title: Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sjögren's Syndrome According to Ancestry.
abstract: The Sjögren's International Collaborative Clinical Alliance (SICCA) is an international data registry and biorepository derived from a multisite observational study of participants in whom genotyping was performed on the Omni2.5M platform and who had undergone deep phenotyping using common protocol-directed methods. The aim of this study was to examine the genetic etiology of Sjögren's syndrome (SS) across ancestry and disease subsets.
  
  
  
  We performed genome-wide association study analyses using SICCA subjects and external controls obtained from dbGaP data sets, one using all participants (1,405 cases, 1,622 SICCA controls, and 3,125 external controls), one using European participants (585, 966, and 580, respectively), and one using Asian participants (460, 224, and 901, respectively) with ancestry adjustments via principal components analyses. We also investigated whether subphenotype distributions differ by ethnicity, and whether this contributes to the heterogeneity of genetic associations.
  
  
  
  We observed significant associations in established regions of the major histocompatibility complex (MHC), IRF5, and STAT4 (P = 3 × 10-42, P = 3 × 10-14, and P = 9 × 10-10, respectively), and several novel suggestive regions (those with 2 or more associations at P < 1 × 10-5). Two regions have been previously implicated in autoimmune disease: KLRG1 (P = 6 × 10-7[Asian cluster]) and SH2D2A (P = 2 × 10-6[all participants]). We observed striking differences between the associations in Europeans and Asians, with high heterogeneity especially in the MHC; representative single-nucleotide polymorphisms from established and suggestive regions had highly significant differences in the allele frequencies in the study populations. We showed that SSA/SSB autoantibody production and the labial salivary gland focus score criteria were associated with the first worldwide principal component, indicative of higher non-European ancestry (P = 4 × 10-15and P = 4 × 10-5, respectively), but that subphenotype differences did not explain most of the ancestry differences in genetic associations.
  
  
  
  Genetic associations with SS differ markedly according to ancestry; however, this is not explained by differences in subphenotypes.
authors.affiliation: University of California, San Francisco.
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Taylor
authors.affiliation: University of Washington, Seattle.
authors.forename: Quenna
authors.initials: Q
authors.lastname: Wong
authors.affiliation: University of Washington, Seattle.
authors.forename: David M
authors.initials: DM
authors.lastname: Levine
authors.affiliation: University of Washington, Seattle.
authors.forename: Caitlin
authors.initials: C
authors.lastname: McHugh
authors.affiliation: University of Washington, Seattle.
authors.forename: Cathy
authors.initials: C
authors.lastname: Laurie
authors.affiliation: Johns Hopkins University, Baltimore, Maryland.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Doheny
authors.affiliation: University of California, San Francisco.
authors.forename: Mi Y
authors.initials: MY
authors.lastname: Lam
authors.affiliation: Johns Hopkins University, Baltimore, Maryland.
authors.forename: Alan N
authors.initials: AN
authors.lastname: Baer
authors.affiliation: Guy's, King's, and St. Thomas' Dental Institute, King's College London, London, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Challacombe
authors.affiliation: University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Hector
authors.initials: H
authors.lastname: Lanfranchi
authors.affiliation: Rigshospitalet, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Schiødt
authors.affiliation: Aravind Eye Hospital, Madurai, India.
authors.forename: M
authors.initials: M
authors.lastname: Srinivasan
authors.affiliation: Kanazawa Medical University, Ishikawa, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Umehara
authors.affiliation: University of Pennsylvania, Philadelphia.
authors.forename: Frederick B
authors.initials: FB
authors.lastname: Vivino
authors.affiliation: Peking Union Medical College Hospital, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: University of California, San Francisco.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Shiboski
authors.affiliation: University of California, San Francisco.
authors.forename: Troy E
authors.initials: TE
authors.lastname: Daniels
authors.affiliation: University of California, San Francisco.
authors.forename: John S
authors.initials: JS
authors.lastname: Greenspan
authors.affiliation: University of California, San Francisco.
authors.forename: Caroline H
authors.initials: CH
authors.lastname: Shiboski
authors.affiliation: University of California, San Francisco.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D044466:Asian People / Q000235:genetics*; D001323:Autoantibodies / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics; D037181:Lectins, C-Type / Q000235:genetics; D008285:Major Histocompatibility Complex; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011971:Receptors, Immunologic; D012042:Registries; D050797:STAT4 Transcription Factor / Q000235:genetics; D012470:Salivary Glands, Minor; D012859:Sjogren's Syndrome / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics; D044465:White People / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001323:Autoantibodies; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; C113413:KLRG1 protein, human; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; C405691:SH2D2A protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators