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.
| Original language | English |
|---|---|
| Article number | e1006343 |
| Journal | PLOS Genetics |
| Volume | 12 |
| Issue number | 10 |
| Number of pages | 20 |
| ISSN | 1553-7390 |
| DOIs | |
| Publication status | Published - 1 Oct 2016 |
Access to Document
- 10.1371/journal.pgen.1006343Licence: CC BY
- No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication StudyFinal published version, 1.81 MBLicence: CC BY
Fingerprint
Dive into the research topics of 'No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study. / Johnson, Emma C.; Bjelland, Douglas W.; Howrigan, Daniel P et al.
In: PLOS Genetics, Vol. 12, No. 10, e1006343, 01.10.2016.Research output: Contribution to journal › Journal article › Research › peer-review
}
TY - JOUR
T1 - No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study
AU - Johnson, Emma C.
AU - Bjelland, Douglas W.
AU - Howrigan, Daniel P
AU - Abdellaoui, Abdel
AU - Breen, Gerome
AU - Borglum, Anders D.
AU - Cichon, Sven
AU - Degenhardt, Franziska
AU - Forstner, Andreas J
AU - Frank, Josef
AU - Genovese, Giulio
AU - Heilmann-Heimbach, Stefanie
AU - Herms, Stefan
AU - Hoffman, Per
AU - Maier, Wolfgang
AU - Mattheisen, Manuel
AU - Morris, Derek W
AU - Mowry, Bryan J
AU - Müller-Mhysok, Betram
AU - Neale, Benjamin M
AU - Nenadic, Igor
AU - Nöthen, Markus M
AU - O’Dushlaine, Colm
AU - Rietschel, Marcella
AU - Ruderfer, Douglas M
AU - Rujescu, Dan
AU - Schulze, Thomas G
AU - Simonson, Matthew A
AU - Stahl, Eli A
AU - Strohmaier, Jana
AU - Witt, Stephanie H.
AU - Ripke, Stephan
AU - Neale, Benjamin M
AU - Corvin, Aiden
AU - Walters, James T. R.
AU - Farh, Kai-How
AU - Holmans, Peter A
AU - Lee, Phil H
AU - Bulik-Sullivan, Brendan
AU - Collier, David A
AU - Huang, Hailiang
AU - Pers, Tune H.
AU - Agartz, Ingrid
AU - Agerbo, Esben
AU - Albus, Margot
AU - Alexander, Madeline
AU - Amin, Farooq
AU - Bacanu, Silviu-Alin
AU - Begemann, Martin
AU - Belliveau, Richard A.
AU - Bene, Judit
AU - Bergen, Sarah E
AU - Bevilacqua, Elizabeth
AU - Bigdeli, Tim B.
AU - Black, Donald W
AU - Bruggeman, Richard
AU - Buccola, Nancy G
AU - Buckner, Randy L.
AU - Byerley, William F
AU - Cahn, Wiepke
AU - Cai, Guiqing
AU - Campion, Dominique
AU - Cantor, Rita M
AU - Carr, Vaughan J
AU - Carrera, Noa
AU - Catts, Stanley V
AU - Chambert, Kimberly D.
AU - Chan, Raymond C.K.
AU - Chen, Ronald Y.L.
AU - Chen, Eric Y H
AU - Cheng, Wei
AU - Cheung, Eric F.C.
AU - Chong, Siow Ann
AU - Robert Cloninger, C.
AU - Cohen, David
AU - Cohen, Nadine
AU - Cormican, Paul
AU - Craddock, Nick
AU - Crowley, James J.
AU - Curtis, David
AU - Davidson, Michael
AU - Davis, Kenneth L.
AU - Del-Favero, Jurgen
AU - Demontis, Ditte
AU - Dikeos, Dimitris
AU - Dinan, Timothy
AU - Djurovic, Srdjan
AU - Donohoe, Gary
AU - Drapeau, Elodie
AU - Duan, Jubao
AU - Dudbridge, Frank
AU - Durmishi, Naser
AU - Eichhammer, Peter
AU - Eriksson, Johan
AU - Escott-Price, Valentina
AU - Essioux, Laurent
AU - Fanous, Ayman H
AU - Farrell, Martilias S.
