Refining genetic associations in multiple sclerosis.
Ontology highlight
ABSTRACT:
SUBMITTER: International Multiple Sclerosis Genetics Consortium (IMSGC)
PROVIDER: S-EPMC2696028 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Multiple sclerosis (MS) is characterized by temporal and spatial dissemination of demyelinating lesions in the central nervous system. Associated neurodegenerative changes contributing to disability have been recognized even at early disease stages. Recent studies show the importance of gray matter damage for the accrual of clinical disability rather than white matter where demyelination is easily visualized by magnetic resonance imaging (MRI). The susceptibility to MS is influenced by genetic risk, but genetic factors associated with the disability are not known. We used MRI data to determine cortical thickness in 557 MS cases and 75 controls and in another cohort of 219 cases. We identified nine areas showing different thickness between cases and controls (regions of interest, ROI) (eight of them were negatively correlated with Kurtzke's expanded disability status scale, EDSS) and conducted genome-wide association studies (GWAS) in 464 and 211 cases available from the two data sets. No marker exceeded genome-wide significance in the discovery cohort. We next combined nominal statistical evidence of association with physical evidence of interaction from a curated human protein interaction network, and searched for subnetworks enriched with nominally associated genes and for commonalities between the two data sets. This network-based pathway analysis of GWAS detected gene sets involved in glutamate signaling, neural development and an adjustment of intracellular calcium concentration. We report here for the first time gene sets associated with cortical thinning of MS. These genes are potentially correlated with disability of MS.
| S-EPMC4857705 | biostudies-literature
Project description:A Case-Controlled Study for genotype-Phenotype Associations in Multiple Sclerosis (Genetic Multiple Sclerosis - GeneMSA)
| PRJNA75473 | ENA
Project description:<p>This is a multi-centre, case-controlled study to develop a dataset containing 1000 MS cases and 1000 matched controls and to associate DNA sequence (allelic) variations with MS phenotypes.</p> <p>Study subjects were enrolled through a prospective effort initiated in 2003. Three MS clinical centres were involved in subject recruitment and biological specimen collection using identical inclusion/exclusion criteria, two in Europe (Vrije Universiteit Medical Center, Amsterdam; and University Hospital Basel) and one in the US (University of California San Francisco). This study recruited subjects of northern-European ancestry with a diagnosis of MS (<a href="http://www.ncbi.nlm.nih.gov/pubmed/11456302" target="_blank">McDonald et al., 2001</a>), with dissemination in time and space. Patients with Clinically Isolated Syndromes (CIS) were also included if they fulfilled 3 of the 4 Barkhof criteria for dissemination in space as per application of the McDonald criteria (<a href="http://www.ncbi.nlm.nih.gov/pubmed/11456302" target="_blank">McDonald et al., 2001</a>). While recruitment predominantly included subjects with a relapsing onset of MS, individuals with all clinical subtypes of the disease participated, including clinically isolated syndrome (CIS), relapsing remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS (PRMS).</p> <p>The control group consisted of unrelated individuals, primarily spouses/partners, friends, and other volunteers. Control subjects were of northern-European ancestry and matched as a group, proportionally with cases according to age (±5 years) and gender. A familial history or current diagnosis of MS as well as a relation to another case or control subject were considered exclusionary for this group.</p> <p>Protocols were approved by the Committees on Human Research at all Institutions and informed consent was obtained from all participants prior to participation in the study.</p> <p><b>Primary Study Objective:</b><br/>To identify DNA sequence variations (genotype) and flanking sequences that are associated with clinical factors (phenotype) which differ between study subjects with and without MS.</p> <p><b>Secondary Study Objectives:</b> <ol> <li>To develop a clinical dataset including quantitative measures of 1000 well-characterized cases with MS, and 1000 ethnically matched controls.</li> <li>To identify other genotype-phenotype associations in MS study subjects such as magnetic resonance imaging (MRI) measures of disease burden and/or severity.</li> <li>To identify or confirm candidate surrogate markers of neurodegeneration using a variety of techniques including biochemical assays, blood transcriptome analysis, plasma proteomics and MRI*.</li> </ol> </p> <p><b><u>Genotyping</u></b><br/>Genotyping of the complete dataset was performed at the Illumina facilities using the Sentrix® HumanHap550 BeadChip.</p> <p><small><i>*MRI results are not available on dbGaP.</i></small></p>
| phs000171 | dbGaP
Project description:Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system mediated by autoimmune and neurodegenerative pathogenic mechanisms. Multiple genes account for its moderate heritability, but the only genetic region shown to have a large replicable effect on MS susceptibility is the major histocompatibility complex (MHC). Strong linkage disequilibrium (LD) across the MHC has made it difficult to fully characterize individual genetic contributions of this region to MS risk in previous studies. African Americans are at a lower risk for MS when compared with northern Europeans and Americans of European descent, but greater haplotypic diversity and distinct patterns of LD suggest that this population may be particularly informative for fine-mapping efforts. To examine the role of the MHC in African American MS, a case-control association study was performed with 499 African American MS patients and 750 African American controls that were genotyped for 6040 MHC region single nucleotide polymorphisms (SNPs). A replication data set consisting of 451 African American patients and 718 African American controls was genotyped for selected SNPs. Two MHC class II SNPs, rs2647040 and rs3135021, were significant in the replication cohort and partially tagged DRB1*15 alleles. Surprisingly, in comparison to similar studies of individuals of European descent, the MHC seems to play a smaller role in MS susceptibility in African Americans, consistent with pervasive genetic heterogeneity across ancestral groups, and may explain the difference in MS susceptibility between African Americans and individuals of European descent.
