Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

Vilariño‐Güell, Carles; Zimprich, Alexander; Boneschi, Filippo Martinelli; Herculano, Bruno; Wang, Zhe; Matesanz, Fuencisla; Urcelay, Elena; Vandenbroeck, Koen; Leyva, Laura; Gris, Denis; Massaad, Charbel; Quandt, Jacqueline A.; Traboulsee, Anthony; Encarnacion, Mary Joy; Bernales, Cecily Q.; Follett, Jordan; Yee, Irene M.; Criscuoli, Maria; Deutschländer, Angela; Reinthaler, Eva M.; Zrzavy, Tobias; Mascia, Elisabetta; Zauli, Andrea; Esposito, Federica; Alcina, Antonio; Izquierdo, Guillermo; Espino-Paisán, Laura; Mena, Jorge; Antigüedad, Alfredo Rodríguez; Urbaneja-Romero, Patricia; Ortega-Pinazo, Jesús; Song, Weihong; Sadovnick, A. Dessa

doi:10.1371/journal.pgen.1008180

Cited by 48 publications

(33 citation statements)

References 181 publications

(243 reference statements)

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“…Rare variants in key inflammasome genes are present in both sporadic and familial forms of MS. A recent analysis of over 1000 alleles demonstrated that NLRP1, NLRP3, and caspase-1 variants were all significantly associated with the onset of both sporadic and familial forms of MS. Additionally, there was a significant association between variant rarity and pathogenicity, with progressively rarer variations in these three genes associated with increased MS severity [80]. Rare exome variants in NLRP12 have also been implicated in a potentially disrupted pro-inflammatory network that may predispose individuals to familial forms of MS [62].…”

Section: Inflammasome Genetics and Msmentioning

confidence: 99%

“…It has been previously demonstrated that muramyl dipeptide induces NLRP1 oligomerization and ATP-binding, allowing for ASC-independent caspase-1 activation [ 61 ]. However, NLRP1 is still capable of ASC-mediated activation of caspase-1 if NLRP1 engages in autolytic cleavage of its CARD domain [ 62 ] (Fig. 5 ).…”

Section: Nod-like Receptors Absent In Melanoma-like Receptors and Mmentioning

confidence: 99%

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Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets

Govindarajan

Vaccari

Keane

2020

J Neuroinflammation

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Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), and it remains the most common immune-mediated disorder affecting the CNS. While the cause of MS is unclear, the underlying pathomechanisms are thought to be either destruction by autoimmune T cells or dysfunction of myelin-producing cells. Recent advances have indicated that inflammasomes contribute the etiology of MS. Inflammasomes are multiprotein complexes of the innate immune response involved in the processing of caspase-1, the activation of pro-inflammatory cytokines interleukin (IL)-1β and IL-18 as well as the cell death-mediated mechanism of pyroptosis and the activation of the adaptive immune response. Here we review the literature to date on the role of different inflammasome signaling pathways in the pathogenesis of MS and how these pathways may be targeted to reduce deleterious inflammatory processes and improve outcomes in this patient population.

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Section: Inflammasome Genetics and Msmentioning

confidence: 99%

Section: Nod-like Receptors Absent In Melanoma-like Receptors and Mmentioning

confidence: 99%

Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets

Govindarajan

Vaccari

Keane

2020

J Neuroinflammation

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“…In the last decade, a number of putative familial high-risk genes were suggested by whole-exome sequencing (WES) studies of multi-case MS families [ 10 , 11 , 12 ]. However, none of these genes were confirmed in independent studies [ 10 , 11 , 12 , 13 , 14 , 15 ]. To elucidate potential putative high-risk genes, we performed WES in four MS families with three or more affected individuals and filtered for rare variants segregating with disease in the respective family.…”

Section: Introductionmentioning

confidence: 97%

Exome-Sequence Analyses of Four Multi-Incident Multiple Sclerosis Families

Zrzavy

Leutmezer

Kristoferitsch

et al. 2020

Genes

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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the Central Nervous System (CNS). Currently, it is estimated that 30–40% of the phenotypic variability of MS can be explained by genetic factors. However, low susceptibility variants identified through Genome Wide Association Study (GWAS) were calculated to explain about 50% of the heritability. Whether familial high-risk variants also contribute to heritability is a subject of controversy. In the last few years, several familial variants have been nominated, but none of them have been unequivocally confirmed. One reason for this may be that genetic heterogeneity and reduced penetrance are hindering detection. Sequencing a large number of MS families is needed to answer this question. In this study, we performed whole exome sequencing in four multi-case families, of which at least three affected individuals per family were analyzed. We identified a total of 138 rare variants segregating with disease in each of the families. Although no single variant showed convincing evidence for disease causation, some genes seemed particularly interesting based on their biological function. The main aim of this study was to provide a complete list of all rare segregating variants to provide the possibility for other researchers to cross-check familial candidate genes in an unbiased manner.

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“…GWAS results are derived from each common variant (signaled by a single nucleotide polymorphism (SNP)) that explains a small fraction of the risk/protection in a given population. The overall genetic risk is largely due to many common variants of small effect spread throughout the genome, except for loci lying in the HLA complex and a handful of rare gene variants that have recently been associated with MS [12][13][14].…”

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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Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

Cited by 48 publications

References 181 publications

Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets

Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets

Exome-Sequence Analyses of Four Multi-Incident Multiple Sclerosis Families

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

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