Landscape of Conditional eQTL in Dorsolateral Prefrontal Cortex and Co-localization with Schizophrenia GWAS

Abstract

Causal genes and variants within genome-wide association study (GWAS) loci can be identified by integrating GWAS statistics with expression quantitative trait loci (eQTL) and determining which variants underlie both GWAS and eQTL signals. Most analyses, however, consider only the marginal eQTL signal, rather than dissect this signal into multiple conditionally independent signals for each gene. Here we show that analyzing conditional eQTL signatures, which could be important under specific cellular or temporal contexts, leads to improved fine mapping of GWAS associations. Using genotypes and gene expression levels from post-mortem human brain samples (n = 467) reported by the CommonMind Consortium (CMC), we find that conditional eQTL are widespread; 63% of genes with primary eQTL also have conditional eQTL. In addition, genomic features associated with conditional eQTL are consistent with context-specific (e.g., tissue-, cell type-, or developmental time point-specific) regulation of gene expression. Integrating the 2014 Psychiatric Genomics Consortium schizophrenia (SCZ) GWAS and CMC primary and conditional eQTL data reveals 40 loci with strong evidence for co-localization (posterior probability > 0.8), including six loci with co-localization of conditional eQTL. Our co-localization analyses support previously reported genes, identify novel genes associated with schizophrenia risk, and provide specific hypotheses for their functional follow-up.

Keywords: GWAS co-localization; complex trait; conditional eQTL; eQTLs; expression quantitative trait loci; fine mapping; gene expression regulation; neuropsychiatric disorder; risk gene; schizophrenia.

Figure 1

Characterization of Conditional eQTL (A) Counts of the numbers of genes (y axis) regulated by at least N (1 ≤ N ≤ 16) independent eQTL (x axis). (B) Median Tau value (y axis) for genes with N independent eQTL (x axis), colored by Tau type (cell type, developmental time point, or tissue type Tau). (C) Density plot representing the distance from eSNP to eGene transcription start site (TSS), colored by eQTL order. Dashed lines represent the median distance to TSS for each order of eQTL.

Figure 2

Enrichments of Primary and Conditional eQTL in Active Regulatory Annotations Plotted are enrichments (regression coefficient estimate ± 95% CI from logistic regression, y axes) of primary (x axis eQTL order = 1) and conditional (eQTL order = 2, ≥ 3) eQTL in functional annotations. (A and B) Enrichment in brain (union of all individual brain regions) and brain-specific (present in brain but not in seven other non-brain tissues) active promoter (green) and enhancer (orange) ChromHMM states from the NIH Roadmap Epigenomics Project. (C) Enrichment in neuronal nuclei (NeuN⁺) for active promoters (intersection of DLPFC H3K4me3 and H3K27ac ChIP-seq peaks, green) and enhancers (H3K27 peaks that do not overlap H3K4me3 peaks, orange). (D) Enrichments in the same annotations, but for DLPFC non-neuronal nuclei (NeuN⁻).

Figure 3

All-but-One Conditional Analysis to Isolate Independent eQTL Signatures (A) Hypothetical GWAS signature (top, green) at a given locus and an overlapping hypothetical eQTL signature (bottom, purple), which comprises two independent eQTL. (B) Same hypothetical GWAS and eQTL signatures after the all-but-one conditional eQTL analysis isolating the primary (red) and secondary (blue) eQTL signatures. Before conditional analysis there is a lack of co-localization between the GWAS signature and eQTL signature. After all-but-one conditional analysis, there is evidence for co-localization between the conditional (secondary) eQTL and GWAS signatures.

Figure 4

GWAS Signature for IREB2 Co-localizes with the Conditional eQTL Signature (A) P-P plots comparing −log₁₀ p values from GWAS (y axes) and all-but-one conditional eQTL analysis (x axes), which show the highest correlation to be between the GWAS and the conditional eQTL rs7171869 (blue, bottom). (B) LocusZoom plots for the IREB2 locus, where the GWAS signal (top) more closely resembles the conditional eQTL signal (rs7171869, bottom) than the primary eQTL signal (rs11639224, third from top) or non-conditional eQTL signal (second from top). For all LocusZoom plots, LD is colored with respect to the GWAS lead SNP (rs8042374, labeled).