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

Johnson, Emma C and Bjelland, Douglas W and Howrigan, Daniel P and Abdellaoui, Abdel and Breen, Gerome and Borglum, Anders and Cichon, Sven and Degenhardt, Franziska and Forstner, Andreas J and Frank, Josef and Genovese, Giulio and Heilmann-Heimbach, Stefanie and Herms, Stefan and Hoffman, Per and Maier, Wolfgang and Mattheisen, Manuel and Morris, Derek and Mowry, Bryan and Müller-Mhysok, Betram and Neale, Benjamin and Nenadic, Igor and Nöthen, Markus M and O'Dushlaine, Colm and Rietschel, Marcella and Ruderfer, Douglas M and Rujescu, Dan and Schulze, Thomas G and Simonson, Matthew A and Stahl, Eli and Strohmaier, Jana and Witt, Stephanie H and Sullivan, Patrick F and Keller, Matthew C and Knight, Joanne (2016) No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study. PLoS Genetics, 12 (10). ISSN 1553-7390

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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.

Item Type:
Journal Article
Journal or Publication Title:
PLoS Genetics
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1306
Subjects:
ID Code:
89771
Deposited By:
Deposited On:
19 Jan 2018 11:44
Refereed?:
Yes
Published?:
Published
Last Modified:
19 Aug 2020 04:13