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No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study
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- PLoS Genetics, PLOS GENETICS, Johnson, E C, Bjelland, D W, Howrigan, D P, Abdellaoui, A, Breen, G, Borglum, A, Cichon, S, Degenhardt, F, Forstner, A J, Frank, J, Genovese, G, Heilmann-Heimbach, S, Herms, S, Hoffman, P, Maier, W, Mattheisen, M, Morris, D, Mowry, B, Müller-Myhsok, B, Neale, B M, Nenadic, I, Nöthen, M M, O'Dushlaine, C, Rietschel, M, Ruderfer, D M, Rujescu, D, Schulze, T G, Simonson, M A, Stahl, E, Strohmaier, J, Witt, S H, Sullivan, P F & Keller, M C 2016, ' No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study ', PLoS Genetics, vol. 12, no. 10, e1006343 . https://doi.org/10.1371/journal.pgen.1006343, Johnson, E C, Bjelland, D W, Howrigan, D P, Abdellaoui, A, Breen, G, Borglum, A, Cichon, S, Degenhardt, F, Forstner, A J, Frank, J, Genovese, G, Heilmann-Heimbach, S, Herms, S, Hoffman, P, Maier, W, Mattheisen, M, Morris, D, Mowry, B, Müller-Mhysok, B, Neale, B, Nenadic, I, Nöthen, M M, O’Dushlaine, C, Rietschel, M, Ruderfer, D M, Rujescu, D, Schulze, T G, Simonson, M A, Stahl, E, Strohmaier, J, Witt, S H, Ripke, S, Neale, B M, Corvin, A, Walters, J T R, Farh, K H, Holmans, P A, Lee, P, Bulik-Sullivan, B, Collier, D A, Huang, H, Pers, T H, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, S A, Begemann, M, Belliveau, R A, Bene, J, Bergen, S E, Bevilacqua, E, Bigdeli, T B, Black, D W, Bruggeman, R, Buccola, N G, Buckner, R L, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, R M, Carr, V J, Carrera, N, Catts, S V, Chambert, K D, Chan, R C K, Chen, R Y L, Chen, E Y H, Cheng, W, Cheung, E F C, Chong, S A, Robert Cloninger, C, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, J J, Curtis, D, Davidson, M, Davis, K L, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, A H, Farrell, M S, Franke, L, Freedman, R, Freimer, N B, Friedl, M, Friedman, J I, Fromer, M, Georgieva, L, Giegling, I, Giusti-Rodríguez, P, Godard, S, Goldstein, J I, Golimbet, V, Gopal, S, Gratten, J, de Haan, L, Hammer, C, Hamshere, M L, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, A M, Henskens, F A, Hirschhorn, J N, Hoffmann, P, Hofman, A, Hollegaard, M V, Hougaard, D M, Ikeda, M, Joa, I, Julià, A, Kahn, R S, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Kennedy, J L, Khrunin, A, Kim, Y, Klovins, J, Knowles, J A, Konte, B, Kucinskas, V, Kucinskiene, Z A, Kuzelova-Ptackova, H, Kähler, A K, Laurent, C, Chee Keong, J L, Hong Lee, S, Legge, S E, Lerer, B, Li, M, Li, T, Liang, K Y, Lieberman, J, Limborska, S, Loughland, C M, Lubinski, J, Lönnqvist, J, Macek, M, Magnusson, P K E, Maher, B S, Mallet, J, Marsal, S, Mattingsdal, M, McCarley, R W, McDonald, C, McIntosh, A M, Meier, S, Meijer, C J, Melegh, B, Melle, I, Mesholam-Gately, R I, Metspalu, A, Michie, P T, Milani, L, Milanova, V, Mokrab, Y, Morris, D W, Mors, O, Murphy, K C, Murray, R M, Myin-Germeys, I, Müller-Myhsok, B, Nelis, M, Nertney, D A, Nestadt, G, Nicodemus, K K, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, Anthony O'Neill, F, Oh, S Y, Olincy, A, Olsen, L, Van Os, J, Pantelis, C, Papadimitriou, G N, Papiol, S, Parkhomenko, E, Pato, M T, Paunio, T, Pejovic-Milovancevic, M, Perkins, D O, Pietiläinen, O, Pimm, J, Pocklington, A J, Powell, J, Price, A, Pulver, A E, Purcell, S M, Quested, D, Rasmussen, H B, Reichenberg, A, Reimers, M A, Richards, A L, Roffman, J