Multiple sclerosis genetic and non-genetic factors interact through the transient transcriptome.

Renato Umeton, Gianmarco Bellucci, Rachele Bigi, Silvia Romano, Maria Chiara Buscarinu, Roberta Reniè, Virginia Rinaldi, Raffaella Pizzolato Umeton, Emanuele Morena, Carmela Romano, Rosella Mechelli, Marco Salvetti, Giovanni Ristori

Journal: Scientific reports 2022;12(1):7536

PMID: 35534508

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Abstract

A clinically actionable understanding of multiple sclerosis (MS) etiology goes through GWAS interpretation, prompting research on new gene regulatory models. Our previous investigations suggested heterogeneity in etiology components and stochasticity in the interaction between genetic and non-genetic factors. To find a unifying model for this evidence, we focused on the recently mapped transient transcriptome (TT), that is mostly coded by intergenic and intronic regions, with half-life of minutes. Through a colocalization analysis, here we demonstrate that genomic regions coding for the TT are significantly enriched for MS-associated GWAS variants and DNA binding sites for molecular transducers mediating putative, non-genetic, determinants of MS (vitamin D deficiency, Epstein Barr virus latent infection, B cell dysfunction), indicating TT-coding regions as MS etiopathogenetic hotspots. Future research comparing cell-specific transient and stable transcriptomes may clarify the interplay between genetic variability and non-genetic factors causing MS. To this purpose, our colocalization analysis provides a freely available data resource at www.mscoloc.com .

Address: Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].; Department of Biological Engineering, Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. [email protected].; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. [email protected].; Department of Neurosciences, Mental Health and Sensory Organs, Centre for Experimental Neurological Therapies (CENTERS), Sapienza University of Rome, Rome, Italy.; Department of Neurosciences, Mental Health and Sensory Organs, Centre for Experimental Neurological Therapies (CENTERS), Sapienza University of Rome, Rome, Italy.; Neuroimmunology Unit, IRCCS Fondazione Santa Lucia, Rome, Italy.; Department of Neurology, UMass Memorial Health Care, Worcester, MA, USA.; University of Massachusetts Medical School, Worcester, MA, USA.; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA.; IRCCS San Raffaele Pisana, Rome, Italy.; San Raffaele Roma Open University, Rome, Italy.; Department of Neurosciences, Mental Health and Sensory Organs, Centre for Experimental Neurological Therapies (CENTERS), Sapienza University of Rome, Rome, Italy. [email protected].; IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy. [email protected].; Department of Neurosciences, Mental Health and Sensory Organs, Centre for Experimental Neurological Therapies (CENTERS), Sapienza University of Rome, Rome, Italy. [email protected].; Neuroimmunology Unit, IRCCS Fondazione Santa Lucia, Rome, Italy. [email protected].

DOI: 10.1038/s41598-022-11444-w

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MeSH Terms: Epstein-Barr Virus Infections, Herpesvirus 4, Human, Humans, Multiple Sclerosis, Transcriptome, Vitamin D Deficiency