title: Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation ofTNFRSF11Aand Identification ofZBTB10and Three Distinct HLA Associations.
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 reportedTNFRSF11Aassociations (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 inTNIP1showed 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 forDQA1*05:01in 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 onDQA1), (b)HLA-Aand (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.
authors.affiliation: Department of Biochemistry and Molecular Medicine, and Department of Medicine, University of California, Davis, California, United States of America.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Seldin
authors.affiliation: Division of Clinical Immunology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Omar K
authors.initials: OK
authors.lastname: Alkhairy
authors.affiliation: 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.
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.affiliation: Centre for Integrated Genomic Medical Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.
authors.forename: Janine A
authors.initials: JA
authors.lastname: Lamb
authors.affiliation: Department of Neurology, Greater Manchester Neuroscience Centre, Manchester, United Kingdom.
authors.forename: Jon
authors.initials: J
authors.lastname: Sussman
authors.affiliation: Department of Neurology, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Ritva
authors.initials: R
authors.lastname: Pirskanen-Matell
authors.affiliation: Department of Neurology, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Piehl
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Jan J G M
authors.initials: JJGM
authors.lastname: Verschuuren
authors.affiliation: Department of Neurology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kostera-Pruszczyk
authors.affiliation: Department of Neurology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Szczudlik
authors.affiliation: Department of Neurology, Greater Manchester Neuroscience Centre, Manchester, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: McKee
authors.affiliation: Department of Neurology, Oslo University Hospital, Ullevål, Oslo, Norway.
authors.forename: Angelina H
authors.initials: AH
authors.lastname: Maniaol
authors.affiliation: Department of Neurology, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors.forename: Hanne F
authors.initials: HF
authors.lastname: Harbo
authors.affiliation: Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway.
authors.forename: Benedicte A
authors.initials: BA
authors.lastname: Lie
authors.affiliation: Department of Neurology, Tübingen University Medical Center, Tübingen, Germany, and Neurologische Klinik, Universitàtsklinikum Erlangen, Erlangen, Germany.
authors.forename: Arthur
authors.initials: A
authors.lastname: Melms
authors.affiliation: INSERM U1173, University of Versailles, Campus Paris-Saclay, France.
authors.forename: Henri-Jean
authors.initials: HJ
authors.lastname: Garchon
authors.affiliation: Nuffield Department of Clinical Neurosciences, Weatherall Institute for Molecular Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Willcox
authors.affiliation: 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.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: Division of Clinical Immunology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Hammarstrom