Beyond GWAS: Deciphering Multiple Sclerosis through the Multiple Facets of Genetics

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 12299

Special Issue Editors

Department of Health Sciences, Azienda Ospedaliera-Universitaria Maggiore della Carità, 28100 Novera, Italy
Interests: medical genetics; multiple sclerosis; systemic lupus erythematosus; amyotrophic lateral sclerosis
Department of Health Sciences, Universita degli Studi del Piemonte Orientale Amedeo Avogadro, Novara, Italy
Interests: genetic of complex diseases; multiple sclerosis; GWAS; NGS

Special Issue Information

Dear Colleagues,

Multiple sclerosis (MS) is a complex autoimmune disorder of the central nervous system. During the past decade, our knowledge about the genomics of complex diseases and particularly of multiple sclerosis has greatly improved thanks to the application of genome-wide association studies to large international datasets, which led to the identification of more than 200 susceptibility loci. However, the currently identified regions explain only about 20% of the total heritability of the disease. A recently published study by the International Multiple Sclerosis Genetics Consortium suggests that some of this missing heritability may reside in rare variants.

For most of the associated genetic regions, a fine mapping was never performed, and thus the primarily associated variant has not been identified. Furthermore, few MS risk variants have been functionally characterised.

Like many complex diseases, multiple sclerosis presents a varied clinical picture. Despite the improvements in the knowledge about disease susceptibility variants, so far little is known about the genetic variants involved in disease severity and progression, or about the response to therapy. Uncovering these aspects can open the way leading to personalised medicine.

In this Special Issue about multiple sclerosis genetics, we make an invitation to submit papers that cover the main topics which are still poorly explored in the study of the genetics of multiple sclerosis:

1) fine mapping of MS-associated genomic regions; 2) functional characterization of MS risk variants; 3) the role of rare variants; 4) the search for genetic factors for disease severity, disease progression, or other clinical hallmarks of MS; 5) genes and response to therapy in MS.

Prof. Sandra D´Alfonso
Dr. Nadia Barizzone
Guest Editors

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Keywords

  • Multiple Sclerosis
  • Fine mapping
  • Association
  • Rare variants
  • Disease Prognostic marker
  • Functional studies
  • Pharmacogenetics

Published Papers (4 papers)

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Research

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16 pages, 1472 KiB  
Article
An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients
by Nadia Barizzone, Rachele Cagliani, Chiara Basagni, Ferdinando Clarelli, Laura Mendozzi, Cristina Agliardi, Diego Forni, Martina Tosi, Elisabetta Mascia, Francesco Favero, Davide Corà, Lucia Corrado, Melissa Sorosina, Federica Esposito, Miriam Zuccalà, Domizia Vecchio, Maria Liguori, Cristoforo Comi, Giancarlo Comi, Vittorio Martinelli, Massimo Filippi, Maurizio Leone, Filippo Martinelli-Boneschi, Domenico Caputo, Manuela Sironi, Franca Rosa Guerini and Sandra D’Alfonsoadd Show full author list remove Hide full author list
Genes 2021, 12(10), 1607; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101607 - 13 Oct 2021
Cited by 4 | Viewed by 2539
Abstract
Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease’s estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian [...] Read more.
Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease’s estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respectively). The genetic burden attributable to known common MS variants was also assessed by weighted genetic risk score (wGRS). We found a significantly higher burden of common variants in the affected family members compared to that observed among sporadic MS patients and healthy controls (HCs). We also identified 34 genes containing at least one low-frequency functional variant shared among all affected family members, showing a significant enrichment in genes involved in specific biological processes—particularly mRNA transport—or neurodegenerative diseases. Altogether, our findings point to a possible pathogenic role of different low-frequency functional MS variants belonging to shared pathways. We propose that these rare variants, together with other known common MS variants, may account for the high number of affected family members within this MS multiplex family. Full article
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7 pages, 758 KiB  
Communication
Fine-Mapping Array Design for Multi-Ethnic Studies of Multiple Sclerosis
by Ashley H. Beecham and Jacob L. McCauley
Genes 2019, 10(11), 903; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10110903 - 07 Nov 2019
Cited by 3 | Viewed by 1947
Abstract
While approximately 200 autosomal genetic associations outside of the major histocompatibility complex (MHC) have been identified for multiple sclerosis (MS) risk in European populations, causal variants identified at the majority of these associated loci have been much more elusive. We propose that knowledge [...] Read more.
While approximately 200 autosomal genetic associations outside of the major histocompatibility complex (MHC) have been identified for multiple sclerosis (MS) risk in European populations, causal variants identified at the majority of these associated loci have been much more elusive. We propose that knowledge gained from replication efforts in Hispanic and African American populations can be utilized to more efficiently fine-map these risk loci. To this end, we have customized a genotyping array by adding ~20,000 bead types (~17,000 variants) to the base content of the Ilumina Infinium expanded multi-ethnic genotyping array and the Infinium ImmunoArray-24 v2 BeadChip. These custom bead types were chosen to allow for the detection of causal variation (1) in the presence of allelic and locus heterogeneity, by incorporating regulatory and coding variation within 1-Mb of previously identified risk variants and (2) in the absence of allelic and locus heterogeneity by incorporation of variants using linkage disequilibrium criteria, which are based on knowledge of replication status in Hispanic and African American study samples. This array has been designed to maximize fine-mapping potential for currently identified MS susceptibility loci, particularly in multi-ethnic populations. The strategies described here could be additionally informative for fine-mapping of other disease phenotypes. Full article
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Review

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18 pages, 388 KiB  
Review
Host Genetics and Gut Microbiome: Perspectives for Multiple Sclerosis
by Alessandro Maglione, Miriam Zuccalà, Martina Tosi, Marinella Clerico and Simona Rolla
Genes 2021, 12(8), 1181; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081181 - 29 Jul 2021
Cited by 12 | Viewed by 3684
Abstract
As a complex disease, Multiple Sclerosis (MS)’s etiology is determined by both genetic and environmental factors. In the last decade, the gut microbiome has emerged as an important environmental factor, but its interaction with host genetics is still unknown. In this review, we [...] Read more.
As a complex disease, Multiple Sclerosis (MS)’s etiology is determined by both genetic and environmental factors. In the last decade, the gut microbiome has emerged as an important environmental factor, but its interaction with host genetics is still unknown. In this review, we focus on these dual aspects of MS pathogenesis: we describe the current knowledge on genetic factors related to MS, based on genome-wide association studies, and then illustrate the interactions between the immune system, gut microbiome and central nervous system in MS, summarizing the evidence available from Experimental Autoimmune Encephalomyelitis mouse models and studies in patients. Finally, as the understanding of influence of host genetics on the gut microbiome composition in MS is in its infancy, we explore this issue based on the evidence currently available from other autoimmune diseases that share with MS the interplay of genetic with environmental factors (Inflammatory Bowel Disease, Rheumatoid Arthritis and Systemic Lupus Erythematosus), and discuss avenues for future research. Full article
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11 pages, 1052 KiB  
Review
Reworking GWAS Data to Understand the Role of Nongenetic Factors in MS Etiopathogenesis
by Rosella Mechelli, Renato Umeton, Grazia Manfrè, Silvia Romano, Maria Chiara Buscarinu, Virginia Rinaldi, Gianmarco Bellucci, Rachele Bigi, Michela Ferraldeschi, Marco Salvetti and Giovanni Ristori
Genes 2020, 11(1), 97; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11010097 - 14 Jan 2020
Cited by 4 | Viewed by 3641
Abstract
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 [...] Read more.
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. Full article
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