Functional DNA methylation signatures for genomic loci that confer an increased risk for autism spectrum disorder: 16p11.2 deletions and CHD8 variants

ABSTRACT: Autism spectrum disorder (ASD) is a common and etiologically heterogeneous neurodevelopmental disorder. Although many genetic causes have been identified (>200 ASD-risk genes), no single gene mutation accounts for >1% of all ASD cases. A role for epigenetic mechanisms in ASD etiology is supported by the fact that many ASD-risk genes function as epigenetic regulators and evidence that epigenetic dysregulation can interrupt normal brain development. To investigate the epigenome in patients with ASD, genome-wide DNA methylation (DNAm) was assessed using the Illumina Infinium HumanMethylation450K array in blood from individuals with ASD of heterogeneous, undefined etiology (n=52) and individuals with 16p11.2 deletions (16p11.2del, n=9) or pathogenic variants in the chromatin modifier CHD8 (CHD8+/-, n=7), two of the most common genomic variants conferring increased risk for ASD. DNAm patterns did not clearly distinguish heterogeneous ASD cases from controls. However, the homogeneous genetically-defined 16p11.2del and CHD8+/- subgroups each exhibited unique DNAm signatures that distinguished 16p11.2del or CHD8+/- individuals from both heterogeneous ASD and control groups with high sensitivity and specificity. These signatures also classified additional 16p11.2del (n=9) and CHD8 (n=9) variants as pathogenic or benign. Our findings that DNAm alterations in each signature targets unique genes in biological pathways relevant to neural development support their functional relevance. Furthermore, genes identified in our CHD8+/- DNAm signature in blood overlapped differentially expressed genes in CHD8+/- human-induced pluripotent cell-derived neurons and cerebral organoids from independent studies. Our study constitutes a novel approach for ASD molecular classification that elucidates the vital cross-talk between genetics and epigenetics in the etiology of ASD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113967 | GEO | 2019/09/01

REPOSITORIES: GEO