| S-EPMC2901136 | biostudies-literature
Project description:We applied a massively parallel reporter assay (MPRA) in lymphoblastoid cells to functionally evaluate 49,256 allelic pairs, representing 30,893 genetic variants in high, local linkage disequilibrium for 744 independent cis-expression quantitative trait loci (eQTLs) assessed for colocalization across 114 traits.
2021-05-24 | GSE174534 | GEO
Project description:Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intra-individual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available.
| S-EPMC6527683 | biostudies-literature
Project description:Cardiac disease is a leading cause of morbidity and mortality in dogs and humans, with dilated cardiomyopathy being a large contributor to this. The Irish Wolfhound (IWH) is one of the most commonly affected breeds and one of the few breeds with genetic loci associated with the disease. Mutations in more than 50 genes are associated with human dilated cardiomyopathy (DCM), yet very few are also associated with canine DCM. Furthermore, none of the identified canine loci explain many cases of the disease and previous work has indicated that genotypes at multiple loci may act together to influence disease development. In this study, loci previously associated with DCM in IWH were tested for associations in a new cohort both individually and in combination. We have identified loci significantly associated with the disease individually, but no genotypes individually or in pairs conferred a significantly greater risk of developing DCM than the population risk. However combining three loci together did result in the identification of a genotype which conferred a greater risk of disease than the overall population risk. This study suggests multiple rather than individual genetic factors, cooperating to influence DCM risk in IWH.
| S-EPMC5187458 | biostudies-other
Project description:THE EPIDEMIOLOGY OF MULTIPLE SCLEROSIS HAS BEEN EXTENSIVELY INVESTIGATED AND TWO FEATURES HAVE CONSISTENTLY EMERGED: marked geographical variation in prevalence and substantial familial clustering. At first sight, geographic variation would seem to imply an environmental cause for the disease, while familial clustering would seem to suggest that genetic factors have the predominant etiological effect. However, given that geographic variation in prevalence could result from variation in the frequency of genetic risk alleles and that familial clustering might result from shared environmental exposure rather than shared genetic risk alleles, it is clear that these crude inferences are unreliable. Epidemiologists have been resourceful in their attempts to resolve this apparent conflict between "nurture and nature" and have employed a whole variety of sophisticated methods to try and untangle the etiology of multiple sclerosis. The body of evidence that has emerged from these efforts has formed the foundation for decades of research seeking to identify relevant genes and this is the obvious place to start any consideration of the genetics of multiple sclerosis.
| S-EPMC2824946 | biostudies-literature
Project description:A previous study using cumulative genetic risk estimations in multiple sclerosis (MS) successfully tracked the aggregation of susceptibility variants in multi-case and single-case families. It used a limited description of susceptibility loci available at the time (17 loci). Even though the full roster of MS risk genes remains unavailable, we estimated the genetic burden in MS families and assess its disease predictive power using up to 64 single-nucleotide polymorphism (SNP) markers according to the most recent literature. A total of 708 controls, 3251 MS patients and their relatives, as well as 117 twin pairs were genotyped. We validated the increased aggregation of genetic burden in multi-case compared with single-case families (P=4.14e-03) and confirm that these data offer little opportunity to accurately predict MS, even within sibships (area under receiver operating characteristic (AUROC)=0.59 (0.55, 0.53)). Our results also suggest that the primary progressive and relapsing-type forms of MS share a common genetic architecture (P=0.368; difference being limited to that corresponding to ± 2 typical MS-associated SNPs). We have confirmed the properties of individual genetic risk score in MS. Comparing with previous reference point for MS genetics (17 SNPs), we underlined the corrective consequences of the integration of the new findings from GWAS and meta-analysis.
| S-EPMC4102601 | biostudies-literature
Project description:Elevated genetic risk for multiple sclerosis originated in Steppe Pastoralist populations
| PRJEB65098 | ENA