Placental methylome reveals a 22q13.33 brain regulatory gene locus associated with autism [WGBS]
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ABSTRACT: Most autism spectrum disorder (ASD) cases involve complex genetics interacting with perinatal environment, complicating the discovery of common genetic risk. The epigenetic layer of DNA methylation shows dynamic developmental changes and molecular memory of in utero experiences, particularly in placenta, a fetal tissue discarded at birth. However, current array-based methods to identify novel ASD risk genes lack coverage of the most structurally and epigenetically variable regions of the human genome. Here we used whole genome bisulfite sequencing (WGBS) in placenta samples from prospective ASD studies to discover a previously uncharacterized ASD risk gene in a co-methylated block at 22q13.33. Differentially methylated region (DMR) analysis identified 139 DMRs common to ASD in placental samples, including a high-confidence 118 kb hypomethylated block at 22q13.33 that replicated in two additional cohorts and identified the novel transcript NHIP as neuronal hypoxia inducible, placenta associated (gene name approved by HGNC). NHIP characterized by high expression in brain, increased expression following neuronal differentiation or hypoxia in vitro, and minimal expression in ASD placenta. Transient NHIP overexpression in cell lines increased cellular proliferation and altered expression of genes regulating synapses and neurogenesis in response to hypoxia, significantly overlapping with NHIP-associated transcript levels in ASD brain and known ASD risk genes. A common Alu insert near a fetal brain enhancer correlated with NHIP placental and brain expression levels and ASD risk, demonstrating a common genetic influence on DNA methylation levels. Together, these results demonstrate a novel environmentally-responsive ASD risk gene relevant to brain development in a hitherto uncharacterized region of the human genome.
ORGANISM(S): Homo sapiens
PROVIDER: GSE178203 | GEO | 2022/01/16
REPOSITORIES: GEO
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