Genome‐wide association studies of multiple sclerosis

Cotsapas, Chris; Mitrovič, Mitja

doi:10.1002/cti2.1018

Cited by 65 publications

(33 citation statements)

References 76 publications

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“…Notably, three X chromosome candidate genes have been at the forefront of genetic association studies in MS: PLP (located on Xq22) (134), cytochrome b-245 β chain (CYBB or NOX2, Xp21) (263), and gamma-aminobutyric acid ionotropic type A receptor (GABRA3, Xq28) (135). Although these studies did produce some evidence for association with MS, none of these genes was actually identified in genomewide association studies (GWAS) (264,265). It should be noted, however, that the X chromosome is usually excluded from GWAS analyses despite being assayed on all current GWAS platforms.…”

Section: The X Chromosomementioning

confidence: 99%

SeXX Matters in Multiple Sclerosis

2020

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Multiple sclerosis (MS) is the most common chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). An interesting feature that this debilitating disease shares with many other inflammatory disorders is that susceptibility is higher in females than in males, with the risk of MS being three times higher in women compared to men. Nonetheless, while men have a decreased risk of developing MS, many studies suggest that males have a worse clinical outcome. MS exhibits an apparent sexual dimorphism in both the immune response and the pathophysiology of the CNS damage, ultimately affecting disease susceptibility and progression differently. Overall, women are predisposed to higher rates of inflammatory relapses than men, but men are more likely to manifest signs of disease progression and worse CNS damage. The observed sexual dimorphism in MS may be due to sex hormones and sex chromosomes, acting in parallel or combination. In this review, we outline current knowledge on the sexual dimorphism in MS and discuss the interplay of sex chromosomes, sex hormones, and the immune system in driving MS disease susceptibility and progression.

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Section: The X Chromosomementioning

confidence: 99%

SeXX Matters in Multiple Sclerosis

2020

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“…GWAS are population-based association studies, comparing disease cases and controls for common genetic variants at variable frequencies in the general population. They have identified more than 200 MS-associated loci across the human genome over the last decade [8][9][10][11]. Methodological advances, increased sample sizes, and improved bio-statistical approaches have all contributed to important progress in the definition of the genetic architecture of MS; complexity is now evident for disease genetics, which had, until 15 years ago, essentially been limited to the role of human leukocyte antigen (HLA).…”

Section: Introductionmentioning

confidence: 99%

Reworking GWAS Data to Understand the Role of Nongenetic Factors in MS Etiopathogenesis

Mechelli

Umeton

Manfrè

et al. 2020

Genes

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Genome-wide association studies have identified more than 200 multiple sclerosis (MS)-associated loci across the human genome over the last decade, suggesting complexity in the disease etiology. This complexity poses at least two challenges: the definition of an etiological model including the impact of nongenetic factors, and the clinical translation of genomic data that may be drivers for new druggable targets. We reviewed studies dealing with single genes of interest, to understand how MS-associated single nucleotide polymorphism (SNP) variants affect the expression and the function of those genes. We then surveyed studies on the bioinformatic reworking of genome-wide association studies (GWAS) data, with aggregate analyses of many GWAS loci, each contributing with a small effect to the overall disease predisposition. These investigations uncovered new information, especially when combined with nongenetic factors having possible roles in the disease etiology. In this context, the interactome approach, defined as “modules of genes whose products are known to physically interact with environmental or human factors with plausible relevance for MS pathogenesis”, will be reported in detail. For a future perspective, a polygenic risk score, defined as a cumulative risk derived from aggregating the contributions of many DNA variants associated with a complex trait, may be integrated with data on environmental factors affecting the disease risk or protection.

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“…Gene therapy has the potential to expand to other conditions involving a few or single key genes. However, this strategy will likely prove challenging in diseases that are highly polygenic, involving small effects from multiple genetic risk factors in combination with environmental contributions [25].…”

Section: Lentiviral Gene Therapymentioning

confidence: 99%

Nucleic Acid-Based Therapeutics Relevant to Neuroimmune Conditions

Greenfield

2019

Neurotherapeutics

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Genome‐wide association studies of multiple sclerosis

Cited by 65 publications

References 76 publications

SeXX Matters in Multiple Sclerosis

SeXX Matters in Multiple Sclerosis

Reworking GWAS Data to Understand the Role of Nongenetic Factors in MS Etiopathogenesis

Nucleic Acid-Based Therapeutics Relevant to Neuroimmune Conditions

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