Abstract
BackgroundAutism spectrum disorder (ASD) involves complex genetics interacting with the 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.ResultsWe use whole genome bisulfite sequencing in placenta samples from prospective ASD studies to discover a previously uncharacterized ASD risk gene, LOC105373085, renamed NHIP. Out of 134 differentially methylated regions associated with ASD in placental samples, a cluster at 22q13.33 corresponds to a 118-kb hypomethylated block that replicates in two additional cohorts. Within this locus, NHIP is functionally characterized as a nuclear peptide-encoding transcript with high expression in brain, and increased expression following neuronal differentiation or hypoxia, but decreased expression in ASD placenta and brain. NHIP overexpression increases cellular proliferation and alters expression of genes regulating synapses and neurogenesis, overlapping significantly with known ASD risk genes and NHIP-associated genes in ASD brain. A common structural variant disrupting the proximity of NHIP to a fetal brain enhancer is associated with NHIP expression and methylation levels and ASD risk, demonstrating a common genetic influence.ConclusionsTogether, these results identify and initially characterize a novel environmentally responsive ASD risk gene relevant to brain development in a hitherto under-characterized region of the human genome.
Highlights
Autism spectrum disorder (ASD) involves complex genetics interacting with the perinatal environment, complicating the discovery of common genetic risk
Cell type, or technical variables were significantly associated with ASD outcome, but scores related to ASD severity and cognition were associated, as expected (FDR-corrected and raw p values from Fisher’s exact for categorical or one-way analysis of variance (ANOVA) for continuous variables is in Additional File 1: Table S1)
Further evidence that Differentially methylated regions (DMRs) identified in placenta reflect epigenetic differences relevant to brain and development came from the significant enrichment of ASD DMRs in fetal brain enhancers, as well as bivalent enhancer and repressed polycomb regions of placenta compared to background regions using ChromHMM-defined chromatin states from the Roadmap Epigenomics Project [35] (Fig. 1c, detailed information on each tissue type and chromatin state is in Additional File 5: Table S4)
Summary
Autism spectrum disorder (ASD) involves complex genetics interacting with the perinatal environment, complicating the discovery of common genetic risk. A large genome-wide association study (GWAS) identified individual genetic variants that contribute to an individual’s ASD risk and showed that the weighed sum of the risk alleles and their effect sizes can be combined to create a polygenic risk score (PRS) for ASD [8]. A PRS derived from a set of 108 previously identified genome-wide significant variants for schizophrenia [11] was shown to be significant only in the presence of early-life maternal complications (ELCs), and the subset of variants interacting with ELCs corresponded with patterns of placental gene expression, consistent with the importance of placental gene regulation as a window into neurodevelopment [12]. Term placenta is an accessible tissue normally discarded at birth; the convergence between placental biology and genetic risk for ASD is relatively unexplored
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