Abstract
Previous studies have identified differences in DNA methylation in autistic individuals compared to neurotypical individuals. Yet, it is unclear if this extends to autistic traits—subclinical manifestation of autism features in the general population. Here, we investigate the association between DNA methylation at birth (cord blood), and scores on the Social and Communication Disorders Checklist (SCDC), a measure of autistic traits, in 701 8-year-olds, by conducting a methylome-wide association study (MWAS). We did not identify significant CpGs associated with SCDC. The most significant CpG site was cg14379490, on chromosome 9 (MWAS beta = − 1.78 ± 0.35, p value = 5.34 × 10−7). Using methylation data for autism in peripheral tissues, we did not identify a significant concordance in effect direction of CpGs with p value < 10−4 in the SCDC MWAS (binomial sign test, p value > 0.5). In contrast, using methylation data for autism from post-mortem brain tissues, we identify a significant concordance in effect direction of CpGs with a p value < 10−4 in the SCDC MWAS (binomial sign test, p value = 0.004). Supporting this, we observe an enrichment for genes that are dysregulated in the post-mortem autism brain (one-sided Wilcoxon rank-sum test, p value = 6.22 × 10−5). Finally, integrating genome-wide association study (GWAS) data for autism (n = 46,350) with mQTL maps from cord-blood (n = 771), we demonstrate that mQTLs of CpGs associated with SCDC scores at p value thresholds of 0.01 and 0.005 are significantly shifted toward lower p values in the GWAS for autism (p < 5 × 10−3). We provide additional support for this using a GWAS of SCDC, and demonstrate a lack of enrichment in a GWAS of Alzheimer’s disease. Our results highlight the shared cross-tissue methylation architecture of autism and autistic traits, and demonstrate that mQTLs associated with differences in DNA methylation associated with childhood autistic traits are enriched for common genetic variants associated with autism and autistic traits.
Highlights
Autism is a neurodevelopmental condition characterized by social-communication difficulties, unusually restrictive, repetitive behavior and narrow interests, and sensory difficulties [1, 2]
To investigate how comparable an methylome-wide association study (MWAS) of an autistic trait is to other MWAS of autism and related phenotypes conducted across different tissues, we investigated the overlap between the MWAS of Social and Communication Disorders Checklist (SCDC) and other MWAS of autism and communication-related traits in peripheral and post-mortem brain tissues
Integrating genome-wide association study (GWAS) data for autism from 46,350 individuals, we investigated if methylation QTLs (mQTLs) of CpGs associated with SCDC scores at various p value thresholds are significantly shifted toward lower p values in the autism GWAS
Summary
Autism is a neurodevelopmental condition characterized by social-communication difficulties, unusually restrictive, repetitive behavior and narrow interests, and sensory difficulties [1, 2]. The condition can be thought as a continuum, with autistic traits being normally distributed in the general population, and autism at the extreme end of the continuum [3,4,5]. Studies of methylation signatures in post-mortem brains in autism have replicably identified differential methylation [17,18,19,20]. They have demonstrated an enrichment for differentially methylated signatures in the immune system, synaptic signaling, and neuronal regulation [17, 18, 20]. The lack of significant results in peripheral tissues may be attributable to small effect sizes, and significant heterogeneity in both CpG methylation and autism
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