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. 2013 Dec;65(12):3239-47.
doi: 10.1002/art.38137.

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

Frederick W Miller  1 , 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, Wei Chen, Christopher I Amos, Peter K Gregersen; Myositis Genetics Consortium
Collaborators, Affiliations

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

Frederick W Miller et al. Arthritis Rheum. 2013 Dec.

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.

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Figures

Figure 1
Figure 1
Results of genome-wide association analysis of dermatomyositis plotted on a genomic scale (Manhattan plot) showing P values for 242,876 successfully genotyped single-nucleotide polymorphisms. The orange line represents the genome-wide level of significance (P = 5x10−8). Chr = chromosome.
Figure 2
Figure 2
(A) Quantile-quantile (Q-Q) plot of the genome-wide meta-analysis (lambda = 1.043). (B) Q-Q plot of the genome-wide meta-analysis without the major histocompatibility complex region (lambda = 1.037).
Figure 3
Figure 3
Quantile-quantile (Q-Q) plot showing an excess of positive associations of published genome-wide association study non-major histocompatibility complex single-nucleotide polymorphisms for autoimmune diseases with those for dermatomyositis (lambda = 2.59).
See this image and copyright information in PMC

References

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