Evidence map›Paper›PMID 35348614›Full record

ArticleBrain : a journal of neurology2023

A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies.

Christine Strippel, Marisol Herrera-Rivero, Mareike Wendorff, Anja K Tietz, Frauke Degenhardt, Anika Witten, Christina Schroeter, Christopher Nelke, Kristin S Golombeck, Marie Madlener and 60 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Brain : a journal of neurology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
19citing papers in PubMed, 1 pooled it
4.1field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

19 citing papers in PubMed, 1 synthesis or guideline pooled it, 36 citations in OpenAlex.

  1. Pooled it
  2. Review
  3. Article
  4. Article
  5. Immune cell profiling reveals expanded stem cell-like memory T cells in anti-GAD65-associated neurological syndromes.Proceedings of the National Academy of Sciences of the United States of America · 2026
    Article
  6. Article
  7. Article
  8. Autoimmune polyglandular syndrome and GAD65 related-temporal lobe epilepsy.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025
    Article
  9. Autoimmune encephalitis-associated epilepsy.Nature reviews. Neurology · 2025
    Review
  10. The limbic and extra-limbic encephalitis associated with glutamic acid decarboxylase (GAD)-65 antibodies: an observational study.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025
    Observational
  11. Article
  12. Review
  13. Article
  14. Recent advances in autoimmune encephalitis.Arquivos de neuro-psiquiatria · 2024
    Review
  15. Review
  16. Article
  17. Review
  18. Review
  19. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

70 authors at 20 institutions in 2 countries.

