AUTHOR=Clarelli Ferdinando , Barizzone Nadia , Mangano Eleonora , Zuccalà Miriam , Basagni Chiara , Anand Santosh , Sorosina Melissa , Mascia Elisabetta , Santoro Silvia ,  PROGEMUS ,  PROGRESSO , Guerini Franca Rosa , Virgilio Eleonora , Gallo Antonio , Pizzino Alessandro , Comi Cristoforo , Martinelli Vittorio , Comi Giancarlo , De Bellis Gianluca , Leone Maurizio , Filippi Massimo , Esposito Federica , Bordoni Roberta , Martinelli Boneschi Filippo , D'Alfonso Sandra , Crociani P , Vecchio D , Ragonese P , Gajofatto A , Scarpini E , Bertolotto A , Caputo D , Gasperini C , Granella F , Cordera S , Cavallo P , Cavallo R , Bergamaschi R , Ristori G , Solaro C , Martinelli F , Passantino F , Pugliatti M , Gallo A , Brambilla L , Clerico C , Capone F , Esposito F , Liberatore G , Rodegher M , Rossi p , Radaelli M , Moiola L , Colombo B , Ghezzi A , Annovazzi A , Capra R , Coniglio G , Amato M. P , Nacmias B , Tedeschi G , D’Ambrosio A , Cavalla P , Patti F , D’Amico E , Galimberti D , Scarpini E , Gallo P , Atzori M , Grimaldi L , Bucello S , Mancardi G , Capello E 

TITLE=Contribution of Rare and Low-Frequency Variants to Multiple Sclerosis Susceptibility in the Italian Continental Population

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.800262

DOI=10.3389/fgene.2021.800262

ISSN=1664-8021

ABSTRACT=<p>Genome-wide association studies identified over 200 risk loci for multiple sclerosis (MS) focusing on common variants, which account for about 50% of disease heritability. The goal of this study was to investigate whether low-frequency and rare functional variants, located in MS-established associated loci, may contribute to disease risk in a relatively homogeneous population, testing their cumulative effect (burden) with gene-wise tests. We sequenced 98 genes in 588 Italian patients with MS and 408 matched healthy controls (HCs). Variants were selected using different filtering criteria based on allelic frequency and <italic>in silico</italic> functional impacts. Genes showing a significant burden (n = 17) were sequenced in an independent cohort of 504 MS and 504 HC. The highest signal in both cohorts was observed for the disruptive variants (stop-gain, stop-loss, or splicing variants) located in <italic>EFCAB13</italic>, a gene coding for a protein of an unknown function (<italic>p</italic> &lt; 10<sup>–4</sup>). Among these variants, the minor allele of a stop-gain variant showed a significantly higher frequency in MS versus HC in both sequenced cohorts (<italic>p</italic> = 0.0093 and <italic>p</italic> = 0.025), confirmed by a meta-analysis on a third independent cohort of 1298 MS and 1430 HC (<italic>p</italic> = 0.001) assayed with an SNP array. Real-time PCR on 14 heterozygous individuals for this variant did not evidence the presence of the stop-gain allele, suggesting a transcript degradation by non-sense mediated decay, supported by the evidence that the carriers of the stop-gain variant had a lower expression of this gene (<italic>p</italic> = 0.0184). In conclusion, we identified a novel low-frequency functional variant associated with MS susceptibility, suggesting the possible role of rare/low-frequency variants in MS as reported for other complex diseases.</p>