Novel Insight Into the Etiology of Autism Spectrum Disorder Gained by Integrating Expression Data With Genome-wide Association Statistics

Oliver Pain, Andrew J. Pocklington, Peter A. Holmans, Nicholas J Bray, Heath E. O'Brien, Lynsey S. Hall, Antonio F Pardiñas, Michael C. O'Donovan, Michael J. Owen, Richard Anney

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)


A recent genome-wide association study (GWAS) of autism spectrum disorders (ASD) (Ncases=18,381, Ncontrols=27,969) has provided novel opportunities for investigating the aetiology of ASD. Here, we integrate the ASD GWAS summary statistics with summary-level gene expression data to infer differential gene expression in ASD, an approach called transcriptome-wide association study (TWAS).
Using FUSION software, ASD GWAS summary statistics were integrated with predictors of gene expression from 16 human datasets, including adult and fetal brain. A novel adaptation of established statistical methods was then used to test for enrichment within candidate pathways, specific tissues, and at different stages of brain development. The proportion of ASD heritability explained by predicted expression of genes in the TWAS was estimated using stratified linkage disequilibrium-score regression.
This study identified 14 genes as significantly differentially expressed in ASD, 13 of which were outside of known genome-wide significant loci (±500kb). XRN2, a gene proximal to an ASD GWAS locus, was inferred to be significantly upregulated in ASD, providing insight into functional consequence of this associated locus. One novel transcriptome-wide significant association from this study is the downregulation of PDIA6, which showed minimal evidence of association in the GWAS, and in gene-based analysis using MAGMA. Predicted gene expression in this study accounted for 13.0% of the total ASD SNP-heritability.
This study has implicated several genes as significantly up-/down-regulated in ASD providing novel and useful information for subsequent functional studies. This study also explores the utility of TWAS-based enrichment analysis and compares TWAS results with a functionally agnostic approach.
Original languageEnglish
Pages (from-to)265-273
Number of pages9
JournalBiological psychiatry
Issue number4
Early online date11 May 2019
Publication statusPublished - 15 Aug 2019


  • ASD
  • Autism
  • Colocalization
  • Expression
  • Transcriptome
  • TWAS


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