Linkage Analysis in Autoimmune Addison's Disease: NFATC1 as a Potential Novel Susceptibility Locus

2.50
Hdl Handle:
http://hdl.handle.net/11287/594021
Title:
Linkage Analysis in Autoimmune Addison's Disease: NFATC1 as a Potential Novel Susceptibility Locus
Authors:
Mitchell, A. L.; Boe Wolff, A.; MacArthur, K.; Weaver, J. U.; Vaidya, Bijay; Sophie Bensing on behalf of The Swedish Addison Registry Study, Group; Erichsen, M. M.; Darlay, R.; Husebye, E. S.; Cordell, H. J.; Pearce, S. H.
Abstract:
BACKGROUND: Autoimmune Addison's disease (AAD) is a rare, highly heritable autoimmune endocrinopathy. It is possible that there may be some highly penetrant variants which confer disease susceptibility that have yet to be discovered. METHODS: DNA samples from 23 multiplex AAD pedigrees from the UK and Norway (50 cases, 67 controls) were genotyped on the Affymetrix SNP 6.0 array. Linkage analysis was performed using Merlin. EMMAX was used to carry out a genome-wide association analysis comparing the familial AAD cases to 2706 UK WTCCC controls. To explore some of the linkage findings further, a replication study was performed by genotyping 64 SNPs in two of the four linked regions (chromosomes 7 and 18), on the Sequenom iPlex platform in three European AAD case-control cohorts (1097 cases, 1117 controls). The data were analysed using a meta-analysis approach. RESULTS: In a parametric analysis, applying a rare dominant model, loci on chromosomes 7, 9 and 18 had LOD scores >2.8. In a non-parametric analysis, a locus corresponding to the HLA region on chromosome 6, known to be associated with AAD, had a LOD score >3.0. In the genome-wide association analysis, a SNP cluster on chromosome 2 and a pair of SNPs on chromosome 6 were associated with AAD (P <5x10-7). A meta-analysis of the replication study data demonstrated that three chromosome 18 SNPs were associated with AAD, including a non-synonymous variant in the NFATC1 gene. CONCLUSION: This linkage study has implicated a number of novel chromosomal regions in the pathogenesis of AAD in multiplex AAD families and adds further support to the role of HLA in AAD. The genome-wide association analysis has also identified a region of interest on chromosome 2. A replication study has demonstrated that the NFATC1 gene is worthy of future investigation, however each of the regions identified require further, systematic analysis.
Citation:
PLoS One. 2015;10(6):e0123550.
Publisher:
PLoS One
Journal:
PloS one
Issue Date:
4-Jun-2015
URI:
http://hdl.handle.net/11287/594021
DOI:
10.1371/journal.pone.0123550
PubMed ID:
26042420
Additional Links:
http://dx.plos.org/10.1371/journal.pone.0123550
Note:
This article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.
Type:
Journal Article; Research Support, Non-U.S. Gov't
Language:
eng
ISSN:
1932-6203
Appears in Collections:
2015 RD&E publications; Diabetes/Endocrine Services

Full metadata record

DC FieldValue Language
dc.contributor.authorMitchell, A. L.en
dc.contributor.authorBoe Wolff, A.en
dc.contributor.authorMacArthur, K.en
dc.contributor.authorWeaver, J. U.en
dc.contributor.authorVaidya, Bijayen
dc.contributor.authorSophie Bensing on behalf of The Swedish Addison Registry Study, Groupen
dc.contributor.authorErichsen, M. M.en
dc.contributor.authorDarlay, R.en
dc.contributor.authorHusebye, E. S.en
dc.contributor.authorCordell, H. J.en
dc.contributor.authorPearce, S. H.en
dc.date.accessioned2016-01-19T12:38:42Zen
dc.date.available2016-01-19T12:38:42Zen
dc.date.issued2015-06-04en
dc.identifier.citationPLoS One. 2015;10(6):e0123550.en
dc.identifier.issn1932-6203en
dc.identifier.pmid26042420en
dc.identifier.doi10.1371/journal.pone.0123550en
dc.identifier.urihttp://hdl.handle.net/11287/594021en
dc.description.abstractBACKGROUND: Autoimmune Addison's disease (AAD) is a rare, highly heritable autoimmune endocrinopathy. It is possible that there may be some highly penetrant variants which confer disease susceptibility that have yet to be discovered. METHODS: DNA samples from 23 multiplex AAD pedigrees from the UK and Norway (50 cases, 67 controls) were genotyped on the Affymetrix SNP 6.0 array. Linkage analysis was performed using Merlin. EMMAX was used to carry out a genome-wide association analysis comparing the familial AAD cases to 2706 UK WTCCC controls. To explore some of the linkage findings further, a replication study was performed by genotyping 64 SNPs in two of the four linked regions (chromosomes 7 and 18), on the Sequenom iPlex platform in three European AAD case-control cohorts (1097 cases, 1117 controls). The data were analysed using a meta-analysis approach. RESULTS: In a parametric analysis, applying a rare dominant model, loci on chromosomes 7, 9 and 18 had LOD scores >2.8. In a non-parametric analysis, a locus corresponding to the HLA region on chromosome 6, known to be associated with AAD, had a LOD score >3.0. In the genome-wide association analysis, a SNP cluster on chromosome 2 and a pair of SNPs on chromosome 6 were associated with AAD (P <5x10-7). A meta-analysis of the replication study data demonstrated that three chromosome 18 SNPs were associated with AAD, including a non-synonymous variant in the NFATC1 gene. CONCLUSION: This linkage study has implicated a number of novel chromosomal regions in the pathogenesis of AAD in multiplex AAD families and adds further support to the role of HLA in AAD. The genome-wide association analysis has also identified a region of interest on chromosome 2. A replication study has demonstrated that the NFATC1 gene is worthy of future investigation, however each of the regions identified require further, systematic analysis.en
dc.language.isoengen
dc.publisherPLoS Oneen
dc.relation.urlhttp://dx.plos.org/10.1371/journal.pone.0123550en
dc.titleLinkage Analysis in Autoimmune Addison's Disease: NFATC1 as a Potential Novel Susceptibility Locusen
dc.typeJournal Articleen
dc.typeResearch Support, Non-U.S. Gov'ten
dc.identifier.journalPloS oneen
dc.description.noteThis article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.en

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