Abstract
Multiple Sclerosis (MS) is a complex multifactorial autoimmune disease, whose sex- and age-adjusted prevalence in Sardinia (Italy) is among the highest worldwide. To date, 233 loci were associated with MS and almost 20% of risk heritability is attributable to common genetic variants, but many low-frequency and rare variants remain to be discovered. Here, we aimed to contribute to the understanding of the genetic basis of MS by investigating potentially functional rare variants. To this end, we analyzed thirteen multiplex Sardinian families with Immunochip genotyping data. For five families, Whole Exome Sequencing (WES) data were also available. Firstly, we performed a non-parametric Homozygosity Haplotype analysis for identifying the Region from Common Ancestor (RCA). Then, on these potential disease-linked RCA, we searched for the presence of rare variants shared by the affected individuals by analyzing WES data. We found: (i) a variant (43181034 T > G) in the splicing region on exon 27 of CUL9; (ii) a variant (50245517 A > C) in the splicing region on exon 16 of ATP9A; (iii) a non-synonymous variant (43223539 A > C), on exon 9 of TTBK1; (iv) a non-synonymous variant (42976917 A > C) on exon 9 of PPP2R5D; and v) a variant (109859349-109859354) in 3′UTR of MYO16.
Highlights
Multiple Sclerosis (MS) is a complex neurological autoimmune disease, which mainly affects people in early adulthood; for this reason, it is considered as the most common cause of neurologic disability in young adults [1,2].The prevalence of the disease is different across the different countries: it has a high prevalence in Europe, with a north to south gradient, and a lower prevalence in Asia and Africa [3]
whole exome-sequencing (WES) data were available for five families only
Our study aims at contributing to the understanding of the genetic risk component of MS and the contribution of rare variants to disease risk through a combination of Homozygosity Haplotype (HH)
Summary
Multiple Sclerosis (MS) is a complex neurological autoimmune disease, which mainly affects people in early adulthood; for this reason, it is considered as the most common cause of neurologic disability in young adults [1,2].The prevalence of the disease is different across the different countries: it has a high prevalence in Europe, with a north to south gradient, and a lower prevalence in Asia and Africa [3]. Multiple Sclerosis (MS) is a complex neurological autoimmune disease, which mainly affects people in early adulthood; for this reason, it is considered as the most common cause of neurologic disability in young adults [1,2]. In line with other common, complex disorders, almost 20% of risk heritability is attributable to common genetic variants in the autosomal genome, including 233 unequivocally MS-associated loci identified over the last 15 years by GWAS (genome-wide association studies), comprising 32 loci within the Major Histocompatibility Complex (MHC) [8,9,10,11,12,13], each of which explain only a small fraction of risk [14]. A recent study by the International Multiple Sclerosis Genetics Consortium (IMSGC) [15] provides evidence that 11.34% of risk heritability is explained by low-frequency variants
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