دورية أكاديمية
A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies.
| العنوان: | A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies. |
|---|---|
| المؤلفون: | Strippel C; Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany., Herrera-Rivero M; Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany., Wendorff M; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany., Tietz AK; Department of Neurology, University of Kiel, Kiel, Germany., Degenhardt F; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany., Witten A; Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany., Schroeter C; Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.; Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany., Nelke C; Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.; Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany., Golombeck KS; Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.; Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany., Madlener M; Department of Neurology, University of Cologne, Cologne, Germany., Rüber T; Department of Epileptology, University of Bonn, Bonn, Germany.; Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, University Hospital Frankfurt, and LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany., Ernst L; Department of Epileptology, University of Bonn, Bonn, Germany., Racz A; Department of Epileptology, University of Bonn, Bonn, Germany., Baumgartner T; Department of Epileptology, University of Bonn, Bonn, Germany., Widman G; Department of Epileptology, University of Bonn, Bonn, Germany., Doppler K; Department of Neurology, University of Würzburg, Würzburg, Germany., Thaler F; Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany.; Biomedical Center (BMC), Medical Faculty, Ludwig-Maximilians-Universität Munich, Martinsried, Germany., Siebenbrodt K; Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, University Hospital Frankfurt, and LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany., Dik A; Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.; Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany., Kerin C; Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany., Räuber S; Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.; Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany., Gallus M; Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany., Kovac S; Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany., Grauer OM; Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany., Grimm A; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany., Prüss H; Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany., Wickel J; Section of Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena, Germany., Geis C; Section of Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena, Germany., Lewerenz J; Department of Neurology, Ulm University, Ulm, Germany., Goebels N; Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany., Ringelstein M; Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.; Center for Neurology and Neuropsychiatry, LVR Klinikum, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany., Menge T; Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.; Center for Neurology and Neuropsychiatry, LVR Klinikum, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany., Tackenberg B; Department of Neurology, University of Marburg/Gießen, Marburg, Germany., Kellinghaus C; Department of Neurology, Klinikum Osnabrück, Osnabrück, Germany., Bien CG; Department of Epileptology (Krankenhaus Mara), Bielefeld University, Medical School, Campus Bielefeld-Bethel, Bielefeld, Germany., Kraft A; Martha Maria Hospital Halle, Halle, Germany., Zettl U; Department of Neurology, University of Rostock, Rostock, Germany., Ismail FS; Department of Neurology, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, Bochum, Germany., Ayzenberg I; Department of Neurology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.; Department of Neurology, St Josefs Krankenhaus Bochum, Ruhr University Bochum, Bochum, Germany., Urbanek C; Department of Neurology, Ludwigshafen Hospital, Ludwigshafen, Germany., Sühs KW; Department of Neurology, University Hospital, MHH, Hannover, Germany., Tauber SC; Department of Neurology, University Hospital RWTH