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


Christine Strippel, Marisol Herrera-Rivero, Mareike Wendorff, Anja Tietz, Frauke Degenhardt, Anika Witten, Christina Schroeter, Christopher Nelke, Kristin Golombeck, Marie Madlener, Theodor Rüber, Leon Ernst, Attila Racz, Tobias Baumgartner, Guido Widman, Kathrin Doppler, Franziska Thaler, Kai Siebenbrodt, Andre Dik, Constanze Kerin, Saskia Räuber, Marco Gallus, Stjepana Kovac, Oliver Grauer, Alexander Grimm, Harald Prüss, Jonathan Wickel, Christian Geis, Jan Lewerenz, Norbert Goebels, Marius Ringelstein, Til Menge, Björn Tackenberg, Christoph Kellinghaus, Christian Bien, Andrea Kraft, Uwe Zettl, Fatme Ismail, Ilya Ayzenberg, Christian Urbanek, Kurt-Wolfram Sühs, Simone Tauber, Sigrid Mues, Peter Körtvélyessy, Robert Markewitz, Asterios Paliantonis, Christian Elger, Rainer Surges, Claudia Sommer, Tania Kümpfel, Catharina Gross, Holger Lerche, Jörg Wellmer, Carlos Quesada, Florian Then Bergh, Klaus-Peter Wandinger, Albert Becker, Wolfram Kunz, Gerd Meyer Zu Hörste, Michael Malter, Felix Rosenow, Heinz Wiendl, Gregor Kuhlenbäumer, Frank Leypoldt, Wolfgang Lieb, Andre Franke, Sven Meuth, Monika Stoll, Nico Melzer




Brain : a journal of neurology




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 1,214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1,047 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%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 eQTL 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.