Integrative genomics identifies a convergent molecular subtype that links epigenomic with transcriptomic differences in autism
Year: 2020
Type: article
Study design: Observational Study
Abstract: Autism spectrum disorder (ASD) is a phenotypically and genetically heterogeneous neurodevelopmental disorder. Despite this heterogeneity, previous studies have shown patterns of molecular convergence in post-mortem brain tissue from autistic subjects. Here, we integrate genome-wide measures of mRNA expression, miRNA expression, DNA methylation, and histone acetylation from ASD and control brains to identify a convergent molecular subtype of ASD with shared dysregulation across both the epigenome and transcriptome. Focusing on this convergent subtype, we substantially expand the repertoire of differentially expressed genes in ASD and identify a component of upregulated immune processes that are associated with hypomethylation. We utilize eQTL and chromosome conformation datasets to link differentially acetylated regions with their cognate genes and identify an enrichment of ASD genetic risk variants in hyperacetylated noncoding regulatory regions linked to neuronal genes. These findings help elucidate how diverse genetic risk factors converge onto specific molecular processes in ASD.
Source: Nature Communications
Authors: Gokul Ramaswami, Hyejung Won, Michael J. Gandal, Jillian Haney, Jerry C. Wang, Chloe C. Y. Wong, Wenjie Sun, Shyam Prabhakar, Jonathan Mill, Daniel H. Geschwind
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,380
Funders: U.S. Department of Health and Human Services, Brain and Behavior Research Foundation, Simons Foundation, National Alliance for Research on Schizophrenia and Depression, Simons Foundation Autism Research Initiative, Agency for Science, Technology and Research, China Aerospace Science and Technology Corporation, National Institutes of Health, Medical Research Council, Bioinformatics Institute, National Institute of Mental Health
Awards: Deciphering Cell-type Specific Regulatory Landscape in Human Brain, 1/3 Building integrative CNS networks for genomic analysis of autism, G3021430819, Systems level integration of genetic, transcriptomic, and epigenomic data in autism, Isoform-level probabilistic transcriptome-wide association to undercover neurogenetic mechanisms underlying complex psychiatric traits, 2/3 Integrative Genomic Analysis of Human Brain Development and Autism, G4913952178, G5209089491, Epigenetic and Transcriptional Dysregulation in Autism Spectrum Disorder, G6607928760, Connecting gene regulatory mechanisms in human brain to psychiatric illness, 1/2 Cross modal integration of molecular and physiological networks in ASD, G7535587850, Population-level and mechanistic dissection of 17q21 structural variant association with psychiatric traits, G7914617348, G868729679
OpenAlex ID: W3088092592