Population‐based identity‐by‐descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia. Issue 3 (23rd February 2019)

• Record Type: Journal Article
• Authors: Harold, Denise; Connolly, Siobhan; Riley, Brien P.; Kendler, Kenneth S.; McCarthy, Shane E.; McCombie, William R.; Richards, Alex; Owen, Michael J.; O'Donovan, Michael C.; Walters, James; Donohoe, Gary; Gill, Michael; Corvin, Aiden; Morris, Derek W.
• Other Names: Donnelly Peter investigator.; Bates Lesley investigator.; Barroso Ines investigator.; Blackwell Jenefer M. investigator.; Bramon Elvira investigator.; Brown Matthew A. investigator.; Casas Juan P. investigator.; Corvin Aiden investigator.; Deloukas Panos investigator.; Duncanson Audrey investigator.; Jankowski Janusz investigator.; Markus Hugh S. investigator.; Mathew Christopher G. investigator.; Palmer Colin N. A. investigator.; Plomin Robert investigator.; Rautanen Anna investigator.; Sawcer Stephen J. investigator.; Trembath Richard C. investigator.; Viswanathan Ananth C. investigator.; Wood Nicholas W. investigator.; Spencer Chris C. A. investigator.; Band Gavin investigator.; Bellenguez Céline investigator.; Freeman Colin investigator.; Hellenthal Garrett investigator.; Giannoulatou Eleni investigator.; Hopkins Lucinda investigator.; Pirinen Matti investigator.; Pearson Richard investigator.; Strange Amy investigator.; Su Zhan investigator.; Vukcevic Damjan investigator.; Langford Cordelia investigator.; Hunt Sarah E. investigator.; Edkins Sarah investigator.; Gwilliam Rhian investigator.; Blackburn Hannah investigator.; Bumpstead Suzannah J. investigator.; Dronov Serge investigator.; Gillman Matthew investigator.; Gray Emma investigator.; Hammond Naomi investigator.; Jayakumar Alagurevathi investigator.; McCann Owen T. investigator.; Liddle Jennifer investigator.; Potter Simon C. investigator.; Ravindrarajah Radhi investigator.; Ricketts Michelle investigator.; Waller Matthew investigator.; Weston Paul investigator.; Widaa Sara investigator.; Whittaker Pamela investigator.; Ripke Stephan investigator.; Neale Benjamin M. investigator.; Corvin Aiden investigator.; Walters James T. R. investigator.; Farh Kai‐How investigator.; Holmans Peter A. investigator.; Lee Phil investigator.; Bulik‐Sullivan Brendan investigator.; Collier David A. investigator.; Huang Hailiang investigator.; Pers Tune H. investigator.; Agartz Ingrid investigator.; Agerbo Esben investigator.; Albus Margot investigator.; Alexander Madeline investigator.; Amin Farooq investigator.; Bacanu Silviu A. investigator.; Begemann Martin investigator.; Belliveau Richard A. investigator.; Bene Judit investigator.; Bergen Sarah E. investigator.; Bevilacqua Elizabeth investigator.; Bigdeli Tim B. investigator.; Black Donald W. investigator.; Bruggeman Richard investigator.; Buccola Nancy G. investigator.; Buckner Randy L. investigator.; Byerley William investigator.; Cahn Wiepke investigator.; Cai Guiqing investigator.; Campion Dominique investigator.; Cantor Rita M. investigator.; Carr Vaughan J. investigator.; Carrera Noa investigator.; Catts Stanley V. investigator.; Chambert Kimberley D. investigator.; Chan Raymond C. K. investigator.; Chan Ronald Y. L. investigator.; Chen Eric Y. H. investigator.; Cheng Wei investigator.; Cheung Eric F. C. investigator.; Chong Siow Ann investigator.; Cloninger C. Robert investigator.; Cohen David investigator.; Cohen Nadine investigator.; Cormican Paul investigator.; Craddock Nick investigator.; Crowley James J. investigator.; Curtis David investigator.; Davidson Michael investigator.; Davis Kenneth L. investigator.; Degenhardt Franziska investigator.; Del Favero Jurgen investigator.; Demontis Ditte investigator.; Dikeos Dimitris investigator.; Dinan Timothy investigator.; Djurovic Srdjan investigator.; Donohoe Gary investigator.; Drapeau Elodie investigator.; Duan Jubao investigator.; Dudbridge Frank investigator.; Durmishi Naser investigator.; Eichhammer