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Blood cell traits' GWAS loci colocalization with variation in PU.1 genomic occupancy prioritizes causal noncoding regulatory variants.

ABSTRACT: Genome-wide association studies (GWASs) have uncovered numerous trait-associated loci across the human genome, most of which are located in noncoding regions, making interpretation difficult. Moreover, causal variants are hard to statistically fine-map at many loci because of widespread linkage disequilibrium. To address this challenge, we present a strategy utilizing transcription factor (TF) binding quantitative trait loci (bQTLs) for colocalization analysis to identify trait associations likely mediated by TF occupancy variation and to pinpoint likely causal variants using motif scores. We applied this approach to PU.1 bQTLs in lymphoblastoid cell lines and blood cell trait GWAS data. Colocalization analysis revealed 69 blood cell trait GWAS loci putatively driven by PU.1 occupancy variation. We nominate PU.1 motif-altering variants as the likely shared causal variants at 51 loci. Such integration of TF bQTL data with other GWAS data may reveal transcriptional regulatory mechanisms and causal noncoding variants underlying additional complex traits.

SUBMITTER: Jeong R

PROVIDER: S-EPMC10363807 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Blood cell traits' GWAS loci colocalization with variation in PU.1 genomic occupancy prioritizes causal noncoding regulatory variants.

Jeong Raehoon R Bulyk Martha L ML

Cell genomics 20230517 7

Genome-wide association studies (GWASs) have uncovered numerous trait-associated loci across the human genome, most of which are located in noncoding regions, making interpretation difficult. Moreover, causal variants are hard to statistically fine-map at many loci because of widespread linkage disequilibrium. To address this challenge, we present a strategy utilizing transcription factor (TF) binding quantitative trait loci (bQTLs) for colocalization analysis to identify trait associations like ...[more]

PMID: 37492098

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Project description:Background: Genome-wide association studies (GWAS) for corneal resistance factor (CRF) have identified 100s of loci and proved useful to uncover genetic determinants for keratoconus, a corneal ectasia of early-adulthood onset and common indication of corneal transplantation. In the current absence of studies to probe the impact of candidate causal variants in the cornea, we aimed to fill some of this knowledge gap by leveraging tissue-shared genetic effects. Methods: 181 CRF signals were examined for evidence of colocalization with genetic signals affecting steady-state gene transcription and splicing in adult, non-eye, tissues of the Genotype-Tissue Expression (GTEx) project. Expression of candidate causal genes thus nominated was evaluated in single cell transcriptomes from adult cornea, limbus and conjunctiva. Fine-mapping and colocalization of CRF and keratoconus GWAS signals was also deployed to support their sharing causal variants. Results and discussion: 26.5% of CRF causal signals colocalized with GTEx v8 signals and nominated genes enriched in genes with high and specific expression in corneal stromal cells amongst tissues examined. Enrichment analyses carried out with nearest genes to all 181 CRF GWAS signals indicated that stromal cells of the limbus could be susceptible to signals that did not colocalize with GTEx's. These cells might not be well represented in GTEx and/or the genetic associations might have context specific effects. The causal signals shared with GTEx provide new insights into mediation of CRF genetic effects, including modulation of splicing events. Functionally relevant roles for several implicated genes' products in providing tensile strength, mechano-sensing and signaling make the corresponding genes and regulatory variants prime candidates to be validated and their roles and effects across tissues elucidated. Colocalization of CRF and keratoconus GWAS signals strengthened support for shared causal variants but also highlighted many ways into which likely true shared signals could be missed when using readily available GWAS summary statistics.

Dataset Information

Blood cell traits' GWAS loci colocalization with variation in PU.1 genomic occupancy prioritizes causal noncoding regulatory variants.

Publications

Blood cell traits' GWAS loci colocalization with variation in PU.1 genomic occupancy prioritizes causal noncoding regulatory variants.

Similar Datasets

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