Identification of Novel Loci Shared by Juvenile Idiopathic Arthritis Subtypes Through Integrative Genetic Analysis

Jin Li; Yun R. Li; Joseph T. Glessner; Jie Yang; Michael E. March; Charlly Kao; Courtney N. Vaccaro; Jonathan P. Bradfield; Junyi Li; Frank D. Mentch; Hui Qi Qu; Xiaohui Qi; Xiao Chang; Cuiping Hou; Debra J. Abrams; Haijun Qiu; Zhi Wei; John J. Connolly; Fengxiang Wang; James Snyder; Berit Flatø; Susan D. Thompson; Carl D. Langefeld; Benedicte A. Lie; Jane E. Munro; Carol Wise; Patrick M.A. Sleiman; Hakon Hakonarson

doi:10.1002/art.42129

Identification of Novel Loci Shared by Juvenile Idiopathic Arthritis Subtypes Through Integrative Genetic Analysis

Jin Li, Yun R. Li, Joseph T. Glessner, Jie Yang, Michael E. March, Charlly Kao, Courtney N. Vaccaro, Jonathan P. Bradfield, Junyi Li, Frank D. Mentch, Hui Qi Qu, Xiaohui Qi, Xiao Chang, Cuiping Hou, Debra J. Abrams, Haijun Qiu, Zhi Wei, John J. Connolly, Fengxiang Wang, James SnyderBerit Flatø, Susan D. Thompson, Carl D. Langefeld, Benedicte A. Lie, Jane E. Munro, Carol Wise, Patrick M.A. Sleiman, Hakon Hakonarson

Computer Science

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5 Scopus citations

Abstract

Objective: Juvenile idiopathic arthritis (JIA) is the most common chronic immune-mediated joint disease among children and encompasses a heterogeneous group of immune-mediated joint disorders classified into 7 subtypes according to clinical presentation. However, phenotype overlap and biologic evidence suggest a shared mechanistic basis between subtypes. This study was undertaken to systematically investigate shared genetic underpinnings of JIA subtypes. Methods: We performed a heterogeneity-sensitive genome-wide association study encompassing a total of 1,245 JIA cases (classified into 7 subtypes) and 9,250 controls, followed by fine-mapping of candidate causal variants at each genome-wide significant locus, functional annotation, and pathway and network analysis. We further identified candidate drug targets and drug repurposing opportunities by in silico analyses. Results: In addition to the major histocompatibility complex locus, we identified 15 genome-wide significant loci shared between at least 2 JIA subtypes, including 10 novel loci. Functional annotation indicated that candidate genes at these loci were expressed in diverse immune cell types. Conclusion: This study identified novel genetic loci shared by JIA subtypes. Our findings identified candidate mechanisms underlying JIA subtypes and candidate targets with drug repurposing opportunities for JIA treatment.

Original language	English (US)
Pages (from-to)	1420-1429
Number of pages	10
Journal	Arthritis and Rheumatology
Volume	74
Issue number	8
DOIs	https://doi.org/10.1002/art.42129
State	Published - Aug 2022

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Rheumatology
Immunology

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10.1002/art.42129

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Li, J., Li, Y. R., Glessner, J. T., Yang, J., March, M. E., Kao, C., Vaccaro, C. N., Bradfield, J. P., Li, J., Mentch, F. D., Qu, H. Q., Qi, X., Chang, X., Hou, C., Abrams, D. J., Qiu, H., Wei, Z., Connolly, J. J., Wang, F., ... Hakonarson, H. (2022). Identification of Novel Loci Shared by Juvenile Idiopathic Arthritis Subtypes Through Integrative Genetic Analysis. Arthritis and Rheumatology, 74(8), 1420-1429. https://doi.org/10.1002/art.42129

@article{5a5e7c4b378548038b3b56d4f1adadc3,

title = "Identification of Novel Loci Shared by Juvenile Idiopathic Arthritis Subtypes Through Integrative Genetic Analysis",

abstract = "Objective: Juvenile idiopathic arthritis (JIA) is the most common chronic immune-mediated joint disease among children and encompasses a heterogeneous group of immune-mediated joint disorders classified into 7 subtypes according to clinical presentation. However, phenotype overlap and biologic evidence suggest a shared mechanistic basis between subtypes. This study was undertaken to systematically investigate shared genetic underpinnings of JIA subtypes. Methods: We performed a heterogeneity-sensitive genome-wide association study encompassing a total of 1,245 JIA cases (classified into 7 subtypes) and 9,250 controls, followed by fine-mapping of candidate causal variants at each genome-wide significant locus, functional annotation, and pathway and network analysis. We further identified candidate drug targets and drug repurposing opportunities by in silico analyses. Results: In addition to the major histocompatibility complex locus, we identified 15 genome-wide significant loci shared between at least 2 JIA subtypes, including 10 novel loci. Functional annotation indicated that candidate genes at these loci were expressed in diverse immune cell types. Conclusion: This study identified novel genetic loci shared by JIA subtypes. Our findings identified candidate mechanisms underlying JIA subtypes and candidate targets with drug repurposing opportunities for JIA treatment.",

