Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease

Despite recent discoveries in the genetics of sporadic Alzheimer's disease, there remains substantial " hidden heritability." It is thought that some of this missing heritability may be because of gene-gene, i.e., epistatic, interactions. We examined potential epistasis between 110 ca...

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Main Authors: Bullock, J, Medway, C, Cortina-Borja, M, Turton, J, Prince, J, Ibrahim-Verbaas, C, Schuur, M, Breteler, M, van Duijn, C, Kehoe, P, Barber, R, Coto, E, Alvarez, V, Deloukas, P, Hammond, N, Combarros, O, Mateo, I, Warden, DR, Lehmann, MG, Belbin, O, Brown, K, Wilcock, G
Format: Journal article
Published: 2013
_version_ 1797065178486931456
author Bullock, J
Medway, C
Cortina-Borja, M
Turton, J
Prince, J
Ibrahim-Verbaas, C
Ibrahim-Verbaas, C
Schuur, M
Schuur, M
Breteler, M
van Duijn, C
Kehoe, P
Barber, R
Coto, E
Alvarez, V
Deloukas, P
Hammond, N
Combarros, O
Mateo, I
Warden, DR
Lehmann, MG
Belbin, O
Belbin, O
Brown, K
Wilcock, G
author_facet Bullock, J
Medway, C
Cortina-Borja, M
Turton, J
Prince, J
Ibrahim-Verbaas, C
Ibrahim-Verbaas, C
Schuur, M
Schuur, M
Breteler, M
van Duijn, C
Kehoe, P
Barber, R
Coto, E
Alvarez, V
Deloukas, P
Hammond, N
Combarros, O
Mateo, I
Warden, DR
Lehmann, MG
Belbin, O
Belbin, O
Brown, K
Wilcock, G
author_sort Bullock, J
collection OXFORD
description Despite recent discoveries in the genetics of sporadic Alzheimer's disease, there remains substantial " hidden heritability." It is thought that some of this missing heritability may be because of gene-gene, i.e., epistatic, interactions. We examined potential epistasis between 110 candidate polymorphisms in 1757 cases of Alzheimer's disease and 6294 control subjects of the Epistasis Project, divided between a discovery and a replication dataset. We found an epistatic interaction, between rs7483 in GSTM3 and rs1111875 in the HHEX/IDE/KIF11 gene cluster, with a closely similar, significant result in both datasets. The synergy factor (SF) in the combined dataset was 1.79, 95% confidence interval [CI], 1.35-2.36; p = 0.00004. Consistent interaction was also found in 7 out of the 8 additional subsets that we examined post hoc: i.e., it was shown in both North Europe and North Spain, in both men and women, in both those with and without the ε4 allele of apolipoprotein E, and in people older than 75 years (SF, 2.27; 95% CI, 1.60-3.20; p < 0.00001), but not in those younger than 75 years (SF, 1.06; 95% CI, 0.59-1.91; p = 0.84). The association with Alzheimer's disease was purely epistatic with neither polymorphism showing an independent effect: odds ratio, 1.0; p ≥ 0.7. Indeed, each factor was associated with protection in the absence of the other factor, but with risk in its presence. In conclusion, this epistatic interaction showed a high degree of consistency when stratifying by sex, the ε4 allele of apolipoprotein E genotype, and geographic region. © 2013 Elsevier Inc.
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spelling oxford-uuid:42c470d4-4d79-4517-a92a-9ba9bd1ce6052022-03-26T14:51:32ZDiscovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's diseaseJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:42c470d4-4d79-4517-a92a-9ba9bd1ce605Symplectic Elements at Oxford2013Bullock, JMedway, CCortina-Borja, MTurton, JPrince, JIbrahim-Verbaas, CIbrahim-Verbaas, CSchuur, MSchuur, MBreteler, Mvan Duijn, CKehoe, PBarber, RCoto, EAlvarez, VDeloukas, PHammond, NCombarros, OMateo, IWarden, DRLehmann, MGBelbin, OBelbin, OBrown, KWilcock, GDespite recent discoveries in the genetics of sporadic Alzheimer's disease, there remains substantial " hidden heritability." It is thought that some of this missing heritability may be because of gene-gene, i.e., epistatic, interactions. We examined potential epistasis between 110 candidate polymorphisms in 1757 cases of Alzheimer's disease and 6294 control subjects of the Epistasis Project, divided between a discovery and a replication dataset. We found an epistatic interaction, between rs7483 in GSTM3 and rs1111875 in the HHEX/IDE/KIF11 gene cluster, with a closely similar, significant result in both datasets. The synergy factor (SF) in the combined dataset was 1.79, 95% confidence interval [CI], 1.35-2.36; p = 0.00004. Consistent interaction was also found in 7 out of the 8 additional subsets that we examined post hoc: i.e., it was shown in both North Europe and North Spain, in both men and women, in both those with and without the ε4 allele of apolipoprotein E, and in people older than 75 years (SF, 2.27; 95% CI, 1.60-3.20; p < 0.00001), but not in those younger than 75 years (SF, 1.06; 95% CI, 0.59-1.91; p = 0.84). The association with Alzheimer's disease was purely epistatic with neither polymorphism showing an independent effect: odds ratio, 1.0; p ≥ 0.7. Indeed, each factor was associated with protection in the absence of the other factor, but with risk in its presence. In conclusion, this epistatic interaction showed a high degree of consistency when stratifying by sex, the ε4 allele of apolipoprotein E genotype, and geographic region. © 2013 Elsevier Inc.
spellingShingle Bullock, J
Medway, C
Cortina-Borja, M
Turton, J
Prince, J
Ibrahim-Verbaas, C
Ibrahim-Verbaas, C
Schuur, M
Schuur, M
Breteler, M
van Duijn, C
Kehoe, P
Barber, R
Coto, E
Alvarez, V
Deloukas, P
Hammond, N
Combarros, O
Mateo, I
Warden, DR
Lehmann, MG
Belbin, O
Belbin, O
Brown, K
Wilcock, G
Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease
title Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease
title_full Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease
title_fullStr Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease
title_full_unstemmed Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease
title_short Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease
title_sort discovery by the epistasis project of an epistatic interaction between the gstm3 gene and the hhex ide kif11 locus in the risk of alzheimer s disease
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