiewicz Jin P, Thirumalai Srinivas, Tooney Paul A, Veijola Juha, Visscher Peter M, Waddington John, Walsh Dermot, Webb Bradley T, Weiser Mark, Wildenauer Dieter B, Williams Nigel M, Williams Stephanie, Witt Stephanie H, Wolen Aaron R, Wormley Brandon K, Wray Naomi R, Wu Jing Qin, Zai Clement C, Adolfsson Rolf, Andreassen Ole A, Blackwood Douglas H R, Bramon Elvira, Buxbaum Joseph D, Cichon Sven, Collier David A, Corvin Aiden, Daly Mark J, Darvasi Ariel, Domenici Enrico, Esko Tõnu, Gejman Pablo V, Gill Michael, Gurling Hugh, Hultman Christina M, Iwata Nakao, Jablensky Assen V, Jönsson Erik G, Kendler Kenneth S, Kirov George, Knight Jo, Levinson Douglas F, Li Qingqin S, McCarroll Steven A, McQuillin Andrew, Moran Jennifer L, Mowry Bryan J, Nöthen Markus M, Ophoff Roel A, Owen Michael J, Palotie Aarno, Pato Carlos N, Petryshen Tracey L, Posthuma Danielle, Rietschel Marcella, Riley Brien P, Rujescu Dan, Sklar Pamela, St Clair David, Walters James T R, Werge Thomas, Sullivan Patrick F, O'Donovan Michael C, Scherer Stephen W, Neale Benjamin M, Sebat Jonathan
机构信息
Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
出版信息
Nat Genet. 2017 Jan;49(1):27-35. doi: 10.1038/ng.3725. Epub 2016 Nov 21.
Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.
拷贝数变异（CNV）与精神分裂症（SCZ）的遗传病因密切相关。然而，由于样本量有限，对CNV在疾病风险中作用的全基因组研究受到了阻碍。我们试图通过对一个包含21,094例病例和20,227例对照的SCZ队列应用集中分析流程来解决这一障碍。在病例组中观察到CNV负荷的总体富集（优势比（OR）= 1.11，P = 5.7×10），在排除先前研究中涉及的位点后该富集仍然存在（OR = 1.07，P = 1.7×10）。CNV负荷在与突触功能相关的基因（OR = 1.68，P = 2.8×10）和小鼠神经行为表型相关的基因中富集（OR = 1.18，P = 7.3×10）。在8个位点获得了全基因组显著证据，包括1q21.1、2p16.3（NRXN1）、3q29、7q11.2、15q13.3、16p11.2远端、16p11.2近端和22q11.2。还发现了另外8个候选易感和保护位点的提示性支持证据，这些位点主要由非等位基因同源重组介导的CNV组成。
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