Cord-Blood Based Methylome-Wide Association Study of the Social and Communication Disorders Checklist

Background: Differentially methylated CpGs (DMCs) have been reported in both cortical tissues and in the blood in autistic individuals compared to non-autistic individuals. However, it is unclear if methylation of CpGs in cord blood is associated with scores on the Social and Communication Disorders Checklist (SCDC) – a measure that is phenotypically and genetically correlated with autism.

Objectives: We sought to investigate if: 1. There are significant DMCs that are associated with scores on the SCDC; 2. The SCDC methylome-wide association study (MWAS) is enriched for specific pathways, DMCs identified in the autism post-mortem cortical tissues, and transcriptionally dysregulated genes in the autism post-mortem cortex.

Methods: We conducted a MWAS on parent-reported SCDC scores in 701 8-year-olds from the Avon Longitudinal Study of Parents and Children. Enrichment analyses were conducted using modified hypergeometric tests and two-sided Kolmogorov-Smirnov Tests.

Results: MWAS did not identify any significant CpGs at a significant threshold < 5x10^-8. However, after FDR correction, nominally significant CpG sites (P < 0.05) were enriched in 24 GO processes including neuronal projection and neuron part. Significant DMCs identified in the post-mortem anterior cingulate cortex in autism showed a significant tendency towards low P-values in the SCDC MWAS (P = 7.7x10^-9, two-sided Kolmogorov-Smirnov test). Nominally significant DMCs were replicably enriched for transcriptionally dysregulated genes in the autism post-mortem cortex in two independent samples.

Conclusions: Pathway specific enrichment identify several interesting pathways and propose an involvement of methylation signatures on neuronal pathways. The enrichment of transcriptionally dysregulated autism genes and DMCs in the post-mortem brain suggest an overlap in biological signatures between SCDC and autism.