PT - JOURNAL ARTICLE AU - Charles E. Mordaunt AU - Bo Y. Park AU - Kelly M. Bakulski AU - Jason I. Feinberg AU - Lisa A. Croen AU - Christine Ladd-Acosta AU - Craig J. Newschaffer AU - Heather E. Volk AU - Sally Ozonoff AU - Irva Hertz-Picciotto AU - Janine M. LaSalle AU - Rebecca J. Schmidt AU - M. Daniele Fallin TI - A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood AID - 10.1101/486498 DP - 2018 Jan 01 TA - bioRxiv PG - 486498 4099 - http://biorxiv.org/content/early/2018/12/05/486498.short 4100 - http://biorxiv.org/content/early/2018/12/05/486498.full AB - Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1% of children in the United States. ASD risk is thought to arise from a combination of genetic and environmental factors, with the perinatal period as a critical window. Understanding early transcriptional changes in ASD would assist in clarifying disease pathogenesis and identifying biomarkers and treatments. However, little is known about umbilical cord blood gene expression profiles in babies later diagnosed with ASD compared to non-typically developing (Non-TD) or neurotypical children.Methods Genome-wide transcript levels were measured by Affymetrix Human Gene 2.0 array in RNA from umbilical cord blood samples from both the Markers of Autism Risk in Babies--Learning Early Signs (MARBLES) and the Early Autism Risk Longitudinal Investigation (EARLI) high-risk pregnancy cohorts that enroll younger siblings of a child previously diagnosed with ASD. An algorithm-based diagnosis from 36 month assessments categorized the younger sibling as either ASD, typically developing (TD), or not ASD but non-typically developing (Non-TD). 59 ASD, 92 Non-TD, and 120 TD subjects were included and differences were identified in ASD versus TD subjects, with Non-TD versus TD as a specificity control. Meta-analysis was used to combine the results from both studies. Functional enrichments of differentially-expressed genes were examined across diagnostic groups.Results While cord blood gene expression differences comparing either ASD or Non-TD to TD did not reach genome-wide significance when adjusting for multiple comparisons, 172 genes were nominally differentially-expressed between ASD and TD cord blood (log2(fold change) > 0.1, p < 0.01). These genes were significantly enriched for toxic substance response and xenobiotic metabolism functions, and gene sets involved in chromatin regulation and systemic lupus erythematosus were significantly upregulated (FDR q < 0.05). In contrast, 66 genes were differentially-expressed between Non-TD and TD cord blood, including only 8 genes that were also differentially-expressed in ASD.Conclusions This is the first study to identify perinatal gene expression differences in umbilical cord blood specific to ASD. The results of this meta-analysis across two prospective ASD cohorts support involvement of environmental, immune, and epigenetic mechanisms in ASD etiology.(ADI-R)Autism Diagnostic Interview-Revised(ADOS)Autism Diagnostic Observation Schedule(ASD)autism spectrum disorder(EARLI)Early Autism Risk Longitudinal Investigation(FDR)false discovery rate(GSEA)gene set enrichment analysis(GPCRs)G-protein coupled receptors(HDAC)histone deacetylase(MARBLES)Markers of Autism Risk in Babies - Learning Early Signs(MSEL)Mullen Scales of Early Learning(NK cells)natural killer cells(Non-TD)non-typically developing(NES)normalized enrichment score(PRC2)polycomb-repressive complex 2(RMA)robust multi-chip average(SFARI)Simons Foundation Autism Research Initiative(SVA)surrogate variable analysis(SLE)systemic lupus erythematosus(TAS2R)taste 2 receptor(TD)typically developing(UC)University of California