Strippel, Christine, Herrera-Rivero, Marisol ORCID: 0000-0001-7064-9487, Wendorff, Mareike, Tietz, Anja K., Degenhardt, Frauke, Witten, Anika, Schroeter, Christina, Nelke, Christopher, Golombeck, Kristin S., Madlener, Marie, Rueber, Theodor, Ernst, Leon, Racz, Attila, Baumgartner, Tobias, Widman, Guido, Doppler, Kathrin ORCID: 0000-0003-2883-0009, Thaler, Franziska, Siebenbrodt, Kai, Dik, Andre, Kerin, Constanze, Rauber, Saskia, Gallus, Marco, Kovac, Stjepana, Grauer, Oliver M., Grimm, Alexander, Pruess, Harald, Wickel, Jonathan, Geis, Christian, Lewerenz, Jan, Goebels, Norbert, Ringelstein, Marius, Menge, Til, Tackenberg, Bjoern, Kellinghaus, Christoph, Bien, Christian G., Kraft, Andrea, Zettl, Uwe, Ismail, Fatme Seval, Ayzenberg, Ilya, Urbanek, Christian, Suhs, Kurt-Wolfram, Tauber, Simone C., Mues, Sigrid, Kortvelyessy, Peter, Markewitz, Robert, Paliantonis, Asterios, Elger, Christian E., Surges, Rainer, Sommer, Claudia, Kumpfel, Tania, Gross, Catharina C., Lerche, Holger, Wellmer, Jorg, Quesada, Carlos M., Bergh, Florian Then, Wandinger, Klaus-Peter, Becker, Albert J., Kunz, Wolfram S., zu Hoerste, Gerd Meyer, Malter, Michael P., Rosenow, Felix, Wiendl, Heinz, Kuhlenbaumer, Gregor, Leypoldt, Frank, Lieb, Wolfgang, Franke, Andre, Meuth, Sven G., Stoll, Monika and Melzer, Nico ORCID: 0000-0002-2420-701X . A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies. Brain. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

Full text not available from this repository.

Abstract

Autoimmune neurological syndromes (AINS) with autoantibodies against the 65kDa 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 x 10(-8)) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 x 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 x 10(-4), OR = 2.5, 95%CI = 1.499-4.157) and DRB1*04:01 allele (P = 8.3 x 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Strippel, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herrera-Rivero, MarisolUNSPECIFIEDorcid.org/0000-0001-7064-9487UNSPECIFIED
Wendorff, MareikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tietz, Anja K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Degenhardt, FraukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witten, AnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroeter, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nelke, ChristopherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Golombeck, Kristin S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Madlener, MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rueber, TheodorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ernst, LeonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Racz, AttilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumgartner, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Widman, GuidoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doppler, KathrinUNSPECIFIEDorcid.org/0000-0003-2883-0009UNSPECIFIED
Thaler, FranziskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siebenbrodt, KaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dik, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kerin, ConstanzeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauber, SaskiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gallus, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kovac, StjepanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grauer, Oliver M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grimm, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pruess, HaraldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wickel, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geis, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lewerenz, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goebels, NorbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ringelstein, MariusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Menge, TilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tackenberg, BjoernUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kellinghaus, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bien, Christian G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kraft, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zettl, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ismail, Fatme SevalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ayzenberg, IlyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Urbanek, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suhs, Kurt-WolframUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tauber, Simone C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mues, SigridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kortvelyessy, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Markewitz, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paliantonis, AsteriosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Elger, Christian E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Surges, RainerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sommer, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kumpfel, TaniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gross, Catharina C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wellmer, JorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Quesada, Carlos M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bergh, Florian ThenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wandinger, Klaus-PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, Albert J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kunz, Wolfram S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
zu Hoerste, Gerd MeyerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Malter, Michael P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenow, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiendl, HeinzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuhlenbaumer, GregorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leypoldt, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lieb, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Franke, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meuth, Sven G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoll, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Melzer, NicoUNSPECIFIEDorcid.org/0000-0002-2420-701XUNSPECIFIED
URN: urn:nbn:de:hbz:38-697868
DOI: 10.1093/brain/awac119
Journal or Publication Title: Brain
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2156
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SUSCEPTIBILITY LOCI; DISEASE; RISK; EPIDEMIOLOGY; GENETICS; DQMultiple languages
Clinical Neurology; NeurosciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69786

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item