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

Johnson, E. C. and Bjelland, D. W. and Howrigan, D. P. and Abdellaoui, A. and Breen, G. and Borglum, A. and Cichon, S. and Degenhardt, F. and Forstner, A. J. and Frank, J. and Genovese, G. and Heilmann-Heimbach, S. and Herms, S. and Hoffman, P. and Maier, W. and Mattheisen, M. and Morris, D. and Mowry, B. and Muller-Mhysok, B. and Neale, B. and Nenadic, I. and Nothen, M. M. and O'Dushlaine, C. and Rietschel, M. and Ruderfer, D. M. and Rujescu, D. and Schulze, T. G. and Simonson, M. A. and Stahl, E. and Strohmaier, J. and Witt, S. H. and Schizophrenia Working Group of the Psychiatric Genomics, Consortium and Sullivan, P. F. and Keller, M. C.. (2016) No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study. PLoS Genetics, 12 (10). e1006343.

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Official URL: https://edoc.unibas.ch/61559/

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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 (beta = 16.1, CI(beta) = [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 (beta = 4.86,CI(beta) = [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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Human Genetics (Cichon)
UniBasel Contributors:Cichon, Sven
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:23 Apr 2019 17:41
Deposited On:23 Apr 2019 17:41

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