author = "Jin Li and Li, {Yun R.} and Glessner, {Joseph T.} and Jie Yang and March, {Michael E.} and Charlly Kao and Vaccaro, {Courtney N.} and Bradfield, {Jonathan P.} and Junyi Li and Mentch, {Frank D.} and Qu, {Hui Qi} and Xiaohui Qi and Xiao Chang and Cuiping Hou and Abrams, {Debra J.} and Haijun Qiu and Zhi Wei and Connolly, {John J.} and Fengxiang Wang and James Snyder and Berit Flat{\o} and Thompson, {Susan D.} and Langefeld, {Carl D.} and Lie, {Benedicte A.} and Munro, {Jane E.} and Carol Wise and Sleiman, {Patrick M.A.} and Hakon Hakonarson",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.",

year = "2022",

month = aug,

doi = "10.1002/art.42129",

language = "English (US)",

volume = "74",

pages = "1420--1429",

journal = "Arthritis and Rheumatology",

issn = "2326-5191",

publisher = "John Wiley and Sons Ltd",

number = "8",

}

Li, J, Li, YR, Glessner, JT, Yang, J, March, ME, Kao, C, Vaccaro, CN, Bradfield, JP, Li, J, Mentch, FD, Qu, HQ, Qi, X, Chang, X, Hou, C, Abrams, DJ, Qiu, H, Wei, Z, Connolly, JJ, Wang, F, Snyder, J, Flatø, B, Thompson, SD, Langefeld, CD, Lie, BA, Munro, JE, Wise, C, Sleiman, PMA & Hakonarson, H 2022, 'Identification of Novel Loci Shared by Juvenile Idiopathic Arthritis Subtypes Through Integrative Genetic Analysis', Arthritis and Rheumatology, vol. 74, no. 8, pp. 1420-1429. https://doi.org/10.1002/art.42129

TY - JOUR

T1 - Identification of Novel Loci Shared by Juvenile Idiopathic Arthritis Subtypes Through Integrative Genetic Analysis

AU - Li, Jin

AU - Li, Yun R.

AU - Glessner, Joseph T.

AU - Yang, Jie

AU - March, Michael E.

AU - Kao, Charlly

AU - Vaccaro, Courtney N.

AU - Bradfield, Jonathan P.

AU - Li, Junyi

AU - Mentch, Frank D.

AU - Qu, Hui Qi

AU - Qi, Xiaohui

AU - Chang, Xiao

AU - Hou, Cuiping

AU - Abrams, Debra J.

AU - Qiu, Haijun

AU - Wei, Zhi

AU - Connolly, John J.

AU - Wang, Fengxiang

AU - Snyder, James

AU - Flatø, Berit

AU - Thompson, Susan D.

AU - Langefeld, Carl D.

AU - Lie, Benedicte A.

AU - Munro, Jane E.

AU - Wise, Carol

AU - Sleiman, Patrick M.A.

AU - Hakonarson, Hakon

PY - 2022/8

Y1 - 2022/8

N2 - Objective: Juvenile idiopathic arthritis (JIA) is the most common chronic immune-mediated joint disease among children and encompasses a heterogeneous group of immune-mediated joint disorders classified into 7 subtypes according to clinical presentation. However, phenotype overlap and biologic evidence suggest a shared mechanistic basis between subtypes. This study was undertaken to systematically investigate shared genetic underpinnings of JIA subtypes. Methods: We performed a heterogeneity-sensitive genome-wide association study encompassing a total of 1,245 JIA cases (classified into 7 subtypes) and 9,250 controls, followed by fine-mapping of candidate causal variants at each genome-wide significant locus, functional annotation, and pathway and network analysis. We further identified candidate drug targets and drug repurposing opportunities by in silico analyses. Results: In addition to the major histocompatibility complex locus, we identified 15 genome-wide significant loci shared between at least 2 JIA subtypes, including 10 novel loci. Functional annotation indicated that candidate genes at these loci were expressed in diverse immune cell types. Conclusion: This study identified novel genetic loci shared by JIA subtypes. Our findings identified candidate mechanisms underlying JIA subtypes and candidate targets with drug repurposing opportunities for JIA treatment.

AB - Objective: Juvenile idiopathic arthritis (JIA) is the most common chronic immune-mediated joint disease among children and encompasses a heterogeneous group of immune-mediated joint disorders classified into 7 subtypes according to clinical presentation. However, phenotype overlap and biologic evidence suggest a shared mechanistic basis between subtypes. This study was undertaken to systematically investigate shared genetic underpinnings of JIA subtypes. Methods: We performed a heterogeneity-sensitive genome-wide association study encompassing a total of 1,245 JIA cases (classified into 7 subtypes) and 9,250 controls, followed by fine-mapping of candidate causal variants at each genome-wide significant locus, functional annotation, and pathway and network analysis. We further identified candidate drug targets and drug repurposing opportunities by in silico analyses. Results: In addition to the major histocompatibility complex locus, we identified 15 genome-wide significant loci shared between at least 2 JIA subtypes, including 10 novel loci. Functional annotation indicated that candidate genes at these loci were expressed in diverse immune cell types. Conclusion: This study identified novel genetic loci shared by JIA subtypes. Our findings identified candidate mechanisms underlying JIA subtypes and candidate targets with drug repurposing opportunities for JIA treatment.

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U2 - 10.1002/art.42129

DO - 10.1002/art.42129

M3 - Article

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AN - SCOPUS:85134025799

SN - 2326-5191

VL - 74

SP - 1420

EP - 1429

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

IS - 8

ER -

Identification of Novel Loci Shared by Juvenile Idiopathic Arthritis Subtypes Through Integrative Genetic Analysis

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