An epigenome-wide association study in the case-control study to explore early development identifies differential DNA methylation near ZFP57 as associated with autistic traits.

Researchers studied blood samples from 857 five-year-old children to look for genetic differences related to autism traits. They found changes in DNA near a gene called ZFP57 that were linked to autism characteristics. This gene helps control how other genes work. The DNA changes were seen both in children with autism and across all children studied, suggesting these genetic variations might help explain differences in autism traits.

This epigenome-wide association study examined DNA methylation patterns in blood samples from 857 children (age 5) to identify genetic variations associated with autism spectrum disorder traits measured by the Social Responsiveness Scale (SRS). Researchers identified a differentially methylated region near the ZFP57 gene on chromosome 6 that was significantly associated with autism traits in both the full sample and among autism cases specifically. ZFP57 encodes a transcription factor involved in gene regulation and imprinting, and this region has previously been linked to autism in brain and oral tissue samples. The findings suggest that DNA methylation changes related to autism traits can be detected in blood samples and may reflect biological heterogeneity within autism populations.

Findings suggest potential for blood-based biomarkers to assess autism trait severity and biological heterogeneity. However, clinical translation requires replication studies and validation. Results provide insight into epigenetic mechanisms underlying autism trait variation but are not ready for diagnostic or clinical use.

Single study with cross-sectional design. DNA methylation measured only in blood, which may not reflect brain changes. Causality cannot be established. Study focused on one specific gene region, and replication in independent samples needed to confirm findings.

Quantitative measures of autism spectrum disorder (ASD)-related traits can provide insight into trait presentation across the population. Previous studies have identified epigenomic variation associated with ASD diagnosis, but few have evaluated quantitative traits. We sought to identify DNA methylation patterns in child blood associated with Social Responsiveness Scale score, Second Edition (SRS). We conducted an epigenome-wide association study of SRS in child blood at approximately age 5 in the Study to Explore Early Development, a case-control study of ASD in the United States.

We measured DNA methylation using the Illumina 450K array with 857 samples in our analysis after quality control. We performed regression of the M-value to identify single sites or differentially methylated regions (DMRs) associated with SRS scores, adjusting for sources of biological and technical variation. We examined methylation quantitative trait loci and conducted gene-ontology-term pathway analyses for regions of interest. We identified a region about 3.5 kb upstream of ZFP57 on chromosome 6 as differentially methylated (family-wise error rate [fwer] < 0.1) by continuous SRS T-score in the full sample (N = 857; fwer = 0.074) and among ASD cases only (N = 390; fwer = 0.021).

ZFP57 encodes a transcription factor involved in imprinting regulation and maintenance, and this DMR has been previously associated with ASD in brain and buccal samples. Blood DNA methylation near ZFP57 was associated (fwer < 0.1) with SRS in the full population sample and appears to be largely driven by trait heterogeneity within the autism case group. Our results indicate DNA methylation associations with ASD quantitative traits are observable in a population and provide insights into specific biologic changes related to autism trait heterogeneity.