0000000001323393
AUTHOR
Christiane Graetz
showing 16 related works from this author
Power estimation for non-standardized multisite studies
2016
A concern for researchers planning multisite studies is that scanner and T1-weighted sequence-related biases on regional volumes could overshadow true effects, especially for studies with a heterogeneous set of scanners and sequences. Current approaches attempt to harmonize data by standardizing hardware, pulse sequences, and protocols, or by calibrating across sites using phantom-based corrections to ensure the same raw image intensities. We propose to avoid harmonization and phantom-based correction entirely. We hypothesized that the bias of estimated regional volumes is scaled between sites due to the contrast and gradient distortion differences between scanners and sequences. Given this…
Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation
2016
Genome-wide study in Germans identifies four novel multiple sclerosis risk genes and confirms already known gene loci.
Genome-wide significant association of ANKRD55 rs6859219 and multiple sclerosis risk.
2013
Multiple sclerosis (MS) is a genetically complex disease that shares a substantial proportion of risk loci with other autoimmune diseases.1 Along these lines, ANKRD55 , originally implicated in rheumatoid arthritis, was recently reported as a potential novel MS risk gene (rs6859219, p=1.9×10−7).2 Here, we comprehensively validated this effect in independent datasets comprising 8846 newly genotyped subjects from Germany and France as well as 5003 subjects from two genome-wide association studies (GWAS). Upon meta-analysis of all available data (19 686 subjects), ANKRD55 rs6859219 now shows compelling evidence for association with MS at genome-wide significance (OR=1.19, p=3.1×10−11). Our stu…
New candidates for CD4 T cell pathogenicity in experimental neuroinflammation and multiple sclerosis
2015
Multiple sclerosis is a chronic autoimmune demyelinating disease of the central nervous system, which is thought to be triggered by environmental factors in genetically susceptible individuals leading to activation of autoreactive T lymphocytes. Large multi-centre genome-wide association studies have identified multiple genetic risk loci in multiple sclerosis. In this study, we investigated T cell transcriptomic changes in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. We correlated these findings with the multiple sclerosis risk genes postulated by the most recent Immunochip analysis and found that multiple sclerosis susceptibility genes were significant…
Successful Replication of GWAS Hits for Multiple Sclerosis in 10,000 Germans Using the Exome Array
2015
Genome-wide association studies (GWAS) successfully identified various chromosomal regions to be associated with multiple sclerosis (MS). The primary aim of this study was to replicate reported associations from GWAS using an exome array in a large German study. German MS cases (n = 4,476) and German controls (n = 5,714) were genotyped using the Illumina HumanExome v1-Chip. Genotype calling was performed with the Illumina Genome Studio(TM) Genotyping Module, followed by zCall. Single-nucleotide polymorphisms (SNPs) in seven regions outside the human leukocyte antigen (HLA) region showed genome-wide significant associations with MS (P values < 5 × 10(-8) ). These associations have been repor…
Genome-wide significant association with seven novel multiple sclerosis risk loci
2015
Objective A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. Methods The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis. Results…
Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis
2019
Background: The course of multiple sclerosis (MS) shows substantial inter-individual variability. The underlying determinants of disease severity likely involve genetic and environmental factors. Objective: The aim of this study was to assess the impact of APOE and HLA polymorphisms as well as smoking and body mass index (BMI) in the very early MS course. Methods: Untreated patients ( n = 263) with a recent diagnosis of relapsing-remitting (RR) MS or clinically isolated syndrome underwent standardized magnetic resonance imaging (MRI). Genotyping was performed for single-nucleotide polymorphisms (SNPs) rs3135388 tagging the HLA-DRB1*15:01 haplotype and rs7412 (Ɛ2) and rs429358 (Ɛ4) in APOE. …
Low frequency and rare coding variation contributes to multiple sclerosis risk
2018
AbstractMultiple sclerosis is a common, complex neurological disease, where almost 20% of risk heritability can be attributed to common genetic variants, including >230 identified by genome-wide association studies (Patsopoulos et al., 2017). Multiple strands of evidence suggest that the majority of the remaining heritability is also due to the additive effects of individual variants, rather than epistatic interactions between these variants, or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that as much as 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independe…
The Multiple Sclerosis Genomic Map: Role of peripheral immune cells and resident microglia in susceptibility
2017
Abstract:We assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the extended MHC. We used an ensemble of methods to prioritize up to 551 potentially associated MS susceptibility genes, that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we do find enrichment for MS genes in these brain -…
Role of IL-17-producing lymphocytes in severity of multiple sclerosis upon natalizumab treatment.
