GWAS-associated variants, non-genetic factors and transient transcriptome in Multiple Sclerosis etiopathogenesis: a colocalization analysis

Umeton, R.; Bellucci, G.; Bigi, R.; Romano, S.; Buscarinu, M. C.; Renie', R.; Rinaldi, V.; Pizzolato Umeton, R.; Morena, E.; Romano, C.; Mechelli, R.; Salvetti, M.; Ristori, G.

doi:10.1101/2021.03.12.434773

bioRxiv · 10.1101/2021.03.12.434773

GWAS-associated variants, non-genetic factors and transient transcriptome in Multiple Sclerosis etiopathogenesis: a colocalization analysis

Umeton, R.·Bellucci, G.·Bigi, R.·Romano, S.·Buscarinu, M. C.·Renie', R.·Rinaldi, V.·Pizzolato Umeton, R.·Morena, E.·Romano, C.·Mechelli, R.·Salvetti, M.·Ristori, G.

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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. We previously suggested a stochastic etiologic model where small-scale random perturbations could reach a threshold for MS development. The recently described mapping of the transient transcriptome (TT), including intergenic and intronic RNAs, seems appropriate to verify this model through a rigorous colocalization analysis. We show that genomic regions coding for the TT were significantly enriched for MS-associated GWAS variants and DNA binding sites for molecular transducers mediating putative, non-genetic, etiopathogenetic factors for MS (e.g., vitamin D deficiency, Epstein Barr virus latent infection, B cell dysfunction). These results suggest a model whereby TT-coding regions are hotspots of convergence between genetic ad non-genetic factors of risk/protection for MS, and plausibly for other complex disorders. Our colocalization analysis also provides a freely available data resource (www.mscoloc.com) for future research on MS transcriptional regulation.

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Umeton, R., Bellucci, G., Bigi, R., Romano, S., Buscarinu, M. C., Renie', R., Rinaldi, V., Pizzolato Umeton, R., Morena, E., Romano, C., Mechelli, R., Salvetti, M., Ristori, G.. 2021-03-12. GWAS-associated variants, non-genetic factors and transient transcriptome in Multiple Sclerosis etiopathogenesis: a colocalization analysis. https://doi.org/10.1101/2021.03.12.434773

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