Exome sequencing of multiple-sclerosis patients and their unaffected first-degree relatives

Garcia-Rosa, Sheila; Amorim, María Galli de; Valieris, Renan; Marques, Vanessa Daccach; Lorenzi, Julio C. C.; Toller, Vania Balardin; Olival, Guilherme Sciascia do; Júnior, Wilson Araújo da Silva; Silva, Israel Tojal da; Barreira, Amilton Antunes; Nunes, Diana Noronha; Dias‐Neto, Emmanuel

doi:10.1186/s13104-017-3072-0

Cited by 5 publications

(3 citation statements)

References 11 publications

(7 reference statements)

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“…Genetic studies in MS have used whole exome sequencing (WES) to investigate somatic mutations (Kemppinen et al, 2014), to define the genetic contribution to MS clinical outcomes (Sadovnick et al, 2017) and to suggest new potential causative variants in families (Dyment et al, 2012; Garcia-Rosa et al, 2017; Maver et al, 2017; Mescheriakova et al, 2018) or unrelated patients (Bernales et al, 2018). WES data in families, suggesting monogenic disease forms caused by rare variants with strong functional impact (Ramagopalan et al, 2011; Wang et al, 2016), were not confirmed in the subsequent replication studies (Ban et al, 2013; International Multiple Sclerosis Genetics Consortium, 2016; Minikel and MacArthur, 2016).…”

Section: Introductionmentioning

confidence: 99%

C6orf10 Low-Frequency and Rare Variants in Italian Multiple Sclerosis Patients

et al. 2019

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In light of the complex nature of multiple sclerosis (MS) and the recently estimated contribution of low-frequency variants into disease, decoding its genetic risk components requires novel variant prioritization strategies. We selected, by reviewing MS Genome Wide Association Studies (GWAS), 107 candidate loci marked by intragenic single nucleotide polymorphisms (SNPs) with a remarkable association ( p -value ≤ 5 × 10 -6 ). A whole exome sequencing (WES)-based pilot study of SNPs with minor allele frequency (MAF) ≤ 0.04, conducted in three Italian families, revealed 15 exonic low-frequency SNPs with affected parent-child transmission. These variants were detected in 65/120 Italian unrelated MS patients, also in combination (22 patients). Compared with databases (controls gnomAD, dbSNP150, ExAC, Tuscany-1000 Genome), the allelic frequencies of C6orf10 rs16870005 and IL2RA rs12722600 were significantly higher (i.e., controls gnomAD, p = 9.89 × 10 -7 and p < 1 × 10 -20 ). TET2 rs61744960 and TRAF3 rs138943371 frequencies were also significantly higher, except in Tuscany-1000 Genome. Interestingly, the association of C6orf10 rs16870005 (Ala431Thr) with MS did not depend on its linkage disequilibrium with the HLA-DRB1 locus. Sequencing in the MS cohort of the C6orf10 3′ region revealed 14 rare mutations (10 not previously reported). Four variants were null, and significantly more frequent than in the databases. Further, the C6orf10 rare variants were observed in combinations, both intra-locus and with other low-frequency SNPs. The C6orf10 Ser389Xfr was found homozygous in a patient with early onset of the MS. Taking into account the potentially functional impact of the identified exonic variants, their expression in combination at the protein level could provide functional insights in the heterogeneous pathogenetic mechanisms contributing to MS.

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Section: Introductionmentioning

confidence: 99%

C6orf10 Low-Frequency and Rare Variants in Italian Multiple Sclerosis Patients

et al. 2019

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“…A CYP27A1 mutation thought to be related to MS has been described in a family including three patients with the disease (Traboulsee et al, ). Another published study design, using WES to study father‐mother‐child trio, includes 28 patients from eight families; however, the results are not known (García‐Rosa et al, ). The only published study on the subject, evaluating VDR variants in 29 patients with familial MS and comparing them to unrelated controls, found a significant difference between groups for the TaqI variant of VDR (Yucel et al, ).…”

