TY - JOUR
T1 - Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sjögren's Syndrome According to Ancestry
AU - Taylor, Kimberly E.
AU - Wong, Quenna
AU - Levine, David M.
AU - McHugh, Caitlin
AU - Laurie, Cathy
AU - Doheny, Kimberly
AU - Lam, Mi Y.
AU - Baer, Alan N.
AU - Challacombe, Stephen
AU - Lanfranchi, Hector
AU - Schiødt, Morten
AU - Srinivasan, M.
AU - Umehara, Hisanori
AU - Vivino, Frederick B.
AU - Zhao, Yan
AU - Shiboski, Stephen C.
AU - Daniels, Troy E.
AU - Greenspan, John S.
AU - Shiboski, Caroline H.
AU - Criswell, Lindsey A.
N1 - Funding Information:
We are very grateful to the SICCA participants for their time and dedication to this research. We would also like to thank the IGANGWAS, COGEND, and AREDS participants and researchers for their valuable contributions. We acknowledge the contribution of data from AREDS, which were accessed through dbGaP (accession no. phs000001.v3.p1). Funding support for AREDS was provided by the National Eye Institute (N01-EY- [NEI AREDS] April 21, 2010, version G Page 5 of 8 0-2127). We also acknowledge the contribution of data from Genetic Architecture of Smoking and Smoking Cessation, accessed through dbGaP (accession no. phs000404.v1.p1). Funding support for genotyping, which was performed at the Center for Inherited Disease Research (CIDR), was provided by 1 X01 HG005274-01. The CIDR is fully funded through a federal contract from the National Institutes of Health to Johns Hopkins University (contract no. HHSN268200782096C). Assistance with the cleaning of genotype data, as well as with general study coordination, was provided by the Gene Environment Association Studies Coordinating Center (U01HG004446). Funding support for the collection of data sets and samples was provided by the Collaborative Study of Nicotine Dependence (P01-CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (grants P50-DA019706 and P50-A084724). Finally, we acknowledge the contribution of data from IGANGWAS, conducted by the IGANGWAS investigators and supported by the NIDDK. The data from IGANGWAS reported herein were derived from dbGaP (accession no. phs000431.v2.p1).
PY - 2017/6
Y1 - 2017/6
N2 - Objective: 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. Methods: 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. Results: 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 × 10−15 and P = 4 × 10−5, respectively), but that subphenotype differences did not explain most of the ancestry differences in genetic associations. Conclusion: Genetic associations with SS differ markedly according to ancestry; however, this is not explained by differences in subphenotypes.
AB - Objective: 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. Methods: 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. Results: 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 × 10−15 and P = 4 × 10−5, respectively), but that subphenotype differences did not explain most of the ancestry differences in genetic associations. Conclusion: Genetic associations with SS differ markedly according to ancestry; however, this is not explained by differences in subphenotypes.
UR - http://www.scopus.com/inward/record.url?scp=85018819254&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018819254&partnerID=8YFLogxK
U2 - 10.1002/art.40040
DO - 10.1002/art.40040
M3 - Article
C2 - 28076899
AN - SCOPUS:85018819254
VL - 69
SP - 1294
EP - 1305
JO - Arthritis and Rheumatology
JF - Arthritis and Rheumatology
SN - 2326-5191
IS - 6
ER -