An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients

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 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.

New Insights into Risk Genes and Their Candidates in Multiple Sclerosis

“…Despite GWASs explaining that there are common SNPs associated with various diseases, known common variants only account for part of the estimated heritability of common complex diseases. Nadia et al identified the rare functional variants analyzed within a large Italian MS multiplex family with five affected members [ 58 ]. Another recent study showed that up to 5% of MS inheritability may be accounted for by rare variations in the gene coding sequence, with four novel low genes driving MS risk independently of common variant signals [ 59 ].…”

A variant in CYP26B1 associated with esophageal squamous cell carcinoma risk by affecting retinoic acid metabolism

“…However, previous studies have not explored the tumor suppressor function of CYP26B1 in ESCC in vivo. Moreover, some studies have found that the rare or low‐frequency risk variants usually function collectively with common variants by affecting one susceptibility gene or pathway 18,19 . Therefore, whether there are common variants that may influence the occurrence of ESCC via affecting the function of CYP26B1 need to be further investigated.…”

A Whole-Genome Sequencing Study Implicates GRAMD1B in Multiple Sclerosis Susceptibility

“…Such a phenomenon can be explained in different ways, including a poor representation of rare variants in typed arrays, epigenetic mechanisms and interaction between genetic and environmental factors, whose role can be better explored in family-based studies that offer a privileged setting of higher prevalence of the disease. This strategy allowed the identification of several rare variants with a possible role in MS susceptibility [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], and several genes were implicated, such as TYK2 [ 15 ], also confirmed in sporadic case [ 4 ], UBR2 and DST [ 11 ], and more recently, among others, MBP, MECP2, and CPT1A [ 13 ].…”