Multiple causal variants underlie genetic associations in humans
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ABSTRACT:
ORGANISM(S): synthetic construct Homo sapiens
PROVIDER: GSE174534 | GEO | 2021/05/24
REPOSITORIES: GEO
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Project description:We performed a massively parallel reporter assay on 2,396 genomic regions containing single nucleotide polymorphisms that are in high linkage disequilibrium with 97 lead variants from an obesity GWAS (PMID: 25673413). Regions were transfected into human SGBS preadipocytes, SGBS mature adipocytes, 3T3-L1 preadipocytes, HT22 hippocampal cells, and GT1-7 cells and assessed for enhancer activity. The processed file contains the MPRA barcodes.
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Project description:Genome-wide association studies (GWAS) have successfully identified 145 genomic regions that contribute to schizophrenia risk, but linkage disequilibrium (LD) makes it challenging to discern causal variants. Computational finemapping prioritized thousands of credible variants, ~98% of which lie within poorly characterized non-coding regions. To functionally validate their regulatory effects, we performed a massively parallel reporter assay (MPRA) on 5,173 finemapped schizophrenia GWAS variants in primary human neural progenitors (HNPs). We identified 440 variants with allelic regulatory effects (MPRA-positive variants), with 72% of GWAS loci containing at least one MPRA-positive variant. Transcription factor binding had modest predictive power for predicting the allelic activity of MPRA-positive variants, while GWAS association, finemap posterior probability, enhancer overlap, and evolutionary conservation failed to predict MPRA-positive variants. Furthermore, 64% of MPRA-positive variants did not exhibit eQTL signature, suggesting that MPRA could identify yet unexplored variants with regulatory potentials. MPRA-positive variants differed from eQTLs, as they were more frequently located in distal neuronal enhancers. Therefore, we leveraged neuronal 3D chromatin architecture to identify 273 genes that physically interact with MPRA-positive variants. These genes annotated by chromatin interactome displayed higher mutational constraints and regulatory complexity than genes annotated by eQTLs, recapitulating a recent finding that eQTL- and GWAS-detected variants map to genes with different properties. Finally, we propose a model in which allelic activity of multiple variants within a GWAS locus can be aggregated to predict gene expression by taking chromatin contact frequency and accessibility into account. In conclusion, we demonstrate that MPRA can effectively identify functional regulatory variants and delineate previously unknown regulatory principles of schizophrenia.
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Project description:Multiple causal variants underlie genetic associations in humans
| PRJNA730497 | ENA
Project description:Genetic variants that impact gene regulation are important contributors to human phenotypic variation. For this reason, considerable efforts have been made to identify genetic associations with differences in mRNA levels of nearby genes, namely, cis expression quantitative trait loci (eQTLs). The phenotypic consequences of eQTLs are presumably due, in most cases, to their ultimate effects on protein expression levels. Yet, only few studies have quantified the impact of genetic variation on proteins levels directly. It remains unclear how faithfully eQTLs are reflected at the protein level, and whether there is a significant layer of cis regulatory variation acting primarily on translation or steady state protein levels. To address these questions, we measured ribosome occupancy by high-throughput sequencing, and relative protein levels by high-resolution quantitative mass spectrometry, in a panel of lymphoblastoid cell lines (LCLs) in which we had previously measured transcript expression using RNA sequencing. We then mapped genetic variants that are associated with changes in transcript expression (eQTLs), ribosome occupancy (rQTLs), or protein abundance (pQTLs). Most of the QTLs we detected are associated with transcript expression levels, with consequent effects on ribosome and protein levels. However, we found that eQTLs tend to have significantly reduced effect sizes on protein levels, suggesting that their potential impact on downstream phenotypes is often attenuated or buffered. Additionally, we confirmed the presence of a class of cis QTLs that specifically affect protein abundance with little or no effect on mRNA levels; most of these QTLs have little effect on ribosome occupancy, and hence may arise from differences in post-translational regulation.
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Project description:We designed a massively parallel reporter assay (MPRA) in an Epstein-Barr virus transformed B cell line to directly characterize the potential for histone post-translational modifications, i.e., histone quantitative trait loci (hQTLs), expression QTLs (eQTLs), and variants on SLE and autoimmune (AI) disease risk haplotypes to modulate regulatory activity in an allele dependent manner. Our study demonstrates that hQTLs, as a group, are more likely to modulate regulatory activity in an MPRA compared to other variant classes tested, including a set of eQTLs previously shown to interact with hQTLs and tested AI risk variants. In addition, we nominate 17 variants (including 11 previously unreported) as putative causal variants for SLE and another 14 for various other AI diseases, prioritizing these variants for future functional studies primary and immortalized B cells. Thus, we uncover important insights into the mechanistic relationships between genotype, epigenetics, and gene expression in SLE and AI disease phenotypes.
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Project description:30 B-lymphoblastoid cell lines (LCLs) with genome-wide genotype data were treated with hydrocortisone (GR agonist) and CORT108297 (GR modulator), followed by RNA-seq to identify PGx-eQTLs. We then integrated GR chromatin immunoprecipitation-sequencing (ChIP-seq) to characterize the epigenetic function of PGx-eQTLs that interfere with GR response elements. We also applied a high-throughput enhancer assay (STARR-seq) using PGx-eQTL loci DNA sequences to “scan” for drug-dependent SNPs.
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Project description:30 B-lymphoblastoid cell lines (LCLs) with genome-wide genotype data were treated with hydrocortisone (GR agonist) and CORT108297 (GR modulator), followed by RNA-seq to identify PGx-eQTLs. We then integrated GR chromatin immunoprecipitation-sequencing (ChIP-seq) to characterize the epigenetic function of PGx-eQTLs that interfere with GR response elements. We also applied a high-throughput enhancer assay (STARR-seq) using PGx-eQTL loci DNA sequences to “scan” for drug-dependent SNPs.
2022-11-16 | GSE185928 | GEO
Project description:30 B-lymphoblastoid cell lines (LCLs) with genome-wide genotype data were treated with hydrocortisone (GR agonist) and CORT108297 (GR modulator), followed by RNA-seq to identify PGx-eQTLs. We then integrated GR chromatin immunoprecipitation-sequencing (ChIP-seq) to characterize the epigenetic function of PGx-eQTLs that interfere with GR response elements. We also applied a high-throughput enhancer assay (STARR-seq) using PGx-eQTL loci DNA sequences to “scan” for drug-dependent SNPs.
2022-11-16 | GSE185908 | GEO
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.'
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