Christine StrippelDepartment of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.
Marisol Herrera-RiveroDepartment of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany.
Mareike WendorffInstitute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
Anja K TietzDepartment of Neurology, University of Kiel, Kiel, Germany.
Frauke DegenhardtInstitute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.ORCID 0000-0001-7516-3179
Anika WittenDepartment of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany.
Christina SchroeterDepartment of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.
Christopher NelkeDepartment of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.
Kristin S GolombeckDepartment of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.
Marie MadlenerDepartment of Neurology, University of Cologne, Cologne, Germany.
Theodor RüberDepartment of Epileptology, University of Bonn, Bonn, Germany.ORCID 0000-0002-6180-7671
Leon ErnstDepartment of Epileptology, University of Bonn, Bonn, Germany.
Attila RaczDepartment of Epileptology, University of Bonn, Bonn, Germany.
Tobias BaumgartnerDepartment of Epileptology, University of Bonn, Bonn, Germany.
Guido WidmanDepartment of Epileptology, University of Bonn, Bonn, Germany.
Kathrin DopplerDepartment of Neurology, University of Würzburg, Würzburg, Germany.
Franziska ThalerInstitute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany.ORCID 0000-0002-2138-2293
Kai SiebenbrodtEpilepsy 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.
Andre DikDepartment of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.
Constanze KerinDepartment of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.
Saskia RäuberDepartment of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.ORCID 0000-0001-8901-5572
Marco GallusDepartment of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.
Stjepana KovacDepartment of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.
Oliver M GrauerDepartment of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.
Alexander GrimmDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Harald PrüssDepartment of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Jonathan WickelSection of Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena, Germany.
Christian GeisSection of Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena, Germany.
Jan LewerenzDepartment of Neurology, Ulm University, Ulm, Germany.
Norbert GoebelsDepartment of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
Marius RingelsteinDepartment of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
Til MengeDepartment of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
Björn TackenbergDepartment of Neurology, University of Marburg/Gießen, Marburg, Germany.
Christoph KellinghausDepartment of Neurology, Klinikum Osnabrück, Osnabrück, Germany.
Christian G BienDepartment of Epileptology (Krankenhaus Mara), Bielefeld University, Medical School, Campus Bielefeld-Bethel, Bielefeld, Germany.ORCID 0000-0003-2225-8654
Andrea KraftMartha Maria Hospital Halle, Halle, Germany.
Uwe ZettlDepartment of Neurology, University of Rostock, Rostock, Germany.
Fatme Seval IsmailDepartment of Neurology, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, Bochum, Germany.
Ilya AyzenbergDepartment of Neurology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.
Christian UrbanekDepartment of Neurology, Ludwigshafen Hospital, Ludwigshafen, Germany.
Kurt-Wolfram SühsDepartment of Neurology, University Hospital, MHH, Hannover, Germany.
Simone C TauberDepartment of Neurology, University Hospital RWTH Aachen, Aachen, Germany.
Sigrid MuesDepartment of Neurology, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, Bochum, Germany.
Peter KörtvélyessyDepartment of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Robert MarkewitzNeuroimmunology, Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/Lübeck, Germany.
Asterios PaliantonisDepartment of Neurology, Alfred-Krupp Hospital, Essen, Germany.
Christian E ElgerDepartment of Epileptology, University of Bonn, Bonn, Germany.
Rainer SurgesDepartment of Epileptology, University of Bonn, Bonn, Germany.
Claudia SommerDepartment of Neurology, University of Würzburg, Würzburg, Germany.
Tania KümpfelInstitute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany.ORCID 0000-0001-7509-5268
Catharina C GrossDepartment of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.
Holger LercheDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Jörg WellmerDepartment of Neurology, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, Bochum, Germany.
Carlos M QuesadaDepartment of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Florian Then BerghDepartment of Neurology, University of Leipzig, Leipzig, Germany.
Klaus-Peter WandingerNeuroimmunology, Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/Lübeck, Germany.
Albert J BeckerSection of Translational Epileptology, Institute of Neuropathology, University of Bonn, Bonn, Germany.
Wolfram S KunzDepartment of Epileptology, University of Bonn, Bonn, Germany.
Gerd Meyer Zu HörsteDepartment of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.
Michael P MalterDepartment of Neurology, University of Cologne, Cologne, Germany.
Felix RosenowEpilepsy 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.
Heinz WiendlDepartment of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.
Gregor KuhlenbäumerDepartment of Neurology, University of Kiel, Kiel, Germany.
Frank LeypoldtDepartment of Neurology, University of Kiel, Kiel, Germany.
Wolfgang LiebInstitute of Epidemiology, Christian-Albrechts-University of Kiel, Kiel, Germany.
Andre FrankeInstitute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
Sven G MeuthDepartment of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.
Monika StollDepartment of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany.
Nico MelzerDepartment of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.ORCID 0000-0002-2420-701X
German Network for Research on Autoimmune Encephalitis (GENERATE)
University of Münster · DEUniversity of Bonn · DEGoethe University Frankfurt · DEChristian-Albrechts-Universität zu Kiel · DEUniversitätsklinikum Knappschaftskrankenhaus Bochum · DEUniversity Hospital Schleswig-Holstein · DEUniversity of Cologne · DEBielefeld University · DEHeinrich Heine University Düsseldorf · DEJena University Hospital · DEUniversität Ulm · DELudwig-Maximilians-Universität München · DESechenov University · RUKlinikum Ludwigshafen · DERWTH Aachen University · DEUniversity of Würzburg · DEHertie Institute for Clinical Brain Research · DEKlinikum Osnabrück · DEMartha-Maria Hospital · DEUniversitätsklinikum Gießen und Marburg · DE

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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.

Indexed as

Genetic Predisposition to DiseaseGenome-Wide Association StudyAllelesAutoantibodiesHaplotypesHistocompatibility Antigens Class IIHLA AntigensHLA-DRB1 ChainsHumansProteomeAutoantibodiesHistocompatibility Antigens Class IIHLA AntigensHLA-DRB1 ChainsProteomeautoimmune encephalitisgenome-wide association studyglutamic acid decarboxylaselimbic encephalitisstiff-person syndrome

Identifiers

PMID35348614
PMCPMC9976967
OpenAlexW4220661916

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.