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.
| Original language | English |
|---|---|
| Article number | e1006343 |
| Journal | PLOS Genetics |
| Volume | 12 |
| Issue number | 10 |
| Number of pages | 20 |
| ISSN | 1553-7390 |
| DOIs | |
| Publication status | Published - 1 Oct 2016 |
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- 10.1371/journal.pgen.1006343Licence: CC BY
- No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication StudyFinal published version, 1.81 MBLicence: CC BY
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In: PLOS Genetics, Vol. 12, No. 10, e1006343, 01.10.2016.
Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study
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AU - O'Dushlaine, Colm T
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AU - Weiser, Mark
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AU - Wormley, Brandon K.
AU - Xi, Hualin Simon
AU - Zai, Clement C.
AU - Zheng, Xuebin
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AU - Wray, Naomi R
AU - Stefansson, Kari
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AU - Blackwood, Douglas H R
AU - Bramon, Elvira
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AU - Darvasi, Ariel
AU - Domenici, Enrico
AU - Ehrenreich, Hannelore
AU - Esko, Tõnu
AU - Gejman, Pablo V
AU - Gill, Michael
AU - Gurling, Hugh
AU - Hultman, Christina M
AU - Iwata, Nakao
AU - Jablensky, Assen V
AU - Jönsson, Erik G
AU - Kendler, Kenneth S
AU - Kirov, George
AU - Knight, Jo
AU - Lencz, Todd
AU - Levinson, Douglas F
AU - Li, Qingqin S.
AU - Liu, Jianjun
AU - Malhotra, Anil K
AU - McCarroll, Steven A
AU - McQuillin, Andrew
AU - Moran, Jennifer L.
AU - Mortensen, Preben B
AU - Mowry, Bryan J
AU - Nöthen, Markus M
AU - Ophoff, Roel A
AU - Owen, Michael J
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AU - Pato, Carlos N
AU - Petryshen, Tracey L.
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AU - Riley, Brien P
AU - Sham, Pak-Chung
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AU - St Clair, David
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AU - Daly, Mark J
AU - O'Donovan, Michael C
AU - Sullivan, Patrick F
AU - Keller, Matthew C
PY - 2016/10/1
Y1 - 2016/10/1
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.
U2 - 10.1371/journal.pgen.1006343
DO - 10.1371/journal.pgen.1006343
M3 - Journal article
C2 - 27792727
AN - SCOPUS:84994314495
SN - 1553-7390
VL - 12
JO - PLOS Genetics
JF - PLOS Genetics
IS - 10
M1 - e1006343
ER -