Homs Raubert, Aïda, 1983-Codina i Solà, Marta, 1988-Rodríguez Santiago, BenjamínVillanueva, Cristina M.Monk, DavidCuscó Martí, Ivon, 1973-Pérez Jurado, Luis Alberto2016-12-052016-12-052016Homs A, Codina-Solà M, Rodríguez-Santiago B, Villanueva CM, Monk D, Cuscó I. et al. Genetic and epigenetic methylation defects and implication of the ERMN gene in autism spectrum disorders. Transl Psychiatry. 2016 Jul 12;6(7):e855. DOI: 10.1038/tp.2016.1202158-3188http://hdl.handle.net/10230/27689Autism spectrum disorders (ASD) are highly heritable and genetically complex conditions. Although highly penetrant mutations in multiple genes have been identified, they account for the etiology of <1/3 of cases. There is also strong evidence for environmental contribution to ASD, which can be mediated by still poorly explored epigenetic modifications. We searched for methylation changes on blood DNA of 53 male ASD patients and 757 healthy controls using a methylomic array (450K Illumina), correlated the variants with transcriptional alterations in blood RNAseq data, and performed a case-control association study of the relevant findings in a larger cohort (394 cases and 500 controls). We found 700 differentially methylated CpGs, most of them hypomethylated in the ASD group (83.9%), with cis-acting expression changes at 7.6% of locations. Relevant findings included: (1) hypomethylation caused by rare genetic variants (meSNVs) at six loci (ERMN, USP24, METTL21C, PDE10A, STX16 and DBT) significantly associated with ASD (q-value <0.05); and (2) clustered epimutations associated to transcriptional changes in single-ASD patients (n=4). All meSNVs and clustered epimutations were inherited from unaffected parents. Resequencing of the top candidate genes also revealed a significant load of deleterious mutations affecting ERMN in ASD compared with controls. Our data indicate that inherited methylation alterations detectable in blood DNA, due to either genetic or epigenetic defects, can affect gene expression and contribute to ASD susceptibility most likely in an additive manner, and implicate ERMN as a novel ASD gene.application/pdfengThis work is licensed under a Creative Commons Attribution 4.0International License. The images or other third party material in thisarticle are included in the article’s Creative Commons license, unless indicatedotherwise in the credit line; if the material is not included under the Creative Commonslicense, users will need to obtain permission from the license holder to reproduce thematerial. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0Autisme -- Aspectes genèticsinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/tp.2016.120info:eu-repo/semantics/openAccess