Combination of Genomic and Transcriptomic Approaches Highlights Vascular and Circadian Clock Components in Multiple Sclerosis

• Published in: International journal of molecular sciences 2021-12, Vol.23 (1), p.310
• Main Authors: Scapoli, Chiara, Ziliotto, Nicole, Lunghi, Barbara, Menegatti, Erica, Salvi, Fabrizio, Zamboni, Paolo, Baroni, Marcello, Mascoli, Francesco, Bernardi, Francesco, Marchetti, Giovanna
• Format: Article
• Language: English
• Subjects: Biological activity; Biological clocks; Blood Vessels - pathology; Brain; Case-Control Studies; Circadian Clocks - genetics; Circadian rhythm; Circadian rhythms; Cohort Studies; Disease; Disease transmission; Entrainment; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Gene Frequency - genetics; Gene Regulatory Networks; Genes; Genome-Wide Association Study; Genomes; Genomics; Humans; Introns - genetics; Italy; Jugular vein; Multiple sclerosis; Multiple Sclerosis - genetics; Neurodegeneration; Period 3 protein; Polymorphism, Single Nucleotide - genetics; Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal transduction; Single-nucleotide polymorphism; Transcription factors; Transcriptome - genetics; Transcriptomes; Transcriptomics; Vascular tissue; Veins & arteries; Whole Exome Sequencing
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23010310

Aiming at exploring vascular components in multiple sclerosis (MS) with brain outflow disturbance, we combined transcriptome analysis in MS internal jugular vein (IJV) wall with WES in MS families with vertical transmission of disease. Main results were the differential expression in IJV wall of 16 MS-GWAS genes and of seven genes ( , , , , , , and ) not previously indicated by GWAS but encoding for proteins functionally interacting with MS candidate gene products. Strikingly, 22/23 genes have been previously associated with vascular or neuronal traits/diseases, nine encoded for transcriptional factors/regulators and six ( , , , , , ) for circadian entrainment/rhythm components. Among the WES low-frequency (MAF ≤ 0.04) SNPs ( = 7) filtered in the 16 genes, the rs17616365 showed significantly different MAF in the Network for Italian Genomes affected cohort than in the 1000 Genome Project Tuscany samples. This pattern was also detected in five nonintronic variants ( rs1805482, rs2640909, rs2970847, rs8192678, and rs3755863) in genes coding for functional partners. Overall, the study proposes specific markers and low-frequency variants that might help (i) to understand perturbed biological processes in vascular tissues contributing to MS disease, and (ii) to characterize MS susceptibility genes for functional association with disease-pathways.