Autism-Associated DNA Methylation at Birth From Multiple Tissues Is Enriched for Autism Genes in the Early Autism Risk Longitudinal Investigation.

Kelly M Bakulski,Margaret D Fallin,Andrew P Feinberg,Max T Aung,Craig J Newschaffer,Susan E Levy,Jason I Feinberg,Rebecca Landa,Lisa A Croen,Heather E Volk,John F Dou,Irva Hertz-Picciotto,Christine Ladd-Acosta

doi:10.3389/fnmol.2021.775390

Abstract

Background: Pregnancy measures of DNA methylation, an epigenetic mark, may be associated with autism spectrum disorder (ASD) development in children. Few ASD studies have considered prospective designs with DNA methylation measured in multiple tissues and tested overlap with ASD genetic risk loci.Objectives: To estimate associations between DNA methylation in maternal blood, cord blood, and placenta and later diagnosis of ASD, and to evaluate enrichment of ASD-associated DNA methylation for known ASD-associated genes.Methods: In the Early Autism Risk Longitudinal Investigation (EARLI), an ASD-enriched risk birth cohort, genome-scale maternal blood (early n = 140 and late n = 75 pregnancy), infant cord blood (n = 133), and placenta (maternal n = 106 and fetal n = 107 compartments) DNA methylation was assessed on the Illumina 450k HumanMethylation array and compared to ASD diagnosis at 36 months of age. Differences in site-specific and global methylation were tested with ASD, as well as enrichment of single site associations for ASD risk genes (n = 881) from the Simons Foundation Autism Research Initiative (SFARI) database.Results: No individual DNA methylation site was associated with ASD at genome-wide significance, however, individual DNA methylation sites nominally associated with ASD (P < 0.05) in each tissue were highly enriched for SFARI genes (cord blood P = 7.9 × 10–29, maternal blood early pregnancy P = 6.1 × 10–27, maternal blood late pregnancy P = 2.8 × 10–16, maternal placenta P = 5.6 × 10–15, fetal placenta P = 1.3 × 10–20). DNA methylation sites nominally associated with ASD across all five tissues overlapped at 144 (29.5%) SFARI genes.Conclusion: DNA methylation sites nominally associated with later ASD diagnosis in multiple tissues were enriched for ASD risk genes. Our multi-tissue study demonstrates the utility of examining DNA methylation prior to ASD diagnosis.

Highlights

Pregnancy measures of DNA methylation, an epigenetic mark, may be associated with autism spectrum disorder (ASD) development in children
After probe and sample filtering, 455,723 cytosine guanine dinucleotide (CpG) sites remained in analysis for 133 cord blood samples, 143 early pregnancy maternal blood samples, 78 late pregnancy maternal blood samples, 101 fetal side placenta samples, and 101 maternal side placenta samples
We identified 215 single CpG sites associated with ASD diagnosis at a P < 0.001, and 17 reached P-value < 1 × 10−4 (Table 2)

Summary

Introduction

Pregnancy measures of DNA methylation, an epigenetic mark, may be associated with autism spectrum disorder (ASD) development in children. Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder estimated to affect one in 54 US children by age 8 years (Maenner et al, 2020). ASD symptomology at 36-months may be improved with intervention during the first year of life (Rogers et al, 2014), and some preschoolers with intervention display reduced ASD outcomes (National Research Council, 2001). Participation in these intervention programs depends on early diagnosis, which is often difficult (Chawarska et al, 2014). Identifying early biomarkers for those at enriched risk of ASD is an important area of research

Objectives

Methods

Results

Discussion

Conclusion