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

ABSTRACT: 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 in silico 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 EFCAB13, a gene coding for a protein of an unknown function (p < 10^-4). Among these variants, the minor allele of a stop-gain variant showed a significantly higher frequency in MS versus HC in both sequenced cohorts (p = 0.0093 and p = 0.025), confirmed by a meta-analysis on a third independent cohort of 1298 MS and 1430 HC (p = 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 (p = 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.

SUBMITTER: Clarelli F

PROVIDER: S-EPMC8762330 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundWhole-genome sequencing and imputation methodologies have enabled the study of the effects of genomic variants with low to very low minor allele frequency (MAF) on variation in complex traits. Our objective was to estimate the proportion of variance explained by imputed sequence variants classified according to their MAF compared with the variance explained by the pedigree-based additive genetic relationship matrix for 17 traits in Nordic Holstein dairy cattle.ResultsImputed sequence variants were grouped into seven classes according to their MAF (0.001-0.01, 0.01-0.05, 0.05-0.1, 0.1-0.2, 0.2-0.3, 0.3-0.4 and 0.4-0.5). The total contribution of all imputed sequence variants to variance in deregressed estimated breeding values or proofs (DRP) for different traits ranged from 0.41 [standard error (SE) = 0.026] for temperament to 0.87 (SE = 0.011) for milk yield. The contribution of rare variants (MAF < 0.01) to the total DRP variance explained by all imputed sequence variants was relatively small (a maximum of 12.5% for the health index). Rare and low-frequency variants (MAF < 0.05) contributed a larger proportion of the explained DRP variances (>13%) for health-related traits than for production traits (<11%). However, a substantial proportion of these variance estimates across different MAF classes had large SE, especially when the variance explained by a MAF class was small. The proportion of DRP variance that was explained by all imputed whole-genome sequence variants improved slightly compared with variance explained by the 50 k Illumina markers, which are routinely used in bovine genomic prediction. However, the proportion of DRP variance explained by imputed sequence variants was lower than that explained by pedigree relationships, ranging from 1.5% for milk yield to 37.9% for the health index.ConclusionsImputed sequence variants explained more of the variance in DRP than the 50 k markers for most traits, but explained less variance than that captured by pedigree-based relationships. Although in humans partitioning variants into groups based on MAF and linkage disequilibrium was used to estimate heritability without bias, many of our bovine estimates had a high SE. For a reliable estimate of the explained DRP variance for different MAF classes, larger sample sizes are needed.

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

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