L, Roussos, P, Salomaa, V, Sanders, A R, Schall, U, Schubert, C R, Schwab, S G, Scolnick, E M, Scott, R J, Seidman, L J, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, J M, Sim, K, Slominsky, P, Smoller, J W, So, H C, Spencer, C C A, Stahl, E A, Stefansson, H, Steinberg, S, Stogmann, E, Straub, R E, Strengman, E, Scott Stroup, T, Subramaniam, M, Suvisaari, J, Svrakic, D M, Szatkiewicz, J P, Söderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, B T, Weiser, M, Wildenauer, D B, Williams, N M, Williams, S, Wolen, A R, Wong, E H M, Wormley, B K, Xi, H S, Zai, C C, Zheng, X, Zimprich, F, Wray, N R, Stefansson, K, Visscher, P M, Adolfsson, R, Andreassen, O A, Blackwood, D H R, Bramon, E, Buxbaum, J D, Børglum, A D, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, P V, Gill, M, Gurling, H, Hultman, C M, Iwata, N, Jablensky, A V, Jönsson, E G, Kendler, K S, Kirov, G, Knight, J, Lencz, T, Levinson, D F, Li, Q S, Liu, J, Malhotra, A K, McCarroll, S A, McQuillin, A, Moran, J L, Mortensen, P B, Mowry, B J, Nöthen, M M, Ophoff, R A, Owen, M J, Palotie, A, Pato, C N, Petryshen, T L, Posthuma, D, Riley, B P, Sham, P C, Sklar, P, Clair, D S, Weinberger, D R, Wendland, J R, Werge, T, Daly, M J, O'Donovan, M C, Sullivan, P F & Keller, M C 2016, ' No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study ', PL o S Genetics, vol. 12, no. 10, e1006343 . https://doi.org/10.1371/journal.pgen.1006343, PLoS Genetics, 12(10):e1006343. Public Library of Science, PLoS Genetics, Vol 12, Iss 10, p e1006343 (2016), Schizophrenia Working Group of the Psychiatric Genomics Consortium 2016, ' No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study ', PLoS Genetics, vol. 12, no. 10, e1006343 . https://doi.org/10.1371/journal.pgen.1006343, Johnson, E C, Bjelland, D W, Howrigan, D P, Abdellaoui, A, Breen, G, Borglum, A D, Cichon, S, Degenhardt, F, Forstner, A J, Frank, J, Genovese, G, Heilmann-Heimbach, S, Herms, S, Hoffman, P, Maier, W, Mattheisen, M, Morris, D W, Mowry, B J, Müller-Mhysok, B, Neale, B M, Nenadic, I, Nöthen, M M, O’Dushlaine, C, Rietschel, M, Ruderfer, D M, Rujescu, D, Schulze, T G, Simonson, M A, Stahl, E A, Strohmaier, J, Witt, S H, Ripke, S, Neale, B M, Corvin, A, Walters, J T R, Farh, K-H, Holmans, P A, Lee, P H, Bulik-Sullivan, B, Collier, D A, Huang, H, Pers, T H, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, S-A, Begemann, M, Belliveau, R A, Bene, J, Bergen, S E, Bevilacqua, E, Bigdeli, T B, Black, D W, Bruggeman, R, Buccola, N G, Buckner, R L, Byerley, W F, Cahn, W, Cai, G, Campion, D, Cantor, R M, Carr, V J, Carrera, N, Catts, S V, Chambert, K D, Chan, R C K, Chen, R Y L, Chen, E Y H, Cheng, W, Cheung, E F C, Chong, S A, Robert Cloninger, C, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, J J, Curtis, D, Davidson, M, Davis, K L, Del-Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, A H, Farrell, M S, Franke, L, Freedman, R, Freimer, N B, Friedl, M, Friedman, J I, Fromer, M, Georgieva, L, Giegling, I, Giusti-Rodríguez, P, Godard, S, Goldstein, J I, Golimbet, V, Gopal, S, Gratten, J, de Haan, L, Hammer, C, Hamshere, M L, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, A M, Henskens, F A, Hirschhorn, J N, Hoffmann, P, Hofman, A, Hollegaard, M V, Hougaard, D M, Ikeda, M, Joa, I, Julià, A, Kahn, R S, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Kennedy, J L, Khrunin, A, Kim, Y, Klovins, J, Knowles, J A, Konte, B, Kucinskas, V, Kucinskiene, Z A, Kuzelova-Ptackova, H, Kähler, A