Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations
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.
This work was supported by the National Institutes of Health (NIH/NIAID RO1-AI-68759 to P K Gregersen); by grants from the Palle Ferb Foundation and the Swedish Research Council (to OK Alkhairy and L Hammarstrom); by program grants from the UK Medical Research Council (to N Willcox); by the Prinses Beatrix Fonds (to JJGM Verschuuren); and by grants from the South-Eastern Norwegian Regional Health Authority and the Norwegian Association for Patients with Muscle Diseases (to AH Maniaol). We thank the Norwegian Bone Marrow Registry for control DNAs. We thank the CIDR for providing access to the Health And Retirement Study (HRS) through dbGaP Study Accession: phs000428.v1.p1. We also thank E Bakker in the Department of Human Genetics, Leiden University Medical Center, the Medical Research Council and Myasthenia Gravis Association in the UK, and the many patients and their physicians in all the centers who generously participated in this study.
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