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Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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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
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
AU - Mowry, Bryan
AU - Müller-Mhysok, Betram
AU - Neale, Benjamin
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
AU - Strohmaier, Jana
AU - Witt, Stephanie H
AU - Sullivan, Patrick F
AU - Keller, Matthew C
AU - Knight, Joanne
AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium
PY - 2016/10/28
Y1 - 2016/10/28
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.
KW - Consanguinity
KW - Female
KW - Genome, Human
KW - Genome-Wide Association Study
KW - Genomics
KW - Homozygote
KW - Humans
KW - Male
KW - Polymorphism, Single Nucleotide
KW - Schizophrenia
KW - Journal Article
U2 - 10.1371/journal.pgen.1006343
DO - 10.1371/journal.pgen.1006343
M3 - Journal article
C2 - 27792727
VL - 12
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
IS - 10
M1 - e1006343
ER -