Common Variants Near ZIC1 and ZIC4 in Autopsy‐Confirmed Multiple System Atrophy

Background: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Objective: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. Methods: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). Results: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Interpretation: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Keywords: ZIC1; ZIC4; autopsy-confirmed; genome-wide association study; multiple system atroph

Genome-wide Association Study Identifies 2 New Loci Associated With Anti-NMDAR Encephalitis

Background and Objectives To investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-NMDA receptor (anti-NMDAR) encephalitis. Methods We performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls, followed by a colocalization analysis to identify putatively causal genes. Results We identified 2 independent risk loci harboring genome-wide significant variants (p = 2.2), 1 on chromosome 15, harboring only the LRRK1 gene, and 1 on chromosome 11 centered on the ACP2 and NR1H3 genes in a larger region of high linkage disequilibrium. Colocalization signals with expression quantitative trait loci for different brain regions and immune cell types suggested ACP2, NR1H3, MADD, DDB2, and C11orf49 as putatively causal genes. The best candidate genes in each region are LRRK1, encoding leucine-rich repeat kinase 1, a protein involved in B-cell development, and NR1H3 liver X receptor alpha, a transcription factor whose activation inhibits inflammatory processes. Discussion This study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the human leukocyte antigen (HLA) region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism

Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy

Background Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Objective Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. Methods We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). Results The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 x 10(-6), all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Interpretation Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Societ

Common variants near ZIC1 and ZIC4 in autopsy-confirmed multiple system atrophy.

BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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

Strippel C, Herrera-Rivero M, Wendorff M, et al. A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies. Brain: A Journal of Neurology . 2022: awac119.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 (p90%) 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. © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain

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

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 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