Dataset Information

Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis.

ABSTRACT: The genetic etiology and the contribution of rare genetic variation in multiple sclerosis (MS) has not yet been elucidated. Although familial forms of MS have been described, no convincing rare and penetrant variants have been reported to date. We aimed to characterize the contribution of rare genetic variation in familial and sporadic MS and have identified a family with two sibs affected by concomitant MS and malignant melanoma (MM). We performed whole exome sequencing in this primary family and 38 multiplex MS families and 44 sporadic MS cases and performed transcriptional and immunologic assessment of the identified variants. We identified a potentially causative homozygous missense variant in NLRP1 gene (Gly587Ser) in the primary family. Further possibly pathogenic NLRP1 variants were identified in the expanded cohort of patients. Stimulation of peripheral blood mononuclear cells from MS patients with putatively pathogenic NLRP1 variants showed an increase in IL-1B gene expression and active cytokine IL-1? production, as well as global activation of NLRP1-driven immunologic pathways. We report a novel familial association of MS and MM, and propose a possible underlying genetic basis in NLRP1 gene. Furthermore, we provide initial evidence of the broader implications of NLRP1-related pathway dysfunction in MS.

SUBMITTER: Maver A

PROVIDER: S-EPMC5473861 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis.

Maver Ales A Lavtar Polona P Ristić Smiljana S Stopinšek Sanja S Simčič Saša S Hočevar Keli K Sepčić Juraj J Drulović Jelena J Pekmezović Tatjana T Novaković Ivana I Alenka Hodžić H Rudolf Gorazd G Šega Saša S Starčević-Čizmarević Nada N Palandačić Anja A Zamolo Gordana G Kapović Miljenko M Likar Tina T Peterlin Borut B

Scientific reports 20170616 1

The genetic etiology and the contribution of rare genetic variation in multiple sclerosis (MS) has not yet been elucidated. Although familial forms of MS have been described, no convincing rare and penetrant variants have been reported to date. We aimed to characterize the contribution of rare genetic variation in familial and sporadic MS and have identified a family with two sibs affected by concomitant MS and malignant melanoma (MM). We performed whole exome sequencing in this primary family a ...[more]

PMID: 28623311

Similar Datasets

Project description:Maize seedlings contain high amounts of 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA), and the effect of DIMBOA is directly associated with multiple insect-resistance against insect pests such as Asian corn borer and corn leaf aphids. Although numerous genetic loci for multiple insect-resistant traits have been identified, little is known about genetic controls regarding DIMBOA content. In this study, the best linear unbiased prediction (BLUP) values of DIMBOA content in two ecological environments across 310 maize inbred lines were calculated; and their phenotypic data and BLUP values were used for marker-trait association analysis. We identified nine SSRs that were significantly associated with DIMBOA content, which explained 4.30-20.04% of the phenotypic variation. Combined with 47 original genetic loci from previous studies, we detected 19 hot loci and approximately 11 hot loci (in Bin 1.04, Bin 2.00-2.01, Bin 2.03-2.04, Bin 4.00-4.03, Bin 5.03, Bin 5.05-5.07, Bin 8.01-8.03, Bin 8.04-8.05, Bin 8.06, Bin 9.01, and Bin 10.04 regions) supported pleiotropy for their association with two or more insect-resistant traits. Within the 19 hot loci, we identified 49 candidate genes, including 12 controlling DIMBOA biosynthesis, 6 involved in sugar metabolism/homeostasis, 2 regulating peroxidases activity, 21 associated with growth and development [(auxin-upregulated RNAs (SAUR) family member and v-myb avian myeloblastosis viral oncogene homolog (MYB)], and 7 involved in several key enzyme activities (lipoxygenase, cysteine protease, restriction endonuclease, and ubiquitin-conjugating enzyme). The synergy and antagonism interactions among these genes formed the complex defense mechanisms induced by multiple insect pests. Moreover, sufficient genetic variation was reported for DIMBOA performance and SSR markers in the 310 tested maize inbred lines, and 3 highly (DIMBOA content was 402.74-528.88 μg g-1 FW) and 15 moderate (DIMBOA content was 312.92-426.56 μg g-1 FW) insect-resistant genotypes were major enriched in the Reid group. These insect-resistant inbred lines can be used as parents in maize breeding programs to develop new varieties.