Peter investigator.; Eriksson Johan investigator.; Escott‐Price Valentina investigator.; Essioux Laurent investigator.; Fanous Ayman H. investigator.; Farrell Martilias S. investigator.; Frank Josef investigator.; Franke Lude investigator.; Freedman Robert investigator.; Freimer Nelson B. investigator.; Friedl Marion investigator.; Friedman Joseph I. investigator.; Fromer Menachem investigator.; Genovese Giulio investigator.; Georgieva Lyudmila investigator.; Giegling Ina investigator.; Giusti‐Rodríguez Paola investigator.; Godard Stephanie investigator.; Goldstein Jacqueline I. investigator.; Golimbet Vera investigator.; Gopal Srihari investigator.; Gratten Jacob investigator.; de Haan Lieuwe investigator.; Hammer Christian investigator.; Hamshere Marian L. investigator.; Hansen Mark investigator.; Hansen Thomas investigator.; Haroutunian Vahram investigator.; Hartmann Annette M. investigator.; Henskens Frans A. investigator.; Herms Stefan investigator.; Hirschhorn Joel N. investigator.; Hoffmann Per investigator.; Hofman Andrea investigator.; Hollegaard Mads V. investigator.; Hougaard David M. investigator.; Ikeda Masashi investigator.; Joa Inge investigator.; Julià Antonio investigator.; Kalaydjieva Luba investigator.; Karachanak‐Yankova Sena investigator.; Karjalainen Juha investigator.; Kavanagh David investigator.; Keller Matthew C. investigator.; Kennedy James L. investigator.; Khrunin Andrey investigator.; Kim Yunjung investigator.; Klovins Janis investigator.; Knowles James A. investigator.; Konte Bettina investigator.; Kucinskas Vaidutis investigator.; Kucinskiene Zita Ausrele investigator.; Kuzelova‐Ptackova Hana investigator.; Kähler Anna K. investigator.; Laurent Claudine investigator.; Lee Jimmy investigator.; Lee S. Hong investigator.; Legge Sophie E. investigator.; Lerer Bernard investigator.; Li Miaoxin investigator.; Li Tao investigator.; Liang Kung‐Yee investigator.; Lieberman Jeffrey investigator.; Limborska Svetlana investigator.; Loughland Carmel M. investigator.; Lubinski Jan investigator.; Lönnqvist Jouko investigator.; Macek Milan investigator.; Magnusson Patrik K. E. investigator.; Maher Brion S. investigator.; Maier Wolfgang investigator.; Mallet Jacques investigator.; Marsal Sara investigator.; Mattheisen Manuel investigator.; Mattingsdal Morten investigator.; McCarley Robert W. investigator.; McDonald Colm investigator.; McIntosh Andrew M. investigator.; Meier Sandra investigator.; Meijer Carin J. investigator.; Melegh Bela investigator.; Melle Ingrid investigator.; Mesholam‐Gately Raquelle I. investigator.; Metspalu Andres investigator.; Michie Patricia T. investigator.; Milani Lili investigator.; Milanova Vihra investigator.; Mokrab Younes investigator.; Morris Derek W. investigator.; Mors Ole investigator.; Murphy Kieran C. investigator.; Murray Robin M. investigator.; Myin‐Germeys Inez investigator.; Müller‐Myhsok Bertram investigator.; Nelis Mari investigator.; Nenadic Igor investigator.; Nertney Deborah A. investigator.; Nestadt Gerald investigator.; Nicodemus Kristin K. investigator.; Nikitina‐Zake Liene investigator.; Nisenbaum Laura investigator.; Nordin Annelie investigator.; O'Callaghan Eadbhard investigator.; O'Dushlaine Colm investigator.; O'Neill F. Anthony investigator.; Oh Sang‐Yun investigator.; Olincy Ann investigator.; Olsen Line investigator.; Van Os Jim investigator.; Pantelis Christos investigator.; Papadimitriou George N. investigator.; Papiol Sergi investigator.; Parkhomenko Elena investigator.; Pato Michele T. investigator.; Paunio Tiina investigator.; Pejovic‐Milovancevic Milica investigator.; Perkins Diana O. investigator.; Pietiläinen Olli investigator.; Pimm Jonathan investigator.; Pocklington Andrew J. investigator.; Price Alkes investigator.; Pulver Ann E. investigator.; Purcell Shaun M. investigator.; Quested Digby investigator.; Rasmussen Henrik B. investigator.; Reichenberg Abraham investigator.; Reimers