title: Genetic and epigenetic methylation defects and implication of the ERMN gene in autism spectrum disorders.
abstract: Autism 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.
authors.affiliation: Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.|Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Homs
authors.affiliation: Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.|Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Codina-Solà
authors.affiliation: Quantitative Genomic Medicine Laboratories, S.L., Barcelona, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Rodríguez-Santiago
authors.affiliation: Center for Research in Environmental Epidemiology, Barcelona, Spain.|Consorcio de Investigación Biomédica de Epidemiología y Salud Pública, Barcelona, Spain.
authors.forename: C M
authors.initials: CM
authors.lastname: Villanueva
authors.affiliation: Cancer Epigenetics Group, Institut d'Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Monk
authors.affiliation: Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.|Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Cuscó
authors.affiliation: Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.|Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain.
authors.forename: L A
authors.initials: LA
authors.lastname: Pérez-Jurado
mesh_terms: D000217:Acyltransferases / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000235:genetics; D008875:Middle Aged; D009185:Myelin Proteins / Q000235:genetics; D010727:Phosphoric Diester Hydrolases / Q000235:genetics; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D051438:Syntaxin 16 / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D055815:Young Adult
chemical_list: C557433:ERMN protein, human; D009185:Myelin Proteins; C496118:STX16 protein, human; D051438:Syntaxin 16; C513810:USP24 protein, human; D008780:Methyltransferases; D000217:Acyltransferases; C033588:dihydrolipoamide acyltransferase; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases; D043222:Ubiquitin Thiolesterase