No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study.
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 geno...
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doaj-73b4778def244d36875bdb4d8766b2362020-11-25T02:25:27ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042016-10-011210e100634310.1371/journal.pgen.1006343No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study.Emma C JohnsonDouglas W BjellandDaniel P HowriganAbdel AbdellaouiGerome BreenAnders BorglumSven CichonFranziska DegenhardtAndreas J ForstnerJosef FrankGiulio GenoveseStefanie Heilmann-HeimbachStefan HermsPer HoffmanWolfgang MaierManuel MattheisenDerek MorrisBryan MowryBetram Müller-MhysokBenjamin NealeIgor NenadicMarkus M NöthenColm O'DushlaineMarcella RietschelDouglas M RuderferDan RujescuThomas G SchulzeMatthew A SimonsonEli StahlJana StrohmaierStephanie H WittSchizophrenia Working Group of the Psychiatric Genomics ConsortiumPatrick F SullivanMatthew C KellerIt 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.http://europepmc.org/articles/PMC5085024?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Emma C Johnson Douglas W Bjelland Daniel P Howrigan Abdel Abdellaoui Gerome Breen Anders Borglum Sven Cichon Franziska Degenhardt Andreas J Forstner Josef Frank Giulio Genovese Stefanie Heilmann-Heimbach Stefan Herms Per Hoffman Wolfgang Maier Manuel Mattheisen Derek Morris Bryan Mowry Betram Müller-Mhysok Benjamin Neale Igor Nenadic Markus M Nöthen Colm O'Dushlaine Marcella Rietschel Douglas M Ruderfer Dan Rujescu Thomas G Schulze Matthew A Simonson Eli Stahl Jana Strohmaier Stephanie H Witt Schizophrenia Working Group of the Psychiatric Genomics Consortium Patrick F Sullivan Matthew C Keller |
spellingShingle |
Emma C Johnson Douglas W Bjelland Daniel P Howrigan Abdel Abdellaoui Gerome Breen Anders Borglum Sven Cichon Franziska Degenhardt Andreas J Forstner Josef Frank Giulio Genovese Stefanie Heilmann-Heimbach Stefan Herms Per Hoffman Wolfgang Maier Manuel Mattheisen Derek Morris Bryan Mowry Betram Müller-Mhysok Benjamin Neale Igor Nenadic Markus M Nöthen Colm O'Dushlaine Marcella Rietschel Douglas M Ruderfer Dan Rujescu Thomas G Schulze Matthew A Simonson Eli Stahl Jana Strohmaier Stephanie H Witt Schizophrenia Working Group of the Psychiatric Genomics Consortium Patrick F Sullivan Matthew C Keller No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study. PLoS Genetics |
author_facet |
Emma C Johnson Douglas W Bjelland Daniel P Howrigan Abdel Abdellaoui Gerome Breen Anders Borglum Sven Cichon Franziska Degenhardt Andreas J Forstner Josef Frank Giulio Genovese Stefanie Heilmann-Heimbach Stefan Herms Per Hoffman Wolfgang Maier Manuel Mattheisen Derek Morris Bryan Mowry Betram Müller-Mhysok Benjamin Neale Igor Nenadic Markus M Nöthen Colm O'Dushlaine Marcella Rietschel Douglas M Ruderfer Dan Rujescu Thomas G Schulze Matthew A Simonson Eli Stahl Jana Strohmaier Stephanie H Witt Schizophrenia Working Group of the Psychiatric Genomics Consortium Patrick F Sullivan Matthew C Keller |
author_sort |
Emma C Johnson |
title |
No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study. |
title_short |
No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study. |
title_full |
No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study. |
title_fullStr |
No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study. |
title_full_unstemmed |
No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study. |
title_sort |
no reliable association between runs of homozygosity and schizophrenia in a well-powered replication study. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2016-10-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC5085024?pdf=render |
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