title: Genome-wide association study in an admixed case series reveals IL12A as a new candidate in Behçet disease.
abstract: BACKGROUND
  The etiology of Behçet's disease (BD) is unknown, but widely considered an excessive T-cell mediated inflammatory response in a genetically susceptible host. Recent genome-wide association studies (GWAS) have shown limited number of novel loci-associations. The rarity and unequal distribution of the disease prevalence amongst different ethnic backgrounds have hampered the use of GWAS in cohorts of mixed ethnicity and sufficient sample size. However, novel statistical approaches have now enabled GWAS in admixed cohorts.
  
  
  METHODS
  We ran a GWAS on 336 BD cases and 5,843 controls. The cases consisted of Western Europeans, Middle Eastern and Turkish individuals. Participants from the Generation R study, a multiethnic birth cohort in Rotterdam, The Netherlands were used as controls. All samples were genotyped and data was combined. Linear regression models were corrected for population stratification using Genomic Principal Components and Linear Mixed Modelling. Meta-analysis was performed on selected results previously published.
  
  
  RESULTS
  We identified SNPs associated at genome-wide significant level mapping to the 6p21.33 (HLA) region. In addition to this known signal two potential novel associations on chromosomes 6 and 18 were identified, yet with low minor allele frequencies. Extended meta-analysis reveal a GWS association with the IL12A variant rs17810546 on chromosome 3.
  
  
  CONCLUSIONS
  We demonstrate that new statistical techniques enable GWAS analyses in a limited sized cohort of mixed ethnicity. After implementation, we confirmed the central role of the HLA region in the disease and identified new regions of interest. Moreover, we validated the association of a variant in the IL2A gene by meta-analysis with previous work. These findings enhance our knowledge of genetic associations and BD, and provide further justification for pursuing collective initiatives in genetic studies given the low prevalence of this and other rare diseases.
authors: Internal medicine, Section immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Jasper H
authors: JH
authors: Kappen
authors: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; Department of epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; The Generation R Study Group, Erasmus M Medical Center C, Rotterdam, The Netherlands.
authors: Carolina
authors: C
authors: Medina-Gomez
authors: Internal medicine, Section immunology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: P Martin
authors: PM
authors: van Hagen
authors: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Lisette
authors: L
authors: Stolk
authors: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Karol
authors: K
authors: Estrada
authors: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; Department of epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; The Generation R Study Group, Erasmus M Medical Center C, Rotterdam, The Netherlands.
authors: Fernando
authors: F
authors: Rivadeneira
authors: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Andre G
authors: AG
authors: Uitterlinden
authors: Department of Ophthalmology, King's College, London, United Kingdom.
authors: Miles R
authors: MR
authors: Stanford
authors: Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Eldat
authors: E
authors: Ben-Chetrit
authors: Centre for Translational Inflammation, University of Birmingham, Birmingham, United Kingdom.
authors: Graham R
authors: GR
authors: Wallace
authors: Department of Ophthalmology, University of Cukurova, School of Medicine, Adana, Turkey.
authors: Merih
authors: M
authors: Soylu
authors: Internal medicine, Section immunology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Jan A M
authors: JA
authors: van Laar
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001528:Behcet Syndrome / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D053765:Interleukin-12 Subunit p35 / Q000235:genetics*; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C508858:IL12A protein, human; D053765:Interleukin-12 Subunit p35