1. No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study
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Johnson, Emma C., Bjelland, Douglas W., Howrigan, Daniel P., Abdellaoui, Abdel, Breen, Gerome, Borglum, Anders, Cichon, Sven, Degenhardt, Franziska, Forstner, Andreas J., Frank, Josef, Genovese, Giulio, Heilmann-Heimbach, Stefanie, Herms, Stefan, Hoffman, Per, Maier, Wolfgang, Mattheisen, Manuel, Morris, Derek, Mowry, Bryan, Müller-Mhysok, Betram, Neale, Benjamin, Nenadic, Igor, Nöthen, Markus M., O’Dushlaine, Colm, Rietschel, Marcella, Ruderfer, Douglas M., Rujescu, Dan, Schulze, Thomas G., Simonson, Matthew A., Stahl, Eli, Strohmaier, Jana, Witt, Stephanie H., Ripke, Stephan, Neale, Benjamin M., Corvin, Aiden, Walters, James T R, Farh, Kai How, Holmans, Peter A., Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A., Huang, Hailiang, Pers, Tune H., Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A., Begemann, Martin, Belliveau, Richard A., Bene, Judit, Bergen, Sarah E., Bevilacqua, Elizabeth, Bigdeli, Tim B., Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M., Carr, Vaughan J., Carrera, Noa, Catts, Stanley V., Chambert, Kimberly D., Chan, Raymond C K, Chen, Ronald Y L, Chen, Eric Y H, Cheng, Wei, Cheung, Eric F C, Chong, Siow Ann, Robert Cloninger, C., Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J., Curtis, David, Davidson, Michael, Davis, Kenneth L., Del Favero, Jurgen, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H., Farrell, Martilias S., Franke, Lude, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Friedman, Joseph I., Fromer, Menachem, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L., Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M., Henskens, Frans A., Hirschhorn, Joel N., Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V., Hougaard, David M., Ikeda, Masashi, Joa, Inge, Julià, Antonio, Kahn, René S., Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Kennedy, James L., Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Knowles, James A., Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kähler, Anna K., Laurent, Claudine, Chee Keong, Jimmy Lee, Hong Lee, S., Legge, Sophie E., Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M., Lubinski, Jan, Lönnqvist, Jouko, Macek, Milan, Magnusson, Patrik K E, Maher, Brion S., Mallet, Jacques, Marsal, Sara, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Meier, Sandra, Meijer, Carin J., Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W., Mors, Ole, Murphy, Kieran C., Murray, Robin M., Myin-Germeys, Inez, Müller-Myhsok, Bertram, Nelis, Mari, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, Anthony O'Neill, F., Oh, Sang Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N., Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O., 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, Salomaa, Veikko, Sanders, Alan R., Schall, Ulrich, Schubert, Christian R., Schwab, Sibylle G., Scolnick, Edward M., Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M., Sim, Kang, Slominsky, Petr, Smoller, Jordan W., So, Hon Cheong, Spencer, Chris C A, Stahl, Eli A., Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E., Strengman, Eric, Scott Stroup, T., Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Söderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Wolen, Aaron R., Wong, Emily H M, Wormley, Brandon K., Xi, Hualin Simon, Zai, Clement C., Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R., Stefansson, Kari, Visscher, Peter M., Adolfsson, Rolf, Andreassen, Ole A., Blackwood, Douglas H R, Bramon, Elvira, Buxbaum, Joseph D., Børglum, Anders D., Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, 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, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., McCarroll, Steven A., McQuillin, Andrew, Moran, Jennifer L., Mortensen, Preben B., Mowry, Bryan J., Ophoff, Roel A., Owen, Michael J., Palotie, Aarno, Pato, Carlos N., Petryshen, Tracey L., Posthuma, Danielle, Riley, Brien P., Sham, Pak C., Sklar, Pamela, Clair, David S., Weinberger, Daniel R., Wendland, Jens R., Werge, Thomas, Daly, Mark J., O'Donovan, Michael C., Sullivan, Patrick F., Keller, Matthew C., Biological Psychology, Johnson, Emma C, Bjelland, Douglas W, Howrigan, Daniel P, Abdellaoui, Abdel, Lee, S Hong, Keller, Matthew C, and Schizophrenia Working Group of the Psychiatric Genomics Consortium
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0301 basic medicine ,Male ,Cancer Research ,Heredity ,Ecology, Evolution, Behavior and Systematics ,Molecular Biology ,Genetics ,Genetics (clinical) ,Social Sciences ,Genome-wide association study ,Disease ,030105 genetics & heredity ,Runs of Homozygosity ,Homozygosity ,Consanguinity ,Sociology ,Polymorphism (computer science) ,Consortia ,Medicine and Health Sciences ,Genetics(clinical) ,Inbreeding ,Ecology ,Depression ,Homozygote ,Genomics ,3. Good health ,Schizophrenia ,Research Design ,Physical Sciences ,Female ,Statistics (Mathematics) ,Research Article ,lcsh:QH426-470 ,Evolution ,Replication Studies ,inbreeding ,Single-nucleotide polymorphism ,Biology ,Genome Complexity ,Research and Analysis Methods ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,SDG 17 - Partnerships for the Goals ,Behavior and Systematics ,SDG 3 - Good Health and Well-being ,Mental Health and Psychiatry ,medicine ,Confidence Intervals ,Humans ,replication study ,Mood Disorders ,Genome, Human ,Biology and Life Sciences ,Computational Biology ,medicine.disease ,schizophrenia ,lcsh:Genetics ,030104 developmental biology ,homozygosity ,Mathematics ,Genome-Wide Association Study - Abstract
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., Author Summary It is well known that mating between relatives increases the risk that a child will have a rare recessive genetic disease, but there has also been increasing interest and inconsistent findings on whether inbreeding is a risk factor for common, complex psychiatric disorders such as schizophrenia. The best powered study to date investigating this theory predicted that the odds of developing schizophrenia increase by approximately 17% for every additional percent of the genome that shows evidence of inbreeding. In this replication, we used genome-wide single nucleotide polymorphism data from 18,562 schizophrenia cases and 21,268 controls to quantify the degree to which they were inbred and to test the hypothesis that schizophrenia cases show higher mean levels of inbreeding. Contrary to the original study, we did not find evidence for distant inbreeding to play a role in schizophrenia risk. There are various confounding factors that could explain the discrepancy in results from the original study and our replication, and this should serve as a cautionary note–careful attention should be paid to issues like ascertainment when using the data from genome-wide case-control association studies for secondary analyses for which the data may not have originally been intended.
- Published
- 2016