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Candidate biomarkers from the integration of methylation and gene expression in discordant autistic sibling pairs

2023; Springer Nature; Volume: 13; Issue: 1 Linguagem: Inglês

10.1038/s41398-023-02407-4

2158-3188

Samuel Perini, Michele Filosi, Giovanni Allibrio, Ilaria Basadonne, Arianna Benvenuto, Serafino Buono, Carmela Bravaccio, Carlo Casonato, Elisa Ceppi, Paolo Curatolo, Bernardo Dalla Bernardina, Lucio Da Ros, Francesca Darra, Anna Eusebi, Alessandra Gabellone, Andrea De Giacomo, Grazia Distefano, Federica Donno, Maurizio Elia, Elisa Fazzi, Michela Gatta, Stefania Giusto, Serenella Grittani, Evamaria Lanzarini, Giovanni Malerba, Elisa Mani, Barbara Manzi, Lucia Margari, Lucia Marzulli, Gabriele Masi, Paola Mattei, Luigi Mazzone, Massimo Molteni, Pierandrea Muglia, S Musumeci, Antonio Narzisi, Antonio Pascotto, Cinzia Pari, Antonia Parmeggiani, Maria Giuseppina Petruzzelli, Alessia Raffagnato, Emiliangelo Ratti, Maria Paola Rossaro, Maria Pia Riccio, Paolo Rizzini, Renato Scifo, Martina Siracusano, Raffaella Tancredi, Alessandra Tiberti, Elisabetta Trabetti, Annalisa Traverso, Paola Venuti, Leonardo Zoccante, Alessandro Zuddas, Enrico Domenici,

Epigenetics and DNA Methylation

Abstract While the genetics of autism spectrum disorders (ASD) has been intensively studied, resulting in the identification of over 100 putative risk genes, the epigenetics of ASD has received less attention, and results have been inconsistent across studies. We aimed to investigate the contribution of DNA methylation (DNAm) to the risk of ASD and identify candidate biomarkers arising from the interaction of epigenetic mechanisms with genotype, gene expression, and cellular proportions. We performed DNAm differential analysis using whole blood samples from 75 discordant sibling pairs of the Italian Autism Network collection and estimated their cellular composition. We studied the correlation between DNAm and gene expression accounting for the potential effects of different genotypes on DNAm. We showed that the proportion of NK cells was significantly reduced in ASD siblings suggesting an imbalance in their immune system. We identified differentially methylated regions (DMRs) involved in neurogenesis and synaptic organization. Among candidate loci for ASD, we detected a DMR mapping to CLEC11A (neighboring SHANK1 ) where DNAm and gene expression were significantly and negatively correlated, independently from genotype effects. As reported in previous studies, we confirmed the involvement of immune functions in the pathophysiology of ASD. Notwithstanding the complexity of the disorder, suitable biomarkers such as CLEC11A and its neighbor SHANK1 can be discovered using integrative analyses even with peripheral tissues.