title: Linkage Analysis in Autoimmune Addison's Disease: NFATC1 as a Potential Novel Susceptibility Locus.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Mitchell
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Anette
authors.initials: A
authors.lastname: Bøe Wolff
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Katie
authors.initials: K
authors.lastname: MacArthur
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Jolanta U
authors.initials: JU
authors.lastname: Weaver
authors.affiliation: Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom.
authors.forename: Bijay
authors.initials: B
authors.lastname: Vaidya
authors.affiliation: Department of Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Martina M
authors.initials: MM
authors.lastname: Erichsen
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Darlay
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Eystein S
authors.initials: ES
authors.lastname: Husebye
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Simon H S
authors.initials: SH
authors.lastname: Pearce
mesh_terms: D000224:Addison Disease / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D015331:Cohort Studies; D008040:Genetic Linkage; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human