Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sjögren's Syndrome According to Ancestry

Kimberly E Taylor; Quenna Wong; David M Levine; Caitlin McHugh; Cathy Laurie; Kimberly Doheny; Mi Y Lam; Alan N Baer; Stephen Challacombe; Hector Lanfranchi; Morten Schiødt; Muthiah Srinivasan; Hisanori Umehara; Frederick B Vivino; Yan Zhao; Stephen C Shiboski; Troy E Daniels; John S Greenspan; Caroline H Shiboski; Lindsey A Criswell

doi:10.1002/art.40040

Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sjögren's Syndrome According to Ancestry

Kimberly E Taylor, Quenna Wong, David M Levine, Caitlin McHugh, Cathy Laurie, Kimberly Doheny, Mi Y Lam, Alan N Baer, Stephen Challacombe, Hector Lanfranchi, Morten Schiødt, Muthiah Srinivasan, Hisanori Umehara, Frederick B Vivino, Yan Zhao, Stephen C Shiboski, Troy E Daniels, John S Greenspan, Caroline H Shiboski, Lindsey A Criswell

Department of Dental, Oral and Maxilliofacial Surgery

113 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Arthritis & rheumatology
Volume	69
Issue number	6
Pages (from-to)	1294-1305
Number of pages	12
ISSN	2326-5191
DOIs	https://doi.org/10.1002/art.40040
Publication status	Published - Jun 2017

Keywords

Adaptor Proteins, Signal Transducing
Asian Continental Ancestry Group
Autoantibodies
Case-Control Studies
European Continental Ancestry Group
Female
Gene Frequency
Genetic Heterogeneity
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Interferon Regulatory Factors
Lectins, C-Type
Major Histocompatibility Complex
Male
Phenotype
Polymorphism, Single Nucleotide
Registries
STAT4 Transcription Factor
Salivary Glands, Minor
Sjogren's Syndrome
Trans-Activators
Journal Article

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Taylor, K. E., Wong, Q., Levine, D. M., McHugh, C., Laurie, C., Doheny, K., Lam, M. Y., Baer, A. N., Challacombe, S., Lanfranchi, H., Schiødt, M., Srinivasan, M., Umehara, H., Vivino, F. B., Zhao, Y., Shiboski, S. C., Daniels, T. E., Greenspan, J. S., Shiboski, C. H., & Criswell, L. A. (2017). Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sjögren's Syndrome According to Ancestry. Arthritis & rheumatology, 69(6), 1294-1305. https://doi.org/10.1002/art.40040

Taylor, KE, Wong, Q, Levine, DM, McHugh, C, Laurie, C, Doheny, K, Lam, MY, Baer, AN, Challacombe, S, Lanfranchi, H, Schiødt, M, Srinivasan, M, Umehara, H, Vivino, FB, Zhao, Y, Shiboski, SC, Daniels, TE, Greenspan, JS, Shiboski, CH & Criswell, LA 2017, 'Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sjögren's Syndrome According to Ancestry', Arthritis & rheumatology, vol. 69, no. 6, pp. 1294-1305. https://doi.org/10.1002/art.40040

@article{112c20c5388b45de9563ec3278c4fdf8,

title = "Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sj{\"o}gren's Syndrome According to Ancestry",

abstract = "OBJECTIVE: The Sj{\"o}gren'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 Sj{\"o}gren'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.",

keywords = "Adaptor Proteins, Signal Transducing, Asian Continental Ancestry Group, Autoantibodies, Case-Control Studies, European Continental Ancestry Group, Female, Gene Frequency, Genetic Heterogeneity, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Interferon Regulatory Factors, Lectins, C-Type, Major Histocompatibility Complex, Male, Phenotype, Polymorphism, Single Nucleotide, Registries, STAT4 Transcription Factor, Salivary Glands, Minor, Sjogren's Syndrome, Trans-Activators, Journal Article",

author = "Taylor, \{Kimberly E\} and Quenna Wong and Levine, \{David M\} and Caitlin McHugh and Cathy Laurie and Kimberly Doheny and Lam, \{Mi Y\} and Baer, \{Alan N\} and Stephen Challacombe and Hector Lanfranchi and Morten Schi{\o}dt and Muthiah Srinivasan and Hisanori Umehara and Vivino, \{Frederick B\} and Yan Zhao and Shiboski, \{Stephen C\} and Daniels, \{Troy E\} and Greenspan, \{John S\} and Shiboski, \{Caroline H\} and Criswell, \{Lindsey A\}",

note = "{\textcopyright} 2017, The Authors. Arthritis \& Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.",

year = "2017",

month = jun,

doi = "10.1002/art.40040",

language = "English",

volume = "69",

pages = "1294--1305",

journal = "Arthritis \& rheumatology",

issn = "2326-5191",

publisher = "John Wiley and Sons Ltd",

number = "6",

}

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, Muthiah

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

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.

KW - Adaptor Proteins, Signal Transducing

KW - Asian Continental Ancestry Group

KW - Autoantibodies

KW - Case-Control Studies

KW - European Continental Ancestry Group

KW - Female

KW - Gene Frequency

KW - Genetic Heterogeneity

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Interferon Regulatory Factors

KW - Lectins, C-Type

KW - Major Histocompatibility Complex

KW - Male

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Registries

KW - STAT4 Transcription Factor

KW - Salivary Glands, Minor

KW - Sjogren's Syndrome

KW - Trans-Activators

KW - Journal Article

UR - https://www.scopus.com/pages/publications/85018819254

U2 - 10.1002/art.40040

DO - 10.1002/art.40040

M3 - Journal article

C2 - 28076899

SN - 2326-5191

VL - 69

SP - 1294

EP - 1305

JO - Arthritis & rheumatology

JF - Arthritis & rheumatology

IS - 6

ER -

Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sjögren's Syndrome According to Ancestry

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Keywords

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