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Colocalization of GWAS and molecular QTL signals in human vascular smooth muscle cells predict candidate causal genes for coronary artery disease and vascular disorders

ABSTRACT: Coronary artery disease (CAD) is the leading cause of death worldwide. A recent meta-analysis of genome-wide association studies (GWAS) identified 175 loci associated with CAD. The majority of these loci are in non-coding regions and are predicted to regulate gene expression. We hypothesized that a subset of the CAD GWAS loci was associated with the regulation of transcription in vascular smooth muscle cells (SMCs), which play critical roles in the development of CAD. We measured gene expression in SMCs isolated from the ascending aortas of 151 ethnically diverse heart transplant donors in quiescent or proliferative conditions and calculated the association of their expression and splicing with ~6.3 million imputed single nucleotide polymorphism (SNP) markers across the genome. We identified 4,910 expression and 4,412 splice quantitative trait loci (sQTL) that represent regions of the genome associated with transcript abundance and splicing. 3,660 of the expression quantitative trait loci (eQTL) had not been observed in the publicly available Genotype-Tissue Expression dataset. Further, 29 and 880 of the eQTLs were SMC- and sex-specific, respectively. To identify the effector transcripts regulated by the CAD GWAS loci, we used four distinct colocalization approaches and identified 84 eQTL and 164 sQTLs that colocalized with CAD loci, suggesting a more significant role for the genetic regulation of mRNA splicing as a molecular mechanism for CAD genetic risk. 20% and 35% of the eQTLs were unique to quiescent or proliferative SMCs, respectively. Two of the CAD loci colocolized with SMC eQTL showed sex-specific (AL160313.1 and TERF2IP) and one of the loci colocalized with SMC-specific eQTLs (ALKBH8). 27% and 37% of the sQTLs were unique to quiescent or proliferative SMCs, respectively. The most significantly associated CAD locus, 9p21, was an sQTL for the long non-coding RNA CDKN2B-AS1, also known as ANRIL, in proliferative SMCs. Collectively, these results provide evidence for the molecular mechanisms of genetic susceptibility to CAD in vascular smooth muscle cells.'

ORGANISM(S): Homo sapiens

PROVIDER: GSE198544 | GEO | 2022/10/03

REPOSITORIES: GEO

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Project description:Coronary artery disease (CAD) is the leading cause of death worldwide. A recent meta-analysis of genome-wide association studies (GWAS) identified 175 loci associated with CAD. The majority of these loci are in non-coding regions and are predicted to regulate gene expression. We hypothesized that a subset of the CAD GWAS loci was associated with the regulation of transcription in vascular smooth muscle cells (SMCs), which play critical roles in the development of CAD. We measured gene expression in SMCs isolated from the ascending aortas of 151 ethnically diverse heart transplant donors in quiescent or proliferative conditions and calculated the association of their expression and splicing with ~6.3 million imputed single nucleotide polymorphism (SNP) markers across the genome. We identified 4,910 expression and 4,412 splice quantitative trait loci (sQTL) that represent regions of the genome associated with transcript abundance and splicing. 3,660 of the expression quantitative trait loci (eQTL) had not been observed in the publicly available Genotype-Tissue Expression dataset. Further, 29 and 880 of the eQTLs were SMC- and sex-specific, respectively. To identify the effector transcripts regulated by the CAD GWAS loci, we used four distinct colocalization approaches and identified 84 eQTL and 164 sQTLs that colocalized with CAD loci, suggesting a more significant role for the genetic regulation of mRNA splicing as a molecular mechanism for CAD genetic risk. 20% and 35% of the eQTLs were unique to quiescent or proliferative SMCs, respectively. Two of the CAD loci colocolized with SMC eQTL showed sex-specific (AL160313.1 and TERF2IP) and one of the loci colocalized with SMC-specific eQTLs (ALKBH8). 27% and 37% of the sQTLs were unique to quiescent or proliferative SMCs, respectively. The most significantly associated CAD locus, 9p21, was an sQTL for the long non-coding RNA CDKN2B-AS1, also known as ANRIL, in proliferative SMCs. Collectively, these results provide evidence for the molecular mechanisms of genetic susceptibility to CAD in vascular smooth muscle cells.'

Project description:Genome-wide association studies (GWASs) have revealed thousands of associations in many complex traits and diseases. Previous studies suggest that a subset of associations are due to alterations in splicing; however, interpreting the effects of splicing on protein isoforms is hindered by limitations in defining full-length transcript isoforms using short-read RNA-seq data. Long-read RNA-seq represents a powerful approach to define and quantify transcript isoforms. In this study, we developed a novel approach that integrates information from GWAS, splicing QTL (sQTL), and PacBio long-read RNA-seq in a disease relevant model to infer the effects of sQTL on the ultimate protein isoform products they encode. Such information enables identification of genes potentially responsible for GWAS associations. As a proof-of-concept, we generated deep coverage (N=~22 million full-length reads) PacBio long-read RNAseq data on human fetal osteoblasts (hFOBs), a cell-line of relevance to the regulation of bone mineral density (BMD). We identified 68,326 protein-coding isoforms, including 17,375 (25%) which were novel. Next, we used Bayesian colocalization to identify 1,863 sQTLs from the Genotype-Tissue Expression (GTEx) project in 732 protein-coding genes which colocalized with BMD associations (H4PP > 0.75). A total of 836 junctions with colocalizing sQTLs in 459 (of the 732) genes were expressed in hFOB long-read RNA-seq data. With these data, we formulated hypotheses regarding the potential mechanism of action of each sQTL. For example, we identified 7 junctions with colocalizing sQTLs (maximum H4PP = 0.98-0.99) in TPM2 for splice junctions between two nearly mutually exclusive exons, and two different transcript termination sites, making it impossible to interpret without long-read RNA-seq data. siRNA mediated knockdown in hFOBs showed two TPM2 isoforms with opposing effects on mineralization. Our results suggest that splicing is a major mechanism underlying GWAS associations and long-read proteogenomics data is critical to precisely define the protein isoforms that are produced from splicing alterations.

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Colocalization of GWAS and molecular QTL signals in human vascular smooth muscle cells predict candidate causal genes for coronary artery disease and vascular disorders

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