Aachen, Aachen, Germany., Mues S; Department of Neurology, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, Bochum, Germany.; Department of Neurology, University Hospital Dresden, Dresden, Germany., Körtvélyessy P; Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.; Department of Neurology, University Hospital Magdeburg, Magdeburg, Germany., Markewitz R; Neuroimmunology, Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/Lübeck, Germany., Paliantonis A; Department of Neurology, Alfred-Krupp Hospital, Essen, Germany., Elger CE; Department of Epileptology, University of Bonn, Bonn, Germany., Surges R; Department of Epileptology, University of Bonn, Bonn, Germany., Sommer C; Department of Neurology, University of Würzburg, Würzburg, Germany., Kümpfel T; Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany.; Biomedical Center (BMC), Medical Faculty, Ludwig-Maximilians-Universität Munich, Martinsried, Germany., Gross CC; Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany., Lerche H; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany., Wellmer J; Department of Neurology, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, Bochum, Germany., Quesada CM; Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Then Bergh F; Department of Neurology, University of Leipzig, Leipzig, Germany., Wandinger KP; Neuroimmunology, Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/Lübeck, Germany., Becker AJ; Section of Translational Epileptology, Institute of Neuropathology, University of Bonn, Bonn, Germany., Kunz WS; Department of Epileptology, University of Bonn, Bonn, Germany., Meyer Zu Hörste G; Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany., Malter MP; Department of Neurology, University of Cologne, Cologne, Germany., Rosenow F; Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, University Hospital Frankfurt, and LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany., Wiendl H; Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany., Kuhlenbäumer G; Department of Neurology, University of Kiel, Kiel, Germany., Leypoldt F; Department of Neurology, University of Kiel, Kiel, Germany.; Neuroimmunology, Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/Lübeck, Germany., Lieb W; Institute of Epidemiology, Christian-Albrechts-University of Kiel, Kiel, Germany., Franke A; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany., Meuth SG; Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.; Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany., Stoll M; Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany., Melzer N; Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.; Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany. |
| مؤلفون مشاركون: | German Network for Research on Autoimmune Encephalitis (GENERATE) |
| المصدر: | Brain : a journal of neurology [Brain] 2023 Mar 01; Vol. 146 (3), pp. 977-990. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: England NLM ID: 0372537 Publication Model: Print Cited Medium: Internet ISSN: 1460-2156 (Electronic) Linking ISSN: 00068950 NLM ISO Abbreviation: Brain Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Oxford : Oxford University Press Original Publication: London. |
| مواضيع طبية MeSH: | Genome-Wide Association Study* , Genetic Predisposition to Disease*/genetics, Humans ; Proteome/genetics ; Histocompatibility Antigens Class II ; HLA Antigens ; Haplotypes ; Alleles ; Autoantibodies ; HLA-DRB1 Chains/genetics |
| مستخلص: | Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P < 5 × 10-8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10-16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187-0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (>90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10-4, OR = 2.5, 95%CI = 1.499-4.157) and DRB1*04:01 allele (P = 8.3 × 10-5, OR = 2.4, 95%CI = 1.548-3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles. (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.) |
