Cross-tissue integration of genetic and epigenetic data offers insight into autism spectrum disorder

Abstract

Integration of emerging epigenetic information with autism spectrum disorder (ASD) genetic results may elucidate functional insights not possible via either type of information in isolation. Here we use the genotype and DNA methylation (DNAm) data from cord blood and peripheral blood to identify SNPs associated with DNA methylation (meQTL lists). Additionally, we use publicly available fetal brain and lung meQTL lists to assess enrichment of ASD GWAS results for tissue-specific meQTLs. ASD-associated SNPs are enriched for fetal brain (OR = 3.55; P < 0.001) and peripheral blood meQTLs (OR = 1.58; P < 0.001). The CpG targets of ASD meQTLs across cord, blood, and brain tissues are enriched for immune-related pathways, consistent with other expression and DNAm results in ASD, and reveal pathways not implicated by genetic findings. This joint analysis of genotype and DNAm demonstrates the potential of both brain and blood-based DNAm for insights into ASD and psychiatric phenotypes more broadly.

Fig. 1

‘Expansion’ of ASD loci through meQTL mapping in peripheral blood, cord blood, and fetal brain. Each tissue-specific panel presents, from bottom to top: genomic location, gene annotations, SNP locations, SNP–CpG associations, CpG locations. Light gray meQTL association lines denote all SNP to CpG associations in that tissue type; Dark meQTL association lines denote SNP–CpG associations for ASD-associated SNPs in PGC (P value < = 1e–04). a Locus at chr8; b Locus at chr19. Data are presented for meQTL maps for fetal brain (top); cord blood meQTLs (middle), and peripheral blood meQTLs (bottom). Please note locus coordinates differ from those in Supplementary Data 6 because in this context they encompass the locations of meQTL target CpG sites

Fig. 2

Enrichment of meQTL target CpG sites in DNaseI hypersensitive sites. We identified the meQTL targets (at FDR 5% in peripheral blood, cord blood and lung, and past 1e–08 P value threshold in fetal brain results) in peripheral blood, cord blood, fetal brain, and lung as well those meQTL targets that were present in the overlap of peripheral blood with the other three tissues. Odds ratio and P value in gray text represent enrichment fold statistic and P value from Fisher’s exact tests examining the tendency of meQTL targets to overlap with DHS sites compared to CpG sites that were not meQTL targets. Odds ratio and P value in black text represent enrichment fold statistic and P value from Fisher’s exact tests examining the tendency of meQTL targets of significant (P value < = 1e–04) SNPs from the PGC cross-disorder results or their proxies (r ² > = 0.8) to overlap with DHS sites compared to CpG sites that were not meQTL targets of the same SNPs. A full list of enrichment statistics and P value for both tests against a total of 181 cell-type-specific DHS sites, cell-type-specific chromatin marks, and transcription factor-binding sites is available in Supplementary Data 7 and 8