K, Laurent, C, Chee Keong, J L, Hong Lee, S, Legge, S E, Lerer, B, Li, M, Li, T, Liang, K-Y, Lieberman, J, Limborska, S, Loughland, C M, Lubinski, J, Lönnqvist, J, Macek, M, Magnusson, P K E, Maher, B S, Mallet, J, Marsal, S, Mattingsdal, M, McCarley, R W, McDonald, C, McIntosh, A M, Meier, S M, Meijer, C J, Melegh, B, Melle, I, Mesholam-Gately, R I, Metspalu, A, Michie, P T, Milani, L, Milanova, V, Mokrab, Y, Morris, D W, Mors, O, Murphy, K C, Murray, R M, Myin-Germeys, I, Müller-Myhsok, B, Nelis, M, Nertney, D A, Nestadt, G, Nicodemus, K K, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C T, Anthony O'Neill, F, Oh, S Y, Olincy, A, Olsen, L, van Os, J, Pantelis, C, Papadimitriou, G N, Papiol, S, Parkhomenko, E, Pato, M T, Paunio, T, Pejovic-Milovancevic, M, Perkins, D O, Pietiläinen, O, Pimm, J, Pocklington, A J, Powell, J, Price, A L, Pulver, A E, Purcell, S M, Quested, D, Rasmussen, H B, Reichenberg, A, Reimers, M A, Richards, A L, Roffman, J L, Roussos, P, Salomaa, V, Sanders, A R, Schall, U, Schubert, C R, Schwab, S G, Scolnick, E M, Scott, R J, Seidman, L J, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, J M, Sim, K, Slominsky, P, Smoller, J W, So, H C, Spencer, C C A, Stahl, E A, Stefansson, H, Steinberg, S, Stogmann, E, Straub, R E, Strengman, E, Scott Stroup, T, Subramaniam, M, Suvisaari, J, Svrakic, D M, Szatkiewicz, J P, Söderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, B T, Weiser, M, Wildenauer, D B, Williams, N M, Watts-Williams, S J, Wolen, A R, Wong, E H M, Wormley, B K, Xi, H S, Zai, C C, Zheng, X, Zimprich, F, Wray, N R, Stefansson, K, Visscher, P M, Adolfsson, R, Andreassen, O A, Blackwood, D H R, Bramon, E, Buxbaum, J D, Børglum, A D, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, P V, Gill, M, Gurling, H, Hultman, C M, Iwata, N, Jablensky, A V, Jönsson, E G, Kendler, K S, Kirov, G, Knight, J, Lencz, T, Levinson, D F, Li, Q S, Liu, J, Malhotra, A K, McCarroll, S A, McQuillin, A, Moran, J L, Mortensen, P B, Mowry, B J, Nöthen, M M, Ophoff, R A, Owen, M J, Palotie, A, Pato, C N, Petryshen, T L, Posthuma, D, Riley, B P, Sham, P-C, Sklar, P, St Clair, D, Weinberger, D R, Wendland, J R, Werge, T, Daly, M J, O'Donovan, M C, Sullivan, P F & Keller, M C 2016, ' No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study ', PLOS Genetics, vol. 12, no. 10, e1006343 . https://doi.org/10.1371/journal.pgen.1006343, Johnson, E C, Bjelland, D W, Howrigan, D P, Abdellaoui, A, Breen, G, Borglum, A, Cichon, S, Degenhardt, F, Forstner, A J, Frank, J, Genovese, G, Heilmann-Heimbach, S, Herms, S, Hoffman, P, Maier, W, Mattheisen, M, Morris, D, Mowry, B, Müller-Mhysok, B, Neale, B, Nenadic, I, Nöthen, M M, O'Dushlaine, C, Rietschel, M, Ruderfer, D M, Rujescu, D, Schulze, T G, Simonson, M A, Stahl, E, Strohmaier, J, Witt, S H, Sullivan, P F, Keller, M C & Schizophrenia Working Group of the Psychiatric Genomics Consortium 2016, ' No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study ', P L o S Genetics, vol. 12, no. 10, pp. e1006343 . https://doi.org/10.1371/journal.pgen.1006343
- Publication Year :
- 2016
- Publisher :
- Public Library of Science, 2016.
-
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.<br />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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 15537404 and 15537390
- Volume :
- 12
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics
- Accession number :
- edsair.doi.dedup.....3920ae03ce5f4d3c22172a79aa9ff8f9