2016
Objective: Natalizumab is known to prevent T-helper cells entering the central nervous system (CNS). We hypothesize that more pathogenic T-helper cells are present outside the CNS and a possible relationship to disease severity. Methods: Characterization and enrichment of human CD4+IL-17+ cells were performed ex vivo using peripheral blood mononuclear cells from natalizumab-treated relapsing-remitting multiple sclerosis (RRMS) patients ( n = 33), untreated RRMS patients ( n = 13), and healthy controls ( n = 33). Magnetic resonance imaging (MRI) scans were performed routinely for patients. Results: Lymphocytes were elevated in peripheral blood of natalizumab-treated patients compared to untr…
Class II HLA interactions modulate genetic risk for multiple sclerosis
2015
Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and cla…
Is APOE ε4 associated with cognitive performance in early MS?
2020
ObjectiveTo assess the impact of APOE polymorphisms on cognitive performance in patients newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS).MethodsThis multicenter cohort study included 552 untreated patients recently diagnosed with CIS or RRMS according to the 2005 revised McDonald criteria. The single nucleotide polymorphisms rs429358 (ε4) and rs7412 (ε2) of the APOE haplotype were assessed by allelic discrimination assays. Cognitive performance was evaluated using the 3-second paced auditory serial addition test and the Multiple Sclerosis Inventory Cognition (MUSIC). Sum scores were calculated to approximate the overall cognitive performance and memo…
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
2013
International audience; Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variant…
Preservation of neuronal function as measured by clinical and MRI endpoints in relapsing-remitting multiple sclerosis: how effective are current trea…
2018
Approved medications for relapsing-remitting multiple sclerosis have shown to be effective in terms of their anti-inflammatory potential. However, it is also crucial to evaluate what long-term effects a patient can expect from current MS drugs in terms of preventing neurodegeneration. Here we aim to provide an overview of the current treatment strategies in MS with a specific focus on potential neuroprotective effects. Areas covered: Randomized, double-blind and placebo or referral-drug controlled phase 2a/b and phase 3 trials were examined; non-blinded phase 4 studies (extension studies) were included to provide long-term data, if not otherwise available. Endpoints considered were expanded…
MSJ763541_supplementary_material – Supplemental material for Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atroph…
2018
Supplemental material, MSJ763541_supplementary_material for Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis by Christiane Graetz, Adriane Gröge, Felix Luessi, Anke Salmen, Daniela Zöller, Janine Schultz, Nelly Siller, Vinzenz Fleischer, Barbara Bellenberg, Achim Berthele, Viola Biberacher, Joachim Havla, Michael Hecker, Reinhard Hohlfeld, Carmen Infante-Duarte, Jan S Kirschke, Tania Kümpfel, Ralf Linker, Friedemann Paul, Steffen Pfeuffer, Philipp Sämann, Gerrit Toenges, Frank Weber, Uwe K Zettl, Antje Jahn-Eimermacher, Gisela Antony, Sergiu Groppa, Heinz Wiendl, Bernhard Hemmer, Mark Mühlau, Carsten Lukas, Ralf Gold, Chri…
Preservation of neuronal function as measured by clinical and MRI endpoints in relapsing-remitting multiple sclerosis: how effective are current trea…
2018
Introduction: Approved medications for relapsing-remitting multiple sclerosis have shown to be effective in terms of their anti-inflammatory potential. However, it is also crucial to evaluate what long-term effects a patient can expect from current MS drugs in terms of preventing neurodegeneration. Here we aim to provide an overview of the current treatment strategies in MS with a specific focus on potential neuroprotective effects. Areas covered: Randomized, double-blind and placebo or referral-drug controlled phase 2a/b and phase 3 trials were examined; non-blinded phase 4 studies (extension studies) were included to provide long-term data, if not otherwise available. Endpoints considered…