Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders

Frederick W. Miller, Robert G. Cooper, Jiří Vencovský, Lisa G. Rider, Katalin Danko, Lucy R. Wedderburn, Ingrid E. Lundberg, Lauren M. Pachman, Ann M. Reed, Steven R Ytterberg, Leonid Padyukov, Albert Selva-O'Callaghan, Timothy R D J Radstake, David A. Isenberg, Hector Chinoy, William E R Ollier, Terrance P. O'Hanlon, Bo Peng, Annette Lee, Janine A. Lamb & 10 others Wei Chen, Christopher I. Amos, Peter K. Gregersen, Christopher Denton, David Hilton-Jones, Patrick Kiely, Paul H. Plotz, Mark Gourley, Paul Scheet, Hemlata Varsani

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Abstract

Objective: To identify new genetic associations with juvenile and adult dermatomyositis (DM). Methods: We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. Results: Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 × 10-8) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C-like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C-C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM. Conclusion: Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.

Original languageEnglish (US)
Pages (from-to)3239-3247
Number of pages9
JournalArthritis and Rheumatism
Volume65
Issue number12
DOIs
StatePublished - Dec 2013

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Dermatomyositis
Genome-Wide Association Study
Major Histocompatibility Complex
Autoimmune Diseases
Single Nucleotide Polymorphism
Genes
CC Chemokines
Type C Phospholipases
Genetic Predisposition to Disease
Protein-Tyrosine Kinases
Ligands

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Miller, F. W., Cooper, R. G., Vencovský, J., Rider, L. G., Danko, K., Wedderburn, L. R., ... Varsani, H. (2013). Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders. Arthritis and Rheumatism, 65(12), 3239-3247. https://doi.org/10.1002/art.38137

Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders. / Miller, Frederick W.; Cooper, Robert G.; Vencovský, Jiří; Rider, Lisa G.; Danko, Katalin; Wedderburn, Lucy R.; Lundberg, Ingrid E.; Pachman, Lauren M.; Reed, Ann M.; Ytterberg, Steven R; Padyukov, Leonid; Selva-O'Callaghan, Albert; Radstake, Timothy R D J; Isenberg, David A.; Chinoy, Hector; Ollier, William E R; O'Hanlon, Terrance P.; Peng, Bo; Lee, Annette; Lamb, Janine A.; Chen, Wei; Amos, Christopher I.; Gregersen, Peter K.; Denton, Christopher; Hilton-Jones, David; Kiely, Patrick; Plotz, Paul H.; Gourley, Mark; Scheet, Paul; Varsani, Hemlata.

In: Arthritis and Rheumatism, Vol. 65, No. 12, 12.2013, p. 3239-3247.

Research output: Contribution to journalArticle

Miller, FW, Cooper, RG, Vencovský, J, Rider, LG, Danko, K, Wedderburn, LR, Lundberg, IE, Pachman, LM, Reed, AM, Ytterberg, SR, Padyukov, L, Selva-O'Callaghan, A, Radstake, TRDJ, Isenberg, DA, Chinoy, H, Ollier, WER, O'Hanlon, TP, Peng, B, Lee, A, Lamb, JA, Chen, W, Amos, CI, Gregersen, PK, Denton, C, Hilton-Jones, D, Kiely, P, Plotz, PH, Gourley, M, Scheet, P & Varsani, H 2013, 'Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders', Arthritis and Rheumatism, vol. 65, no. 12, pp. 3239-3247. https://doi.org/10.1002/art.38137
Miller, Frederick W. ; Cooper, Robert G. ; Vencovský, Jiří ; Rider, Lisa G. ; Danko, Katalin ; Wedderburn, Lucy R. ; Lundberg, Ingrid E. ; Pachman, Lauren M. ; Reed, Ann M. ; Ytterberg, Steven R ; Padyukov, Leonid ; Selva-O'Callaghan, Albert ; Radstake, Timothy R D J ; Isenberg, David A. ; Chinoy, Hector ; Ollier, William E R ; O'Hanlon, Terrance P. ; Peng, Bo ; Lee, Annette ; Lamb, Janine A. ; Chen, Wei ; Amos, Christopher I. ; Gregersen, Peter K. ; Denton, Christopher ; Hilton-Jones, David ; Kiely, Patrick ; Plotz, Paul H. ; Gourley, Mark ; Scheet, Paul ; Varsani, Hemlata. / Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders. In: Arthritis and Rheumatism. 2013 ; Vol. 65, No. 12. pp. 3239-3247.
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title = "Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders",
abstract = "Objective: To identify new genetic associations with juvenile and adult dermatomyositis (DM). Methods: We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. Results: Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 × 10-8) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C-like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C-C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM. Conclusion: Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.",
author = "Miller, {Frederick W.} and Cooper, {Robert G.} and Jiř{\'i} Vencovsk{\'y} and Rider, {Lisa G.} and Katalin Danko and Wedderburn, {Lucy R.} and Lundberg, {Ingrid E.} and Pachman, {Lauren M.} and Reed, {Ann M.} and Ytterberg, {Steven R} and Leonid Padyukov and Albert Selva-O'Callaghan and Radstake, {Timothy R D J} and Isenberg, {David A.} and Hector Chinoy and Ollier, {William E R} and O'Hanlon, {Terrance P.} and Bo Peng and Annette Lee and Lamb, {Janine A.} and Wei Chen and Amos, {Christopher I.} and Gregersen, {Peter K.} and Christopher Denton and David Hilton-Jones and Patrick Kiely and Plotz, {Paul H.} and Mark Gourley and Paul Scheet and Hemlata Varsani",
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T1 - Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders

AU - Miller, Frederick W.

AU - Cooper, Robert G.

AU - Vencovský, Jiří

AU - Rider, Lisa G.

AU - Danko, Katalin

AU - Wedderburn, Lucy R.

AU - Lundberg, Ingrid E.

AU - Pachman, Lauren M.

AU - Reed, Ann M.

AU - Ytterberg, Steven R

AU - Padyukov, Leonid

AU - Selva-O'Callaghan, Albert

AU - Radstake, Timothy R D J

AU - Isenberg, David A.

AU - Chinoy, Hector

AU - Ollier, William E R

AU - O'Hanlon, Terrance P.

AU - Peng, Bo

AU - Lee, Annette

AU - Lamb, Janine A.

AU - Chen, Wei

AU - Amos, Christopher I.

AU - Gregersen, Peter K.

AU - Denton, Christopher

AU - Hilton-Jones, David

AU - Kiely, Patrick

AU - Plotz, Paul H.

AU - Gourley, Mark

AU - Scheet, Paul

AU - Varsani, Hemlata

PY - 2013/12

Y1 - 2013/12

N2 - Objective: To identify new genetic associations with juvenile and adult dermatomyositis (DM). Methods: We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. Results: Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 × 10-8) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C-like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C-C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM. Conclusion: Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.

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