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No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

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Buckner, William F Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M Cantor, Vaughan J Carr, Noa Carrera, Stanley V Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y H Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Jurgen Del-Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H Fanous, Martilias S. Farrell, Lude Franke, Robert Freedman, Nelson B Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Lyudmila Georgieva, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M Hartmann, Frans A Henskens, Joel N Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K Kähler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Patrik K E Magnusson, Brion S Maher, Jacques Mallet, Sara Marsal, Morten Mattingsdal, Robert W McCarley, Colm McDonald, Andrew M. McIntosh, Sandra M Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W Morris, Ole Mors, Kieran C Murphy, Robin M Murray, Inez Myin-Germeys, Bertram Müller-Myhsok, Mari Nelis, Deborah A Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O'Callaghan, Colm T O'Dushlaine, F. Anthony O'Neill, Sang Yun Oh, Ann Olincy, Line Olsen, Jim van Os, Christos Pantelis, George N Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes L Price, Ann E Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L Roffman, Panos Roussos, Veikko Salomaa, Alan R Sanders, Ulrich Schall, Christian R. Schubert, Sibylle G Schwab, Edward M. Scolnick, Rodney J Scott, Larry J. 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Andreassen, Douglas H R Blackwood, Elvira Bramon, Joseph D Buxbaum, Anders D Børglum, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tõnu Esko, Pablo V Gejman, Michael Gill, Hugh Gurling, Christina M Hultman, Nakao Iwata, Assen V Jablensky, Erik G Jönsson, Kenneth S Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F Levinson, Qingqin S. Li, Jianjun Liu, Anil K Malhotra, Steven A McCarroll, Andrew McQuillin, Jennifer L. Moran, Preben B Mortensen, Bryan J Mowry, Markus M Nöthen, Roel A Ophoff, Michael J Owen, Aarno Palotie, Carlos N Pato, Tracey L. Petryshen, Danielle Posthuma, Brien P Riley, Pak-Chung Sham, Pamela Sklar, David St Clair, Daniel R Weinberger, Jens R. Wendland, Thomas Werge, Mark J Daly, Michael C O'Donovan, Patrick F Sullivan, Matthew C Keller

It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (β = 16.1, CI(β) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (β = 4.86,CI(β) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest.

Original languageEnglish
Article numbere1006343
JournalPLOS Genetics
Volume12
Issue number10
Number of pages20
ISSN1553-7390
DOIs
Publication statusPublished - Oct 2016

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