| Title |
Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations
|
|---|---|
| Published in |
Molecular Medicine, November 2015
|
| DOI | 10.2119/molmed.2015.00232 |
| Pubmed ID | |
| Authors |
Michael F. Seldin, Omar K. Alkhairy, Annette T. Lee, Janine A. Lamb, Jon Sussman, Ritva Pirskanen-Matell, Fredrik Piehl, Jan J. G. M. Verschuuren, Anna Kostera-Pruszczyk, Piotr Szczudlik, David McKee, Angelina H. Maniaol, Hanne F. Harbo, Benedicte A. Lie, Arthur Melms, Henri-Jean Garchon, Nicholas Willcox, Peter K. Gregersen, Lennart Hammarstrom |
| 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. |
X Demographics
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 1 | 33% |
| United Kingdom | 1 | 33% |
| Unknown | 1 | 33% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 2 | 67% |
| Scientists | 1 | 33% |
Mendeley readers
The data shown below were compiled from readership statistics for 51 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 51 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 8 | 16% |
| Student > Bachelor | 8 | 16% |
| Researcher | 5 | 10% |
| Other | 4 | 8% |
| Professor > Associate Professor | 4 | 8% |
| Other | 11 | 22% |
| Unknown | 11 | 22% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 17 | 33% |
| Biochemistry, Genetics and Molecular Biology | 6 | 12% |
| Agricultural and Biological Sciences | 5 | 10% |
| Immunology and Microbiology | 5 | 10% |
| Neuroscience | 3 | 6% |
| Other | 3 | 6% |
| Unknown | 12 | 24% |
Attention Score in Context
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 14 November 2015.
All research outputs
#14,828,066
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Outputs from Molecular Medicine
#781
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Outputs of similar age
#155,999
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Outputs of similar age from Molecular Medicine
#7
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