Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood.

Estimated correlation of genetic effects of cis-eQTLs between tissues. We estimated rb between brain regions, between brain and blood tissues, and between data sets. The top-associated cis-eQTLs (one for each gene) were selected from GTEx-muscle at PeQTL < 5 × 10−8. Shown in each cell is the estimate of rb with its standard error given in the parentheses (Methods). In the Braineac data, the eQTLs effect sizes were estimated from gene expression levels averaged across 10 brain regions

Enrichment of tissue-specific cis-eQTLs in functional annotations. a The distribution of cis-eQTLs across 14 functional categories derived from RMEC (Methods). b Estimated enrichment of TD (testing for the difference in cis-eQTL effect between CMC-brain and GTEx-blood) in each functional category (Methods). Error bars represent 95% confidence intervals around the estimates. The black dash line represents fold enrichment of 1. Different colors in a and b correspond to 14 functional categories: TssA: active transcription start site, Prom: upstream/downstream TSS promoter, Tx: actively transcribed state, TxWk: weak transcription, TxEn: transcribed and regulatory Prom/Enh, EnhA: active enhancer, EnhW: weak enhancer, DNase: primary DNase, ZNF/Rpts: state associated with zinc finger protein genes, Het: constitutive heterochromatin, PromP: poised promoter, PromBiv: bivalent regulatory states, ReprPC: repressed Polycomb states, and Quies: a quiescent state

Correlation of difference in cis-eQTL effect and difference in expression level. Each dot represents one of the 3569 genes between GTEx-cerebellum and GTEx-blood. The 3569 genes were ascertained with at least one cis-eQTL with PeQTL < 5 × 10−8 in GTEx-muscle and expressed in GTEx-cerebellum and GTEx-blood (i.e. genes which have at least 10 samples with RPKM >0.1 and raw read counts >6). In this analysis, we used cis-eQTL effects in SD units and gene expression levels in log2(RPKM) units to avoid confounding of the correlation by the mean–variance relationship in gene expression

Similarity and difference in cis-mQTL effects between brain and blood. a Estimated rb for cis-mQTLs between brain and blood from four independent data sets. The cis-mQTLs (one for each DNAm probe) were selected at PmQTL < 1 × 10−10 using data from the Hannon et al. study. Shown in each cell is the estimate of rb with its standard error given in the parentheses (Methods). b The distribution of cis-mQTLs across 14 functional categories derived from RMEC (Methods). c Estimated enrichment of TD (testing for the difference in cis-mQTL effect between Jaffe-brain and LBC-blood) in each functional category (Methods). Error bars represent 95% confidence intervals around the estimates. The black dash line represents the fold enrichment of 1

Identification of genes and DNAm sites associated with four brain-related traits. Genes (DNAm sites) associated with the brain-related traits were identified by a SMR analysis of GWAS data with eQTL (mQTL) data from brain and blood samples. The four brain-related traits are smoking, IQ, SCZ, and EduYears. a, c show the number of genes (DNAm sites) with at least one significant SNP at P < 5 × 10−8 in different data sets. b, d show the number of genes (DNAm sites) associated with traits identified in different data sets. Sample sizes of the brain studies: GTEx-brain (n = ~233), CMC (n = 467), ROSMAP (n = 494), Brain-eMeta (neff = ~1194), and Jaffe et al. (n = 526). Sample sizes of the blood studies: CAGE (n = 2765), eQTLGen (n = 14,115), LBC + BSGS (n = 1980)