Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations.

Michael F Seldin,Lennart Hammarstrom,Nicholas Willcox,Fredrik Piehl,Omar K Alkhairy,Peter K Gregersen,Piotr Szczudlik,Angelina H Maniaol,Anna Kostera-Pruszczyk,Annette T Lee,Ritva Pirskanen-Matell,Benedicte A Lie,Janine A Lamb,David Mckee,Henri-Jean Garchon,Jon Sussman,Arthur Melms,Hanne F Harbo,Jan J G M Verschuuren

doi:10.2119/molmed.2015.00232

Abstract

To investigate the genetics of late-onset myasthenia gravis (LOMG), we conducted a genome-wide association study imputation of>6 million single nucleotide polymorphisms (SNPs) in 532 LOMG cases (anti-acetylcholine receptor [AChR] antibody positive; onset age≥50 years) and 2,128 controls matched for sex and population substructure. The data confirm reported TNFRSF11A associations (rs4574025, P = 3.9 × 10-7, odds ratio [OR] 1.42) and identify a novel candidate gene, ZBTB10, achieving genome-wide significance (rs6998967, P = 8.9 × 10-10, OR 0.53). Several other SNPs showed suggestive significance including rs2476601 (P = 6.5 × 10-6, OR 1.62) encoding the PTPN22 R620W variant noted in early-onset myasthenia gravis (EOMG) and other autoimmune diseases. In contrast, EOMG-associated SNPs in TNIP1 showed no association in LOMG, nor did other loci suggested for EOMG. Many SNPs within the major histocompatibility complex (MHC) region showed strong associations in LOMG, but with smaller effect sizes than in EOMG (highest OR ~2 versus ~6 in EOMG). Moreover, the strongest associations were in opposite directions from EOMG, including an OR of 0.54 for DQA1*05:01 in LOMG (P = 5.9 × 10-12) versus 2.82 in EOMG (P = 3.86 × 10-45). Association and conditioning studies for the MHC region showed three distinct and largely independent association peaks for LOMG corresponding to (a) MHC class II (highest attenuation when conditioning on DQA1), (b) HLA-A and (c) MHC class III SNPs. Conditioning studies of human leukocyte antigen (HLA) amino acid residues also suggest potential functional correlates. Together, these findings emphasize the value of subgrouping myasthenia gravis patients for clinical and basic investigations and imply distinct predisposing mechanisms in LOMG.

Highlights

Myasthenia gravis (MG) is an uncommon idiopathic autoimmune disease characterized by impaired neuromuscular transmission and fatigable muscle weakness
We tested for associations with variants imputed with high confidence (r2 ≥ 0.8, required for each imputed variant from both genomewide association study (GWAS) panels); the analyses included over 6 million variants with minor allele frequencies ≥0.02
With respect to immunologic functions, TNFRSF11A appears to be important in lymph node development and thymic selection [50], and its expression on dendritic cells may be critical to specific interactions with T cells [51,52]

Summary

Introduction

Myasthenia gravis (MG) is an uncommon idiopathic autoimmune disease characterized by impaired neuromuscular transmission and fatigable muscle weakness. Its overall incidence is ~3/100,000, and its prevalence is ~2 per 10,000. Both incidence and prevalence have apparently increased in recent decades, especially in subjects aged >50 years at onset [1,2,3]. Over 80% of patients with generalized MG have antibodies (Abs) to the skeletal muscle acetylcholine receptor (AChR), which are generally accepted to be pathogenic [2,4]. About 10% of them have thymomas, which mostly generate (and export) abundant T cells. The neoplastic thymic epithelial cells usually fail to express both human leukocyte antigen

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