DESCRIPTION:

List of positional candidate genes after correcting for multiple testing and controlling the false discovery rate from genome wide association studies (GWAS) retrieved from the NHGRI-EBI Catalog of published genome-wide association studies (http://www.ebi.ac.uk/gwas/). The disease/trait examined in this study, as reported by the authors, was Late-onset myasthenia gravis. The EFO term late-onset myasthenia gravis was annotated to this set after curation by NHGRI-EBI. Intergenic SNPS were mapped to both the upstream and downstream gene. P-value uploaded. This gene set was generated using gwas2gs v. 0.1.8 and the GWAS Catalog v. 1.0.1.

LABEL:

GWAS: late-onset myasthenia gravis

SCORE TYPE:

P-Value

DATE ADDED:

2017-05-02

DATE UPDATED:

2024-04-25

SPECIES:

AUTHORS:

MF Seldin, OK Alkhairy, AT Lee, JA Lamb, J Sussman, R Pirskanen-Matell, F Piehl, JJ Verschuuren, A Kostera-Pruszczyk, P Szczudlik, D Mckee, AH Maniaol, HF Harbo, BA Lie, A Melms, HJ Garchon, N Willcox, PK Gregersen, L Hammarstrom

TITLE:

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

JOURNAL:

Molecular medicine (Cambridge, Mass.) Oct 2015, Vol None, pp. None

ABSTRACT:

To investigate the genetics of late-onset myasthenia gravis (LOMG), we conducted a genome-wide association study imputation of >6 million 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(-07), 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(-06), OR =1.62) encoding the PTPN22 R620W variant noted in early-onset MG (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 vs. ~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)) vs. 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 i) MHC class II (highest attenuation when conditioning on DQA1), ii) HLA-A and iii) MHC class III SNPs. Conditioning studies of HLA amino acid residues also suggest potential functional correlates. Together, these findings emphasize the value of subgrouping MG patients for clinical and basic investigations, and imply distinct predisposing mechanisms in LOMG. PUBMED: 26562150
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