| References: | J Endocrinol Invest. 2018 Dec;41(12):1409-1416. (PMID: 29931474) Nat Genet. 2016 Oct;48(10):1284-1287. (PMID: 27571263) Nat Genet. 2015 Mar;47(3):291-5. (PMID: 25642630) Gigascience. 2015 Feb 25;4:7. (PMID: 25722852) Am J Hum Genet. 2011 Jan 7;88(1):76-82. (PMID: 21167468) Genome Res. 2003 Nov;13(11):2498-504. (PMID: 14597658) Nat Commun. 2017 Nov 28;8(1):1826. (PMID: 29184056) Nucleic Acids Res. 2019 Jan 8;47(D1):D1005-D1012. (PMID: 30445434) Genet Epidemiol. 2011 Dec;35(8):831-44. (PMID: 22125222) J Neurol. 2006 May;253(5):636-9. (PMID: 16502215) N Engl J Med. 2010 May 6;362(18):1686-97. (PMID: 20410501) Ann Clin Transl Neurol. 2021 Dec;8(12):2289-2301. (PMID: 34841709) Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2012 Jun;55(6-7):831-5. (PMID: 22736164) Hum Immunol. 1992 Jun;34(2):135-41. (PMID: 1429034) Nat Genet. 2015 Oct;47(10):1114-20. (PMID: 26323059) J Clin Endocrinol Metab. 2014 Jan;99(1):E177-82. (PMID: 24187405) Neurol Neuroimmunol Neuroinflamm. 2017 Dec 05;5(1):e416. (PMID: 29379821) F1000Res. 2014 Jul 01;3:146. (PMID: 25309732) Neurol Neuroimmunol Neuroinflamm. 2020 Mar 2;7(3):. (PMID: 32123047) Diabetes. 2007 Sep;56(9):2405-9. (PMID: 17513705) J Neurol. 2020 Jul;267(7):1906-1911. (PMID: 32152690) Nucleic Acids Res. 2020 Jul 2;48(W1):W185-W192. (PMID: 32496546) Brain. 2008 Oct;131(Pt 10):2553-63. (PMID: 18687732) J Neurol Sci. 2001 Mar 1;184(2):101-22. (PMID: 11239944) Hum Mol Genet. 2021 Apr 27;30(5):356-369. (PMID: 33555323) Nat Genet. 2012 May 06;44(6):676-80. (PMID: 22561518) J Neurol Sci. 2020 Jun 15;413:116860. (PMID: 32388243) J Endocrinol Invest. 2021 May;44(5):883-890. (PMID: 33332019) Diabetes. 1997 Jan;46(1):143-9. (PMID: 8971095) Lancet Neurol. 2016 Apr;15(4):391-404. (PMID: 26906964) J Hum Genet. 2015 Nov;60(11):657-64. (PMID: 26223182) Nat Methods. 2013 Jan;10(1):5-6. (PMID: 23269371) Pharmacogenomics J. 2014 Apr;14(2):192-200. (PMID: 23712092) Nat Genet. 2016 Nov;48(11):1418-1424. (PMID: 27723757) Diabetes. 2008 Apr;57(4):1084-92. (PMID: 18252895) Ann Neurol. 2018 Jan;83(1):166-177. (PMID: 29293273) |
| فهرسة مساهمة: | Investigator: M Adelmann; L Appeltshauser; I Ayzenberg; C Baade-Büttner; A van Baalen; S Baatz; B Balint; S Bauer; A Baumgartner; S Benesch; R Berger; S Berning; S Bernsen; C Bien; C Bien; A Binder; S Bittner; D Bittner; F Blaes; A Blaschek; J Dargvainiene; J Decker; A Dik; K Doppler; M Dreesmann; F Ebinger; L Edelhoff; S Ehrlich; K Eisenhut; D Endres; M Entscheva; J Hartmut Faiss; K Kristin Falk; W Fazeli; A Finke; C Finke; D Fitzner; M Flotats-Bastardas; M Fousse; P Friedemann; M Friese; M Gallus; M Gebhard; C Geis; C Goedel; A Gorsler; A Grau; O Grauer; C Groß; H Gül; C Ha-Yeun; A Haghikia; R Handreka; N Hansen; M Häusler; J Havla; W Heide; V Held; K Hellwig; P Hillebrand; F Hoffmann; A Hoffmann; U Hofstadt-van Oy; P Huppke; F Seval Ismail; M Jansen; A Juranek; M Karenfort; M Kaufmann; C Kellinghaus; C Kerin; S Knake; P Körtvélyessy; S Kovac; A Kraft; M Krämer; C Krogias; T Kümpfel; C Lehrich; J Lewerenz; F Leypoldt; A Linsa; J Lünemann; M Malter; M Meister; N Melzer; K Stefanie Melzer; T Menge; S Meuth; G Meyer Zu Hörste; ML Mono; S Mues; M Nagel; C Nelke; T Neumann-Haefelin; J Obrocki; L Penner; L Kristina Pfeffer; T Pfefferkorn; A Philipsen; J Piepgras; F von Poderwils; J Priller; AK Pröbstel; H Prüß; J Maria Helena Rau; S Jania Räuber; G Reimann; R Reinecke; M Ringelstein; H Rohner; F Rosenow; K Rostasy; T Rüber; S Rüegg; J Schaumberg; R Schilling; M Schimmel; J Schmidt; II Schmütz; S Schreiber; G Schreyer; I Schröder; C Schröter; S Schuster; G Seidel; M Senel; K Siebenbrodt; C Sommer; O Stammel; M Stangel; H Stolze; M Stoppe; K Storm van S Gravesande; C Strippel; D Sturm; KW Sühs; S Syrbe; S Tauber; M Teußer; F Thaler; F Then Bergh; C Trebst; G Trendelenburg; R Trollmann; H Tumani; M Türedi; C Urbanek; N Vogel; M von Mering; J Wagner; KP Wandinger; R Weissert; J Wickel; H Wiendl; B Wildemann; K Witt; B Wunderlich; L Zieger Keywords: autoimmune encephalitis; genome-wide association study; glutamic acid decarboxylase; limbic encephalitis; stiff-person syndrome |
| المشرفين على المادة: | 0 (Proteome) 0 (Histocompatibility Antigens Class II) 0 (HLA Antigens) 0 (Autoantibodies) 0 (HLA-DRB1 Chains) |
| تواريخ الأحداث: | Date Created: 20220329 Date Completed: 20230303 Latest Revision: 20230328 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC9976967 |
| DOI: | 10.1093/brain/awac119 |
| PMID: | 35348614 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1460-2156 |
|---|---|
| DOI: | 10.1093/brain/awac119 |