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Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.

ABSTRACT: 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 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). 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.

SUBMITTER: Marshall CR

PROVIDER: S-EPMC5737772 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.

Marshall Christian R CR Howrigan Daniel P DP Merico Daniele D Thiruvahindrapuram Bhooma B Wu Wenting W Greer Douglas S DS Antaki Danny D Shetty Aniket A Holmans Peter A PA Pinto Dalila D Gujral Madhusudan M Brandler William M WM Malhotra Dheeraj D Wang Zhouzhi Z Fajarado Karin V Fuentes KVF Maile Michelle S MS Ripke Stephan S Agartz Ingrid I Albus Margot M Alexander Madeline M Amin Farooq F Atkins Joshua J Bacanu Silviu A SA Belliveau Richard A RA Bergen Sarah E SE Bertalan Marcelo M Bevilacqua Elizabeth E Bigdeli Tim B TB Black Donald W DW Bruggeman Richard R Buccola Nancy G NG Buckner Randy L RL Bulik-Sullivan Brendan B Byerley William W Cahn Wiepke W Cai Guiqing G Cairns Murray J MJ Campion Dominique D Cantor Rita M RM Carr Vaughan J VJ Carrera Noa N Catts Stanley V SV Chambert Kimberley D KD Cheng Wei W Cloninger C Robert CR Cohen David D Cormican Paul P Craddock Nick N Crespo-Facorro Benedicto B Crowley James J JJ Curtis David D Davidson Michael M Davis Kenneth L KL Degenhardt Franziska F Del Favero Jurgen J DeLisi Lynn E LE Dikeos Dimitris D Dinan Timothy T Dinan Timothy T Djurovic Srdjan S Donohoe Gary G Drapeau Elodie E Duan Jubao J Dudbridge Frank F Eichhammer Peter P Eriksson Johan J Escott-Price Valentina V Essioux Laurent L Fanous Ayman H AH Farh Kai-How KH Farrell Martilias S MS Frank Josef J Franke Lude L Freedman Robert R Freimer Nelson B NB Friedman Joseph I JI Forstner Andreas J AJ Fromer Menachem M Genovese Giulio G Georgieva Lyudmila L Gershon Elliot S ES Giegling Ina I Giusti-Rodríguez Paola P Godard Stephanie S Goldstein Jacqueline I JI Gratten Jacob J de Haan Lieuwe L Hamshere Marian L ML Hansen Mark M Hansen Thomas T Haroutunian Vahram V Hartmann Annette M AM Henskens Frans A FA Herms Stefan S Hirschhorn Joel N JN Hoffmann Per P Hofman Andrea A Huang Hailiang H Ikeda Masashi M Joa Inge I Kähler Anna K AK Kahn René S RS Kalaydjieva Luba L Karjalainen Juha J Kavanagh David D Keller Matthew C MC Kelly Brian J BJ Kennedy James L JL Kim Yunjung Y Knowles James A JA Konte Bettina B Laurent Claudine C Lee Phil P Lee S Hong SH Legge Sophie E SE Lerer Bernard B Levy Deborah L DL Liang Kung-Yee KY Lieberman Jeffrey J Lönnqvist Jouko J Loughland Carmel M CM Magnusson Patrik K E PKE Maher Brion S BS Maier Wolfgang W Mallet Jacques J Mattheisen Manuel M Mattingsdal Morten M McCarley Robert W RW McDonald Colm C McIntosh Andrew M AM Meier Sandra S Meijer Carin J CJ Melle Ingrid I Mesholam-Gately Raquelle I RI Metspalu Andres A Michie Patricia T PT Milani Lili L Milanova Vihra V Mokrab Younes Y Morris Derek W DW Müller-Myhsok Bertram B Murphy Kieran C KC Murray Robin M RM Myin-Germeys Inez I Nenadic Igor I Nertney Deborah A DA Nestadt Gerald G Nicodemus Kristin K KK Nisenbaum Laura L Nordin Annelie A O'Callaghan Eadbhard E O'Dushlaine Colm C Oh Sang-Yun SY Olincy Ann A Olsen Line L O'Neill F Anthony FA Van Os Jim J Pantelis Christos C Papadimitriou George N GN Parkhomenko Elena E Pato Michele T MT Paunio Tiina T Perkins Diana O DO Pers Tune H TH Pietiläinen Olli O Pimm Jonathan J Pocklington Andrew J AJ Powell John J Price Alkes A Pulver Ann E AE Purcell Shaun M SM Quested Digby D Rasmussen Henrik B HB Reichenberg Abraham A Reimers Mark A MA Richards Alexander L AL Roffman Joshua L JL Roussos Panos P Ruderfer Douglas M DM Salomaa Veikko V Sanders Alan R AR Savitz Adam A Schall Ulrich U Schulze Thomas G TG Schwab Sibylle G SG Scolnick Edward M EM Scott Rodney J RJ Seidman Larry J LJ Shi Jianxin J Silverman Jeremy M JM Smoller Jordan W JW Söderman Erik E Spencer Chris C A CCA Stahl Eli A EA Strengman Eric E Strohmaier Jana J Stroup T Scott TS Suvisaari Jaana J Svrakic Dragan M DM Szatkiewicz Jin P JP Thirumalai Srinivas S Tooney Paul A PA Veijola Juha J Visscher Peter M PM Waddington John J Walsh Dermot D Webb Bradley T BT Weiser Mark M Wildenauer Dieter B DB Williams Nigel M NM Williams Stephanie S Witt Stephanie H SH Wolen Aaron R AR Wormley Brandon K BK Wray Naomi R NR Wu Jing Qin JQ Zai Clement C CC Adolfsson Rolf R Andreassen Ole A OA Blackwood Douglas H R DHR Bramon Elvira E Buxbaum Joseph D JD Cichon Sven S Collier David A DA Corvin Aiden A Daly Mark J MJ Darvasi Ariel A Domenici Enrico E Esko Tõnu T Gejman Pablo V PV Gill Michael M Gurling Hugh H Hultman Christina M CM Iwata Nakao N Jablensky Assen V AV Jönsson Erik G EG Kendler Kenneth S KS Kirov George G Knight Jo J Levinson Douglas F DF Li Qingqin S QS McCarroll Steven A SA McQuillin Andrew A Moran Jennifer L JL Mowry Bryan J BJ Nöthen Markus M MM Ophoff Roel A RA Owen Michael J MJ Palotie Aarno A Pato Carlos N CN Petryshen Tracey L TL Posthuma Danielle D Rietschel Marcella M Riley Brien P BP Rujescu Dan D Sklar Pamela P St Clair David D Walters James T R JTR Werge Thomas T Sullivan Patrick F PF O'Donovan Michael C MC Scherer Stephen W SW Neale Benjamin M BM Sebat Jonathan J

Nature genetics 20161121 1

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<sup>-15</sup>), which persisted after excluding loci im ...[more]

PMID: 27869829

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Project description:Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5-3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.

Dataset Information

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.

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Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.

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