Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic autism in post-mortem human brain tissue

作者：Chloe C. Y. Wong, Rebecca G. Smith, Eilís Hannon, Gokul Ramaswami, Neelroop Parikshak, Elham Assary, Claire Troakes, Jérémie Poschmann, Leonard C. Schalkwyk, Wenjie Sun, Shyam Prabhakar, Daniel H. Geschwind, Jonathan Mill · 发表于：Human Molecular Genetics · 年份：2019 · DOI：10.1093/hmg/ddz052 · 被引用次数：105 · 研究领域：Autism Spectrum Disorder Research、Genetics and Neurodevelopmental Disorders、Epigenetics and DNA Methylation

Autism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behaviour. Building on recent studies supporting a role for developmentally moderated regulatory genomic variation in the molecular aetiology of ASD, we quantified genome-wide patterns of DNA methylation in 223 post-mortem tissues samples isolated from three brain regions [prefrontal cortex, temporal cortex and cerebellum (CB)] dissected from 43 ASD patients and 38 non-psychiatric control donors. We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the CB. Individuals carrying a duplication on chromosome 15q (dup15q), representing a genetically defined subtype of ASD, were characterized by striking differences in DNA methylationacross a discrete domain spanning an imprinted gene cluster within the duplicated region. In addition to the dramatic cis-effects on DNA methylation observed in dup15q carriers, we identified convergent methylomic signatures associated with both iASD and dup15q, reflecting the findings from previous studies of gene expression and H3K27ac. Cortical co-methylation network analysis identified a number of co-methylated modules significantly associated with ASD that are enriched for genomic regions annotated to genes involved in the immune system, synaptic sig...