Section: Discussionmentioning

confidence: 99%

Exonic variants of genes related to the vitamin D signaling pathway in the families of familial multiple sclerosis using whole‐exome next generation sequencing

et al. 2019

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Introduction Vitamin D (VD) deficiency has been associated with multiple sclerosis (MS) and other autoimmune diseases (AIDs). However, the effect of the genetics of VD on the risk of MS is subject to debate. This study focuses on genes linked to the VD signaling pathway in families with MS. The evaluation of gene variants in all the members of families could contribute to an additional knowledge on the information obtained from case‐control studies that use nonrelated healthy people. Material and Methods We studied 94 individuals from 15 families including at least two patients with MS. We performed whole‐exome next generation sequencing on all individuals and analyzed variants of the DHCR7, CYP2R1, CYP3A4, CYP27A1, GC, CYP27B1, LRP2, CUBN, DAB2, FCGR, RXR, VDR, CYP24A1, and PDIA3 genes. We also studied PTH, FGF23, METTL1, METTL21B, and the role of the linkage disequilibrium block on the long arm of chromosome 12, through analysis of the CDK4, TSFM, AGAP2, and AVIL genes. We compared patients with MS, other AIDs and unaffected members from different family types. Results The study described the variants in the VD signaling pathway that appear in families with at least two patients with MS. Some infrequent variants were detected in these families, but no significant difference was observed between patients with MS and/or other AIDs and unaffected family members in the frequency of these variants. Variants previously associated with MS in the literature were not observed in these families or were distributed similarly in patients and unaffected family members. Conclusion The study of genes involved in the VD signaling pathway in families that include more than one patient with MS did not identify any variants that could explain the presence of the disease, suggesting that VD metabolism could probably play a role in MS more as an environmental factor rather than as a genetic factor. Our study also supports the analysis of cases and unaffected individuals within families in order to determine the influence of genetic factors.

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“…Heritability estimates from twin studies on MS genetics propose monozygotic concordance rates of 25-30% with minimal dizygotic concordance rates, suggesting a complex interplay of multiple genetic contributions and environmental influences on disease development (7,25,36,103). To begin understanding these rare polygenic contributions to MS, whole genome/ exome sequencing has begun identifying rare variants that contribute to disease (32,48,61,81). Building a network of genes based on these genetic insights would help in establishing a systems risk assessment while expanding pathways that yield additional rare genetic variants that contribute to MS in a personalized medicine strategy.…”

Section: Introductionmentioning

confidence: 99%

Breakdown of multiple sclerosis genetics to identify an integrated disease network and potential variant mechanisms

Shepard

Cline

Hinds

et al. 2019

Physiological Genomics

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Genetics of multiple sclerosis (MS) are highly polygenic with few insights into mechanistic associations with pathology. In this study, we assessed MS genetics through linkage disequilibrium and missense variant interpretation to yield a MS gene network. This network of 96 genes was taken through pathway analysis, tissue expression profiles, single cell expression segregation, expression quantitative trait loci (eQTLs), genome annotations, transcription factor (TF) binding profiles, structural genome looping, and overlap with additional associated genetic traits. This work revealed immune system dysfunction, nerve cell myelination, energetic control, transcriptional regulation, and variants that overlap multiple autoimmune disorders. Tissue-specific expression and eQTLs of MS genes implicate multiple immune cell types including macrophages, neutrophils, and T cells, while the genes in neural cell types enrich for oligodendrocyte and myelin sheath biology. There are eQTLs in linkage with lead MS variants in 25 genes including the multitissue eQTL, rs9271640, for HLA-DRB1/ DRB5. Using multiple functional genomic databases, we identified noncoding variants that disrupt TF binding for GABPA, CTCF, EGR1, YY1, SPI1, CLOCK, ARNTL, BACH1, and GFI1. Overall, this paper suggests multiple genetic mechanisms for MS associated variants while highlighting the importance of a systems biology and network approach when elucidating intersections of the immune and nervous system.

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Exome sequencing of multiple-sclerosis patients and their unaffected first-degree relatives

Cited by 5 publications

References 11 publications

C6orf10 Low-Frequency and Rare Variants in Italian Multiple Sclerosis Patients

C6orf10 Low-Frequency and Rare Variants in Italian Multiple Sclerosis Patients

Exonic variants of genes related to the vitamin D signaling pathway in the families of familial multiple sclerosis using whole‐exome next generation sequencing

Breakdown of multiple sclerosis genetics to identify an integrated disease network and potential variant mechanisms

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