PMID- 26562150 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20191120 IS - 1528-3658 (Electronic) IS - 1076-1551 (Print) IS - 1076-1551 (Linking) VI - 21 IP - 1 DP - 2016 Mar TI - Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations. PG - 769-781 LID - 10.2119/molmed.2015.00232 [doi] AB - 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 x 10(-7), odds ratio [OR] 1.42) and identify a novel candidate gene, ZBTB10, achieving genome-wide significance (rs6998967, P = 8.9 x 10(-10), OR 0.53). Several other SNPs showed suggestive significance including rs2476601 (P = 6.5 x 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 x 10(-12)) versus 2.82 in EOMG (P = 3.86 x 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. FAU - Seldin, Michael F AU - Seldin MF AD - Department of Biochemistry and Molecular Medicine, and Department of Medicine, University of California, Davis, California, United States of America. FAU - Alkhairy, Omar K AU - Alkhairy OK AD - Division of Clinical Immunology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden. FAU - Lee, Annette T AU - Lee AT AD - The Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, United States of America. FAU - Lamb, Janine A AU - Lamb JA AD - Centre for Integrated Genomic Medical Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom. FAU - Sussman, Jon AU - Sussman J AD - Department of Neurology, Greater Manchester Neuroscience Centre, Manchester, United Kingdom. FAU - Pirskanen-Matell, Ritva AU - Pirskanen-Matell R AD - Department of Neurology, Karolinska University Hospital Solna, Stockholm, Sweden. FAU - Piehl, Fredrik AU - Piehl F AD - Department of Neurology, Karolinska University Hospital Solna, Stockholm, Sweden. FAU - Verschuuren, Jan J G M AU - Verschuuren JJGM AD - Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands. FAU - Kostera-Pruszczyk, Anna AU - Kostera-Pruszczyk A AD - Department of Neurology, Medical University of Warsaw, Warsaw, Poland. FAU - Szczudlik, Piotr AU - Szczudlik P AD - Department of Neurology, Medical University of Warsaw, Warsaw, Poland. FAU - McKee, David AU - McKee D AD - Department of Neurology, Greater Manchester Neuroscience Centre, Manchester, United Kingdom. FAU - Maniaol, Angelina H AU - Maniaol AH AD - Department of Neurology, Oslo University Hospital, Ulleval, Oslo, Norway. FAU - Harbo, Hanne F AU - Harbo HF AD - Department of Neurology, Oslo University Hospital and University of Oslo, Oslo, Norway. FAU - Lie, Benedicte A AU - Lie BA AD - Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway. FAU - Melms, Arthur AU - Melms A AD - Department of Neurology, Tubingen University Medical Center, Tubingen, Germany, and Neurologische Klinik, Universitatsklinikum Erlangen, Erlangen, Germany. FAU - Garchon, Henri-Jean AU - Garchon HJ AD - INSERM U1173, University of Versailles, Campus Paris-Saclay, France. FAU - Willcox, Nicholas AU - Willcox N AD - Nuffield Department of Clinical Neurosciences, Weatherall Institute for Molecular Medicine, University of Oxford, Oxford, United Kingdom. FAU - Gregersen, Peter K AU - Gregersen PK AD - The Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, United States of America. FAU - Hammarstrom, Lennart AU - Hammarstrom L AD - Division of Clinical Immunology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden. LA - eng GR - R01 AI068759/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20151110 PL - England TA - Mol Med JT - Molecular medicine (Cambridge, Mass.) JID - 9501023 PMC - PMC4749491 EDAT- 2015/11/13 06:00 MHDA- 2015/11/13 06:01 PMCR- 2015/11/10 CRDT- 2015/11/13 06:00 PHST- 2015/11/04 00:00 [received] PHST- 2015/11/09 00:00 [accepted] PHST- 2015/11/13 06:00 [pubmed] PHST- 2015/11/13 06:01 [medline] PHST- 2015/11/13 06:00 [entrez] PHST- 2015/11/10 00:00 [pmc-release] AID - molmed.2015.00232 [pii] AID - 15_232_seldin [pii] AID - 10.2119/molmed.2015.00232 [doi] PST - ppublish SO - Mol Med. 2016 Mar;21(1):769-781. doi: 10.2119/molmed.2015.00232. Epub 2015 Nov 10.