Mark A. investigator.; Richards Alexander L. investigator.; Roffman Joshua L. investigator.; Roussos Panos investigator.; Ruderfer Douglas M. investigator.; Salomaa Veikko investigator.; Sanders Alan R. investigator.; Schall Ulrich investigator.; Schubert Christian R. investigator.; Schulze Thomas G. investigator.; Schwab Sibylle G. investigator.; Scolnick Edward M. investigator.; Scott Rodney J. investigator.; Seidman Larry J. investigator.; Shi Jianxin investigator.; Sigurdsson Engilbert investigator.; Silagadze Teimuraz investigator.; Silverman Jeremy M. investigator.; Sim Kang investigator.; Slominsky Petr investigator.; Smoller Jordan W. investigator.; So Hon‐Cheong investigator.; Spencer Chris C. A. investigator.; Stahl Eli A. investigator.; Stefansson Hreinn investigator.; Steinberg Stacy investigator.; Stogmann Elisabeth investigator.; Straub Richard E. investigator.; Strengman Eric investigator.; Strohmaier Jana investigator.; Stroup T. Scott investigator.; Subramaniam Mythily investigator.; Suvisaari Jaana investigator.; Svrakic Dragan M. investigator.; Szatkiewicz Jin P. investigator.; Söderman Erik investigator.; Thirumalai Srinivas investigator.; Toncheva Draga investigator.; Tosato Sarah investigator.; Veijola Juha investigator.; Waddington John investigator.; Walsh Dermot investigator.; Wang Dai investigator.; Wang Qiang investigator.; Webb Bradley T. investigator.; Weiser Mark investigator.; Wildenauer Dieter B. investigator.; Williams Nigel M. investigator.; Williams Stephanie investigator.; Witt Stephanie H. investigator.; Wolen Aaron R. investigator.; Wong Emily H. M. investigator.; Wormley Brandon K. investigator.; Xi Hualin Simon investigator.; Zai Clement C. investigator.; Zheng Xuebin investigator.; Zimprich Fritz investigator.; Wray Naomi R. investigator.; Stefansson Kari investigator.; Visscher Peter M. investigator.; Adolfsson Rolf investigator.; Andreassen Ole A. investigator.; Blackwood Douglas H. R. investigator.; Bramon Elvira investigator.; Buxbaum Joseph D. investigator.; Børglum Anders D. investigator.; Darvasi Ariel investigator.; Domenici Enrico investigator.; Ehrenreich Hannelore investigator.; Esko Tõnu investigator.; Gejman Pablo V. investigator.; Gill Michael investigator.; Gurling Hugh investigator.; Hultman Christina M. investigator.; Iwata Nakao investigator.; Jablensky Assen V. investigator.; Jönsson Erik G. investigator.; Kendler Kenneth S. investigator.; Kirov George investigator.; Knight Jo investigator.; Lencz Todd investigator.; Levinson Douglas F. investigator.; Li Qingqin S. investigator.; Liu Jianjun investigator.; Malhotra Anil K. investigator.; McCarroll Steven A. investigator.; McQuillin Andrew investigator.; Moran Jennifer L. investigator.; Mortensen Preben B. investigator.; Mowry Bryan J. investigator.; Owen Michael J. investigator.; Palotie Aarno investigator.; Pato Carlos N. investigator.; Petryshen Tracey L. investigator.; Posthuma Danielle investigator.; Riley Brien P. investigator.; Rujescu Dan investigator.; Sham Pak C. investigator.; Sklar Pamela investigator.; Clair David St investigator.; Weinberger Daniel R. investigator.; Wendland Jens R. investigator.; Werge Thomas investigator.; Daly Mark J. investigator.; Sullivan Patrick F. investigator.; O'Donovan Michael C. investigator.;
• Is Part Of: American journal of medical genetics. Volume 180:Issue 3(2019)
• Page Start: 223
• Page End: 231
• Publication Date: 2019-02-23
• Subjects: GWAS -- IBD mapping -- rare variants; Neuropsychiatry -- Periodicals; Medical genetics -- Periodicals; 616.8904205
• DOI: 10.1002/ajmg.b.32716
• Languages: English
• ISSNs: 1552-4841

Abstract

Abstract : Genome‐wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re‐analyze an Irish schizophrenia GWAS dataset ( n = 3, 473) by performing identity‐by‐descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow‐up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.