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.

IF 4 2区医学 Q1 CLINICAL NEUROLOGY

Journal of Neurodevelopmental Disorders Pub Date : 2025-08-16 DOI:10.1186/s11689-025-09637-1

Ellen M Howerton, Valerie Morrill, Rose Schrott, Jason Daniels, Ashley Y Song, Kelly Benke, Heather Volk, Homayoon Farzadegan, Aimee Anido Alexander, Amanda L Tapia, Gabriel S Dichter, Lisa A Croen, Lisa Wiggins, Genevieve Wojcik, M Daniele Fallin, Christine Ladd-Acosta

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引用次数: 0

Abstract

Background: 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).

Methods: 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.

Results: 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.

Conclusions: 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.

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在一项研究早期发育的病例对照研究中，一项全表观基因组关联研究发现，ZFP57附近的差异DNA甲基化与自闭症特征相关。

背景：自闭症谱系障碍（ASD）相关特征的定量测量可以深入了解整个人群的特征表现。以前的研究已经确定了与ASD诊断相关的表观基因组变异，但很少评估数量性状。我们试图确定儿童血液中的DNA甲基化模式与社会反应量表评分，第二版（SRS）相关。方法：我们在美国ASD的病例对照研究“探索早期发展研究”中对大约5岁儿童血液中的SRS进行了一项全表观基因组关联研究。在质量控制后，我们使用Illumina 450K阵列测量了857个样本的DNA甲基化。我们对m值进行了回归，以确定与SRS评分相关的单个位点或差异甲基化区域（DMRs），并对生物和技术变异的来源进行了调整。我们检查了甲基化数量性状位点，并对感兴趣的区域进行了基因本体术语通路分析。结果：我们在6号染色体上ZFP57上游约3.5 kb的区域发现了差异甲基化（家族误差率[fwer]）

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来源期刊

Journal of Neurodevelopmental Disorders 医学-临床神经学

CiteScore

7.60

自引率

4.10%

发文量

审稿时长

>12 weeks

期刊介绍： Journal of Neurodevelopmental Disorders is an open access journal that integrates current, cutting-edge research across a number of disciplines, including neurobiology, genetics, cognitive neuroscience, psychiatry and psychology. The journal’s primary focus is on the pathogenesis of neurodevelopmental disorders including autism, fragile X syndrome, tuberous sclerosis, Turner Syndrome, 22q Deletion Syndrome, Prader-Willi and Angelman Syndrome, Williams syndrome, lysosomal storage diseases, dyslexia, specific language impairment and fetal alcohol syndrome. With the discovery of specific genes underlying neurodevelopmental syndromes, the emergence of powerful tools for studying neural circuitry, and the development of new approaches for exploring molecular mechanisms, interdisciplinary research on the pathogenesis of neurodevelopmental disorders is now increasingly common. Journal of Neurodevelopmental Disorders provides a unique venue for researchers interested in comparing and contrasting mechanisms and characteristics related to the pathogenesis of the full range of neurodevelopmental disorders, sharpening our understanding of the etiology and relevant phenotypes of each condition.