Gene-Based Tests of a Genome-Wide Association Study Dataset Highlight Novel Multiple Sclerosis Risk Genes

Abstract

Multiple sclerosis (MS) is an autoimmune disorder influenced by genetic and environmental factors. Many studies have provided insights into genetic factors’ contribution to MS via large-scale genome-wide association study (GWAS) datasets. However, genetic variants identified to date do not adequately explain genetic risks for MS. This study hypothesized that novel MS risk genes could be identified by analyzing the MS-GWAS dataset using gene-based tests. We analyzed a GWAS dataset consisting of 9,772 MS cases and 17,376 healthy controls of European descent. We performed gene-based tests of 464,357 autosomal single nucleotide polymorphisms (SNPs) using two methods (PLINK and VEGAS2) and identified 28 shared genes satisfied p-value < 4.56 × 10–6. In further gene expression analysis, ten of the 28 genes were significantly differentially expressed in the MS case-control gene expression omnibus (GEO) database. GALC and HLA-DOB showed the most prominent differences in gene expression (two- and three-fold, respectively) between MS patients and healthy controls. In conclusion, our results reveal more information about MS hereditary characteristics and provide a basis for further studies.

Risk Factors from Pregnancy to Adulthood in Multiple Sclerosis Outcome

“…Epidemiological studies in Europe and North America have shown that 7.3% of the population may present a genetic susceptibility to MS development, with women being more susceptible than men [50]. Research based on single nucleotide polymorphisms (SNPs) that use a large-scale genome-wide association (GWAS) has revealed at least 200 SNPs in the innate and adaptive immune cells of MS patients [51][52][53][54]. In addition, the genetic variants of vitamin D's metabolism have also been associated with MS [55][56][57], a topic that will be addressed later in this review.…”

Decision trees to evaluate the risk of developing multiple sclerosis

“…This is partly due to the fact that the majority of MS’s heritable component has yet to be discovered. While large-scale and collaborative genome-wide association studies (GWAS) and targeted functional studies continue to uncover new risk loci ( Li et al, 2021 ), the risk linked to HLA alleles remains the highest among other susceptibility genetic variants ( De Silvestri et al, 2019 ; Lorefice et al, 2019 ). In this context, it is worth noting that the proposed method shares similarities with studies employing the Polygenic Risk Score (PRS) approach, given its potential to consider and incorporate the information from HLA alleles, which have been consistently shown to possess the highest risk among other genetic variants associated with susceptibility to MS ( Hone et al, 2021 ; Breedon et al, 2023 ).…”

Neurodegenerative Disorder Risk in Krabbe Disease Carriers

“…Notably, several papers report KD patients, prevalently with late onset KD, and misdiagnosed as affected by MS. Sahai et al [ 13 ] discussed the MS family history of a KD patient with infantile-onset KD. In addition, genome-wide association studies (GWAS) and expression analyses recognized, in the GALC SNPs and expression levels, highly significant patterns distinguishing a number of people with MS (PwMS) from healthy controls [ 14 , 15 , 16 ]. Currently, the GALC gene (14q31) is actually considered a susceptibility locus for MS [ 15 ].…”

“…In addition, genome-wide association studies (GWAS) and expression analyses recognized, in the GALC SNPs and expression levels, highly significant patterns distinguishing a number of people with MS (PwMS) from healthy controls [ 14 , 15 , 16 ]. Currently, the GALC gene (14q31) is actually considered a susceptibility locus for MS [ 15 ]. Furthermore, α-synuclein fibrillization and Lewy body (LB) formation, which are characteristic features of synucleinopathies, lipidoses, other LSDs, and mitochondrial diseases, were described in KD human and mouse brains [ 17 , 18 ].…”