Identification of a Novel Risk Locus for Multiple Sclerosis at 13q31.3 by a Pooled Genome-Wide Scan of 500,000 Single Nucleotide Polymorphisms

Comabella, Manuel; Craig, David W.; Camiña-Tato, Montse; Morcillo, Carlos; López, Cristina; Navarro, Arcadi; Río, Jordi; Montalbán, Xavier; Martin, Roland

doi:10.1371/journal.pone.0003490

Cited by 97 publications

(56 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The three significant findings were simultaneously replicated in independent studies from the United Kingdom, the United States and the Nordic countries 31, 32. This opened the floodgates, with several successive studies GWAS and meta‐analysis followed in rapid succession, so that by 2011, common variants in 26 genomic loci had been associated with MS risk and independently replicated, but clearly only explained a fraction of MS risk attributable to genetic factors 33, 34, 35, 36, 37, 38, 39, 40, 41, 42. These studies collectively showed that non‐MHC MS risk alleles have modest effects on disease (odds ratios < 1.2) and that even larger sample sizes (over 10 000 cases and controls) would be needed to identify more loci 22.…”

Section: Genome‐wide Association Studiesmentioning

confidence: 91%

Genome‐wide association studies of multiple sclerosis

Cotsapas¹,

Mitrovič

2018

Clin & Trans Imm

View full text Add to dashboard Cite

Large‐scale genetic studies of multiple sclerosis have identified over 230 risk effects across the human genome, making it a prototypical common disease with complex genetic architecture. Here, after a brief historical background on the discovery and definition of the disease, we summarise the last fifteen years of genetic discoveries and map out the challenges that remain to translate these findings into an aetiological framework and actionable clinical understanding.

show abstract

Section: Genome‐wide Association Studiesmentioning

confidence: 91%

Genome‐wide association studies of multiple sclerosis

Cotsapas¹,

Mitrovič

2018

Clin & Trans Imm

View full text Add to dashboard Cite

show abstract

“…IL2R and IL7R are of particular interest because they are expressed on regulatory T cells, which have been strongly implicated in the regulation of the immune response in MS (66). Eight additional GWASs and a meta-analysis were performed and, in total, identified approximately 14 regions with genome-wide significance (77,(79)(80)(81)(82)(83)(84)(85), including several previously identified associations; among these are CD58, IL2RA, EVI5, CLEC16A, IL7RA, and TYK2 (77) and TNFRSF1A, IRF8, and CD6 (78).…”

Section: Genetics Of Msmentioning

confidence: 99%

Multiple sclerosis

Nylander¹,

Hafler²

2012

J. Clin. Invest.

468

359

View full text Add to dashboard Cite

Multiple sclerosis (MS) is a multifocal demyelinating disease with progressive neurodegeneration caused by an autoimmune response to self-antigens in a genetically susceptible individual. While the formation and persistence of meningeal lymphoid follicles suggest persistence of antigens to drive the continuing inflammatory and humoral response, the identity of an antigen or infectious agent leading to the oligoclonal expansion of B and T cells is unknown. In this review we examine new paradigms for understanding the immunopathology of MS, present recent data defining the common genetic variants underlying disease susceptibility, and explore how improved understanding of immune pathway disruption can inform MS prognosis and treatment decisions. IntroductionMS is a multifocal demyelinating disease with progressive neurodegeneration caused by an autoimmune response to self-antigens in a genetically susceptible individual. Clinical symptoms vary based on the site of neurologic lesions and often correlate with invasion of inflammatory cells across the blood-brain barrier with resulting demyelination and edema (1). Patients often exhibit an initial clinically isolated syndrome, followed by a series of subacute clinical events that spontaneously abate, referred to as relapsing remitting MS (RRMS). While patients generally return to near normal neurologic function at the cessation of each episode, over a variable period of time there can be irreversible progression of clinical disability termed secondary progressive MS (SPMS), although early therapeutic intervention may delay time to progression (2, 3). However, 10%-15% of MS patients will instead experience primary progressive MS, characterized by clinical progression from the initiation of disease without preceding relapses and remissions (4).The diagnosis is made primarily on the basis of the medical history and physical exam, which was formalized as the McDonald criteria and updated to reflect the increased reliance on imaging for lesion identification (5-7). These criteria indicate that the neurologic lesions should be disseminated in both space and time to distinguish them from monophasic self-limiting diseases such as acute disseminated encephalomyelitis, and additionally they should reflect a pattern of neurological inflammation typical of MS in the absence of a more appropriate diagnosis. A diagnosis of MS reflects clinical evaluation of episodes of intermittent neurological impairment and may take into account laboratory data, such as the characteristic oligoclonal bands in the cerebrospinal fluid (CSF), which indicate intrathecal immunoglobulin production, or abnormal visual evoked responses in the absence of optic neuritis. Over the past two decades, the diagnosis has come to include the more sensitive and specific spatial identification of white matter lesions via evaluation of T2-hyperintense lesions and gadolinium-enhancing T1 lesions on MRI (8). Gadolinium enhancement serves as a marker of focal inflammation when the dye leaks through vessels due to the ...

show abstract

“…Patients with a certain MS form were examined only in two GWASs, one involving patients with bout-onset MS (RRMS or SPMS) (Comabella et al 2008), and the other with PPMS (Martinelli-Boneschi et al 2012). This allowed searching for SNPs specifically involved in the given MS form development, but at the same time restricted potential sample size, thereby decreasing the power to identify associations.…”

Section: Gwas Data For Multiple Sclerosismentioning

confidence: 99%

A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches

et al. 2015

View full text Add to dashboard Cite

Multiple sclerosis (MS) is a common complex neurodegenerative disease of the central nervous system. It develops with autoimmune inflammation and demyelination. Genome-wide association studies (GWASs) serve as a powerful tool for investigating the genetic architecture of MS and are generally used to identify the genetic factors of disease susceptibility, clinical phenotypes, and treatment response. This review considers the main achievements and challenges of using GWAS to identify the genes involved in MS. It also describes hypothesis-driven studies with extensive genome coverage of the selected regions, complementary to GWASs. To date, over 100 MS risk loci have been identified by the combination of both approaches; 40 of them were found in at least two GWASs and meet genome-wide significance threshold (p ≤ 5 × 10(-8)) in at least one GWAS, whereas the threshold for the rest of GWASs was set in our review at p < 1 × 10(-5). Yet, MS risk loci identified to date explain only a part of the total heritability, and the reasons of "missing heritability" are discussed. The functions of MS-associated genes are described briefly; the majority of them encode immune-response proteins involved in the main stages of MS pathogenesis.

show abstract

Identification of a Novel Risk Locus for Multiple Sclerosis at 13q31.3 by a Pooled Genome-Wide Scan of 500,000 Single Nucleotide Polymorphisms

Cited by 97 publications

References 22 publications

Genome‐wide association studies of multiple sclerosis

Genome‐wide association studies of multiple sclerosis

Multiple sclerosis

A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches

Contact Info

Product

Resources

About