ID

45843

Beskrivning

Principal Investigator: Daniel H. Geschwind, MD, PhD, University of California, Los Angeles, Los Angeles, CA, USA MeSH: Autistic Disorder https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001022 Our current understanding of autism spectrum disorders (ASD) delineates a highly heritable, yet etiologically heterogeneous disease. Forward genetic approaches to find disease associated mutations or common variation have been successful and continue to offer considerable power. Yet, given the accumulating evidence for very significant heterogeneity and environmental influences, complementary approaches to classic forward genetics become necessary. Genetic polymorphism and mutation data to date have identified dozens of causal or contributory variants, yet our preliminary data from autism brain suggest that common molecular pathways are involved in a significant subset of cases. This convergence at the tissue level suggests that other mechanisms, specifically epigenetic changes, combined with genetic background, are contributing to such final common pathways. We further tested this hypothesis by taking a comprehensive and integrative genome-wide approach to assessing brain gene-expression, miRNA levels and the related, causal epigenetic mechanisms in ASD etiology. We performed RNA-seq analyses of four cerebral cortical regions and cerebellum from ASD cases and controls, to assess mRNA, miRNA, and splicing isoform regulation. In parallel, we identified key differences in chromatin state and DNA methylation across multiple brain regions in the same ASD and control individuals used in the expression analyses using ChIP-Seq and MeDIP. We assessed the mechanisms by which changes in DNA methylation, histone modification, and DNA sequence contribute to the observed differences in gene expression. This work, which represents an unprecedented effort to unify these often disparate data (usually produced without integration in mind), delineates potential shared molecular pathways in ASD and the underlying mechanism of these differences at the level of miRNA, the chromatin regulatory apparatus, and DNA methylation. The following substudies are part of the PsychENCODE release at dbGaP and offer additional molecular data:- PsychENCODE: RNA-Sequencing - SRRM4 Splicing Study phs000872 - PsychENCODE: Global Changes in Patterning, Splicing and lncRNAs phs001061 - PsychENCODE: Chromatin Contact Map in Fetal Cortical Laminae phs001190 - PsychENCODE: Epigenetic Dysregulation in Autism Spectrum Disorder phs001220

Länk

https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001022

Nyckelord

Versioner (1)

1. 2023-08-24 2023-08-24 - Arman Ghanaat

Rättsinnehavare

Daniel H. Geschwind, MD, PhD, University of California, Los Angeles, Los Angeles, CA, USA

Uppladdad den

24 augusti 2023

DOI

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