AU - Franke, Lude
AU - Freedman, Robert
AU - Freimer, Nelson B
AU - Friedl, Marion
AU - Friedman, Joseph I.
AU - Fromer, Menachem
AU - Georgieva, Lyudmila
AU - Giegling, Ina
AU - Giusti-Rodríguez, Paola
AU - Godard, Stephanie
AU - Goldstein, Jacqueline I
AU - Golimbet, Vera
AU - Gopal, Srihari
AU - Gratten, Jacob
AU - de Haan, Lieuwe
AU - Hammer, Christian
AU - Hamshere, Marian L.
AU - Hansen, Mark
AU - Hansen, Thomas
AU - Haroutunian, Vahram
AU - Hartmann, Annette M
AU - Henskens, Frans A
AU - Hirschhorn, Joel N
AU - Hoffmann, Per
AU - Hofman, Andrea
AU - Hollegaard, Mads V
AU - Hougaard, David M.
AU - Ikeda, Masashi
AU - Joa, Inge
AU - Julià, Antonio
AU - Kahn, René S
AU - Kalaydjieva, Luba
AU - Karachanak-Yankova, Sena
AU - Karjalainen, Juha
AU - Kavanagh, David
AU - Kennedy, James L.
AU - Khrunin, Andrey
AU - Kim, Yunjung
AU - Klovins, Janis
AU - Knowles, James A.
AU - Konte, Bettina
AU - Kucinskas, Vaidutis
AU - Kucinskiene, Zita Ausrele
AU - Kuzelova-Ptackova, Hana
AU - Kähler, Anna K
AU - Laurent, Claudine
AU - Chee Keong, Jimmy Lee
AU - Hong Lee, S.
AU - Legge, Sophie E.
AU - Lerer, Bernard
AU - Li, Miaoxin
AU - Li, Tao
AU - Liang, Kung-Yee
AU - Lieberman, Jeffrey
AU - Limborska, Svetlana
AU - Loughland, Carmel M
AU - Lubinski, Jan
AU - Lönnqvist, Jouko
AU - Macek, Milan
AU - Magnusson, Patrik K E
AU - Maher, Brion S
AU - Mallet, Jacques
AU - Marsal, Sara
AU - Mattingsdal, Morten
AU - McCarley, Robert W
AU - McDonald, Colm
AU - McIntosh, Andrew M.
AU - Meier, Sandra M
AU - Meijer, Carin J.
AU - Melegh, Bela
AU - Melle, Ingrid
AU - Mesholam-Gately, Raquelle I.
AU - Metspalu, Andres
AU - Michie, Patricia T
AU - Milani, Lili
AU - Milanova, Vihra
AU - Mokrab, Younes
AU - Morris, Derek W
AU - Mors, Ole
AU - Murphy, Kieran C
AU - Murray, Robin M
AU - Myin-Germeys, Inez
AU - Müller-Myhsok, Bertram
AU - Nelis, Mari
AU - Nertney, Deborah A
AU - Nestadt, Gerald
AU - Nicodemus, Kristin K.
AU - Nikitina-Zake, Liene
AU - Nisenbaum, Laura
AU - Nordin, Annelie
AU - O'Callaghan, Eadbhard
AU - O'Dushlaine, Colm T
AU - Anthony O'Neill, F.
AU - Oh, Sang Yun
AU - Olincy, Ann
AU - Olsen, Line
AU - van Os, Jim
AU - Pantelis, Christos
AU - Papadimitriou, George N
AU - Papiol, Sergi
AU - Parkhomenko, Elena
AU - Pato, Michele T
AU - Paunio, Tiina
AU - Pejovic-Milovancevic, Milica
AU - Perkins, Diana O.
AU - Pietiläinen, Olli
AU - Pimm, Jonathan
AU - Pocklington, Andrew J.
AU - Powell, John
AU - Price, Alkes L
AU - Pulver, Ann E
AU - Purcell, Shaun M.