Project description:Multiple sclerosis (MS) is characterized as an autoimmune demyelinating disease. Numerous family studies have confirmed a strong genetic component underlying its etiology. After several decades of frustrating research, the advent and application of affordable genotyping of dense SNP maps in large data sets has ushered in a new era in which rapid progress is being made in our understanding of the genetics underlying many complex traits. For MS, one of the first discoveries to emerge in this new era was the association with rs6897932[T244I] in the interleukin-7 receptor alpha chain (IL7RA) gene (Gregory et al. in Nat Genet 39(9):1083-1091, 2007; International Multiple Sclerosis Genetics Consortium in N Engl J Med 357(9):851-862, 2007; Lundmark in Nat Genet 39(9):1108-1113, 2007), a discovery that was accompanied by functional data that suggest this variant is likely to be causative rather than a surrogate proxy (Gregory et al. in Nat Genet 39(9):1083-1091, 2007). We hypothesized that variations in other genes functionally related to IL7RA might also influence MS. We investigated this hypothesis by examining genes in the extended biological pathway related to IL7RA to identify novel associations. We identified 73 genes with putative functional relationships to IL7RA and subsequently genotyped 7,865 SNPs in and around these genes using an Illumina Infinium BeadChip assay. Using 2,961 case-control data sets, two of the gene regions examined, IL7 and SOCS1, had significantly associated single-nucleotide polymorphisms (SNPs) that further replicated in an independent case-control data set (4,831 samples) with joint p values as high as 8.29 x 10(-6) and 3.48 x 10(-7), respectively, exceeding the threshold for experiment-wise significance. Our results also implicate two additional novel gene regions that are likely to be associated with MS: PRKCE with p values reaching 3.47 x 10(-4), and BCL2 with p values reaching 4.32 x 10(-4). The TYK2 gene, which also emerged in our analysis, has recently been associated with MS (Ban et al. 2009). These results help to further delineate the genetic architecture of MS and validate our pathway approach as an effective method to identify novel associations in a complex disease.

Project description:Multiple sclerosis (MS) is the most common neurological disorder in young adults. Despite extensive studies, only a fraction of MS heritability has been explained, with association studies focusing primarily on protein-coding genes, essentially for the difficulty of interpreting non-coding features. However, non-coding RNAs (ncRNAs) and functional elements, such as super-enhancers (SE), are crucial regulators of many pathways and cellular mechanisms, and they have been implicated in a growing number of diseases. In this work, we searched for possible enrichments in non-coding elements at MS genome-wide associated loci, with the aim to highlight their possible involvement in the susceptibility to the disease. We first reconstructed the linkage disequilibrium (LD) structure of the Italian population using data of 727,478 single-nucleotide polymorphisms (SNPs) from 1,668 healthy individuals. The genomic coordinates of the obtained LD blocks were intersected with those of the top hits identified in previously published MS genome-wide association studies (GWAS). By a bootstrapping approach, we hence demonstrated a striking enrichment of non-coding elements, especially of circular RNAs (circRNAs) mapping in the 73 LD blocks harboring MS-associated SNPs. In particular, we found a total of 482 circRNAs (annotated in publicly available databases) vs. a mean of 194 ± 65 in the random sets of LD blocks, using 1,000 iterations. As a proof of concept of a possible functional relevance of this observation, we experimentally verified that the expression levels of a circRNA derived from an MS-associated locus, i.e., hsa_circ_0043813 from the STAT3 gene, can be modulated by the three genotypes at the disease-associated SNP. Finally, by evaluating RNA-seq data of two cell lines, SH-SY5Y and Jurkat cells, representing tissues relevant for MS, we identified 18 (two novel) circRNAs derived from MS-associated genes. In conclusion, this work showed for the first time that MS-GWAS top hits map in LD blocks enriched in circRNAs, suggesting circRNAs as possible novel contributors to the disease pathogenesis.

Project description:Glutamate is the main excitatory neurotransmitter in the mammalian brain. Appropriate transmission of nerve impulses through glutamatergic synapses is required throughout the brain and forms the basis of many processes including learning and memory. However, abnormally high levels of extracellular brain glutamate can lead to neuroaxonal cell death. We have previously reported elevated glutamate levels in the brains of patients suffering from multiple sclerosis. Here two complementary analyses to assess the extent of genomic control over glutamate levels were used. First, a genome-wide association analysis in 382 patients with multiple sclerosis using brain glutamate concentration as a quantitative trait was conducted. In a second approach, a protein interaction network was used to find associated genes within the same pathway. The top associated marker was rs794185 (P < 6.44 x 10(-7)), a non-coding single nucleotide polymorphism within the gene sulphatase modifying factor 1. Our pathway approach identified a module composed of 70 genes with high relevance to glutamate biology. Individuals carrying a higher number of associated alleles from genes in this module showed the highest levels of glutamate. These individuals also showed greater decreases in N-acetylaspartate and in brain volume over 1 year of follow-up. Patients were then stratified by the amount of annual brain volume loss and the same approach was performed in the 'high' (n = 250) and 'low' (n = 132) neurodegeneration groups. The association with rs794185 was highly significant in the group with high neurodegeneration. Further, results from the network-based pathway analysis remained largely unchanged even after stratification. Results from these analyses indicated that variance in the activity of neurochemical pathways implicated in neurodegeneration is explained, at least in part, by the inheritance of common genetic polymorphisms. Spectroscopy-based imaging provides a novel quantitative endophenotype for genetic association studies directed towards identifying new factors that contribute to the heterogeneity of clinical expression of multiple sclerosis.

Dataset Information

Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis.

Publications

Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets