{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T14:23:58Z","timestamp":1790346238049,"version":"4.1.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,3,28]],"date-time":"2022-03-28T00:00:00Z","timestamp":1648425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"crossref","award":["ERARE18-202"],"award-info":[{"award-number":["ERARE18-202"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"name":"German Federal Ministry of Education and Research"},{"name":"Innovative Medizinische Forschung M\u00fcnster","award":["ST 212006"],"award-info":[{"award-number":["ST 212006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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.<\/jats:p><jats:p>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.<\/jats:p><jats:p>Our GWAS identified 16 genome-wide significant (P &amp;lt; 5 \u00d7 10\u22128) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 \u00d7 10\u221216, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187\u20130.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (&amp;gt;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 \u00d7 10\u22124, OR = 2.5, 95%CI = 1.499\u20134.157) and DRB1*04:01 allele (P = 8.3 \u00d7 10\u22125, OR = 2.4, 95%CI = 1.548\u20133.682) 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.<\/jats:p><jats:p>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.<\/jats:p>","DOI":"10.1093\/brain\/awac119","type":"journal-article","created":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T22:34:13Z","timestamp":1648247653000},"page":"977-990","source":"Crossref","is-referenced-by-count":41,"title":["A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies"],"prefix":"10.1093","volume":"146","author":[{"given":"Christine","family":"Strippel","sequence":"first","affiliation":[{"name":"Department of Neurology with Institute of Translational Neurology, University of M\u00fcnster , M\u00fcnster , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisol","family":"Herrera-Rivero","sequence":"additional","affiliation":[{"name":"Department of Genetic Epidemiology, Institute of Human Genetics, University of M\u00fcnster , M\u00fcnster , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mareike","family":"Wendorff","sequence":"additional","affiliation":[{"name":"Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel , Kiel , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja K","family":"Tietz","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Kiel , Kiel , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7516-3179","authenticated-orcid":false,"given":"Frauke","family":"Degenhardt","sequence":"additional","affiliation":[{"name":"Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel , Kiel , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anika","family":"Witten","sequence":"additional","affiliation":[{"name":"Department of Genetic Epidemiology, Institute of Human Genetics, University of M\u00fcnster , M\u00fcnster , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Schroeter","sequence":"additional","affiliation":[{"name":"Department of Neurology with Institute of Translational Neurology, University of M\u00fcnster , M\u00fcnster , Germany"},{"name":"Department of Neurology, Medical Faculty, Heinrich-Heine University D\u00fcsseldorf , D\u00fcsseldorf , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Nelke","sequence":"additional","affiliation":[{"name":"Department of Neurology with Institute of Translational Neurology, University of M\u00fcnster , M\u00fcnster , Germany"},{"name":"Department of Neurology, Medical Faculty, Heinrich-Heine University D\u00fcsseldorf , D\u00fcsseldorf , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin S","family":"Golombeck","sequence":"additional","affiliation":[{"name":"Department of Neurology with Institute of Translational Neurology, University of M\u00fcnster , M\u00fcnster , Germany"},{"name":"Department of Neurology, Medical Faculty, Heinrich-Heine University D\u00fcsseldorf , D\u00fcsseldorf , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Madlener","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Cologne , Cologne , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6180-7671","authenticated-orcid":false,"given":"Theodor","family":"R\u00fcber","sequence":"additional","affiliation":[{"name":"Department of Epileptology, University of Bonn , Bonn , Germany"},{"name":"Epilepsy 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