AU - Quested, Digby
AU - Rasmussen, Henrik B.
AU - Reichenberg, Abraham
AU - Reimers, Mark A.
AU - Richards, Alexander L.
AU - Roffman, Joshua L
AU - Roussos, Panos
AU - Salomaa, Veikko
AU - Sanders, Alan R
AU - Schall, Ulrich
AU - Schubert, Christian R.
AU - Schwab, Sibylle G
AU - Scolnick, Edward M.
AU - Scott, Rodney J
AU - Seidman, Larry J.
AU - Shi, Jianxin
AU - Sigurdsson, Engilbert
AU - Silagadze, Teimuraz
AU - Silverman, Jeremy M
AU - Sim, Kang
AU - Slominsky, Petr
AU - Smoller, Jordan W.
AU - So, Hon Cheong
AU - Spencer, Chris C A
AU - Stahl, Eli A
AU - Stefansson, Hreinn
AU - Steinberg, Stacy
AU - Stogmann, Elisabeth
AU - Straub, Richard E.
AU - Strengman, Eric
AU - Scott Stroup, T.
AU - Subramaniam, Mythily
AU - Suvisaari, Jaana
AU - Svrakic, Dragan M.
AU - Szatkiewicz, Jin P.
AU - Söderman, Erik
AU - Thirumalai, Srinivas
AU - Toncheva, Draga
AU - Tosato, Sarah
AU - Veijola, Juha
AU - Waddington, John
AU - Walsh, Dermot
AU - Wang, Dai
AU - Wang, Qiang
AU - Webb, Bradley T.
AU - Weiser, Mark
AU - Wildenauer, Dieter B
AU - Williams, Nigel M
AU - Watts-Williams, Stephanie J.
AU - Wolen, Aaron R.
AU - Wong, Emily H.M.
AU - Wormley, Brandon K.
AU - Xi, Hualin Simon
AU - Zai, Clement C.
AU - Zheng, Xuebin
AU - Zimprich, Fritz
AU - Wray, Naomi R
AU - Stefansson, Kari
AU - Visscher, Peter M
AU - Adolfsson, Rolf
AU - Andreassen, Ole A.
AU - Blackwood, Douglas H R
AU - Bramon, Elvira
AU - Buxbaum, Joseph D
AU - Børglum, Anders D
AU - Darvasi, Ariel
AU - Domenici, Enrico
AU - Ehrenreich, Hannelore
AU - Esko, Tõnu
AU - Gejman, Pablo V
AU - Gill, Michael
AU - Gurling, Hugh
AU - Hultman, Christina M
AU - Iwata, Nakao
AU - Jablensky, Assen V
AU - Jönsson, Erik G
AU - Kendler, Kenneth S
AU - Kirov, George
AU - Knight, Jo
AU - Lencz, Todd
AU - Levinson, Douglas F
AU - Li, Qingqin S.
AU - Liu, Jianjun
AU - Malhotra, Anil K
AU - McCarroll, Steven A
AU - McQuillin, Andrew
AU - Moran, Jennifer L.
AU - Mortensen, Preben B
AU - Mowry, Bryan J
AU - Nöthen, Markus M
AU - Ophoff, Roel A
AU - Owen, Michael J
AU - Palotie, Aarno
AU - Pato, Carlos N
AU - Petryshen, Tracey L.
AU - Posthuma, Danielle
AU - Riley, Brien P
AU - Sham, Pak-Chung
AU - Sklar, Pamela
AU - St Clair, David
AU - Weinberger, Daniel R
AU - Wendland, Jens R.
AU - Werge, Thomas
AU - Daly, Mark J
AU - O'Donovan, Michael C
AU - Sullivan, Patrick F
AU - Keller, Matthew C
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pgen.1006343
DO - 10.1371/journal.pgen.1006343
M3 - Journal article
C2 - 27792727
AN - SCOPUS:84994314495
SN - 1553-7390
VL - 12
JO - P L o S Genetics
JF - P L o S Genetics
IS - 10
M1 - e1006343
ER -