No reliable association between runs of homozygosity and schizophrenia in a well-powered replication study

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, Muller-Mhysok, Betram, Neale, Benjamin, Nenadic, Igor, Nothen, 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, Cloninger, C. Robert, 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-Rodriguez, 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, Julia, 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, Kahler, Anna K., Laurent, Claudine, Chee Keong, Jimmy Lee, Lee, S. Hong, Legge, Sophie E., Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M., Lubinski, Jan, Lonnqvist, 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, Muller-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, O'Neill, F. Anthony, 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., Pietilainen, 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, Stroup, T. Scott, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Soderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T., Weiserb, 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., Borglum, 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., Jonsson, 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., Nothen, Markus M., Ophoff, Roel A., Owen, Michael J., Palotie, Aarno, Pato, Carlos N., Petryshen, Tracey L., Posthuma, Danielle, Riley, Brien P., Sham, Pak C., Sklar, Pamela, St Clair, David, Weinberger, Daniel R., Wendland, Jens R., Werge, Thomas, Daly, Mark J., O'Donovan, Michael C., Sullivan, Patrick F. and Keller, Matthew C. (2016) No reliable association between runs of homozygosity and schizophrenia in a well-powered replication study. PLoS Genetics, 12 10: e1006343. doi:10.1371/journal.pgen.1006343


Author 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
Muller-Mhysok, Betram
Neale, Benjamin
Nenadic, Igor
Nothen, 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
Cloninger, C. Robert
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-Rodriguez, 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
Julia, 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
Kahler, Anna K.
Laurent, Claudine
Chee Keong, Jimmy Lee
Lee, S. Hong
Legge, Sophie E.
Lerer, Bernard
Li, Miaoxin
Li, Tao
Liang, Kung-Yee
Lieberman, Jeffrey
Limborska, Svetlana
Loughland, Carmel M.
Lubinski, Jan
Lonnqvist, 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
Muller-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
O'Neill, F. Anthony
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.
Pietilainen, 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
Stroup, T. Scott
Subramaniam, Mythily
Suvisaari, Jaana
Svrakic, Dragan M.
Szatkiewicz, Jin P.
Soderman, Erik
Thirumalai, Srinivas
Toncheva, Draga
Tosato, Sarah
Veijola, Juha
Waddington, John
Walsh, Dermot
Wang, Dai
Wang, Qiang
Webb, Bradley T.
Weiserb, 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.
Borglum, 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.
Jonsson, 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.
Nothen, Markus M.
Ophoff, Roel A.
Owen, Michael J.
Palotie, Aarno
Pato, Carlos N.
Petryshen, Tracey L.
Posthuma, Danielle
Riley, Brien P.
Sham, Pak C.
Sklar, Pamela
St Clair, David
Weinberger, Daniel R.
Wendland, Jens R.
Werge, Thomas
Daly, Mark J.
O'Donovan, Michael C.
Sullivan, Patrick F.
Keller, Matthew C.
Title No reliable association between runs of homozygosity and schizophrenia in a well-powered replication study
Journal name PLoS Genetics   Check publisher's open access policy
ISSN 1553-7404
1553-7390
Publication date 2016-10-28
Year available 2016
Sub-type Article (original research)
DOI 10.1371/journal.pgen.1006343
Open Access Status DOI
Volume 12
Issue 10
Start page e1006343
Total pages 20
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Language eng
Subject 1105 Ecology, Evolution, Behavior and Systematics
1312 Molecular Biology
1311 Genetics
2716 Genetics (clinical)
1306 Cancer Research
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.
Formatted 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.
Keyword Genetics & Heredity
Genetics & Heredity
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID K01MH085812
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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