Systems genetics in human endothelial cells identifies non-coding variants modifying enhancers, expression, and complex disease traits
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PROVIDER: PRJNA643307 | ENA |
REPOSITORIES: ENA
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Project description:Systems genetics in human endothelial cells identifies non-coding variants modifying enhancers, expression, and complex disease traits
| PRJNA643308 | ENA
Project description:The identification of causal variants and mechanisms underlying complex disease traits in humans is important for the progress of human disease genetics; this requires finding strategies to detect functional regulatory variants in disease-relevant cell types. To achieve this, we collected genetic and transcriptomic data from the aortic endothelial cells of up to 157 donors and four epigenomic phenotypes in up to 44 human donors representing individuals of both sexes and three major ancestries. We found thousands of expression quantitative trait loci (eQTLs) at all ranges of effect sizes not detected by the Gene-Tissue Expression Project (GTEx) in human tissues, showing that novel biological relationships unique to endothelial cells (ECs) are enriched in this dataset. Epigenetic profiling enabled discovery of over 3,000 regulatory elements whose activity is modulated by genetic variants that most frequently mutated ETS, AP-1, and NF-kB binding motifs, implicating these motifs as governors of EC regulation. Using CRISPR interference (CRISPRi), allele-specific reporter assays, and chromatin conformation capture, we validated candidate enhancer variants located up to 750 kb from their target genes, VEGFC, FGD6, and KIF26B. Regulatory SNPs identified were enriched in coronary artery disease (CAD) loci, and this result has specific implications for PECAM-1, FES, and AXL. We also found significant roles for EC regulatory variants in modifying the traits pulse pressure, blood protein levels, and monocyte count. Lastly, we present two unlinked SNPs in the promoter of MFAP2 that exhibit pleiotropic effects on human disease traits. Together, this supports the possibility that genetic predisposition for complex disease is manifested through the endothelium.
| S-EPMC7273528 | biostudies-literature
Project description:The evolution of maize yields under drought is of particular concern in the context of climate change and human population growth. To better understand the mechanisms associated with the genetic polymorphisms underlying the variations of traits related to drought tolerance, we used a systems genetics approach integrating high-throughput phenotypic, proteomics and genomics data acquired on 254 maize hybrids grown under two watering conditions. We show that the genetic architecture of protein abundances depends on protein function and that water deficit strongly remodeled the proteome and induced a reprogramming of the genetic control of the abundances of proteins involved in drought and stress response. These findings bring several lines of evidence supporting candidate genes at many loci and provide novel insight into the molecular mechanisms of drought tolerance.
2020-06-16 | MSV000085594 | MassIVE
Project description:Brisbane Systems Genetics Study comprises of a total of 862 individuals from 374 families. Families consist of combinations of both MZ and DZ twin pairs, their siblings and for 72 families their parents.
2013-12-11 | GSE53195 | GEO
Project description:The directed differentiation of pluripotent stem cells (PSCs) from panels of genetically diverse individuals is emerging as a powerful experimental system for understanding genotype-phenotype relationships and modeling polygenic traits and disorders. Here, we establish a genetic reference panel of naïve and primed PSCs (n = 250) from the Diversity Outbred (DO) mouse stock to enable high resolution quantitative trait locus mapping of molecular phenotypes in developing cellular systems. These data, methods, and cellular resources provide a roadmap for population-scale studies to dissect the genetic basis of complex traits that will complement and empower similar studies in human populations.
2024-07-21 | GSE272490 | GEO
Project description:Systems genetics of sleep regulation
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Project description:We used a systems genetics approach in the BXD genetic reference population of mice and assembled a comprehensive experimental knowledge base comprising a deep ‘sleep-wake’ phenome, central and peripheral transcriptomes, and plasma metabolome data, collected under undisturbed baseline conditions and after sleep deprivation.
2018-06-26 | GSE114845 | GEO
Project description:Brisbane Systems Genetics Study comprises of a total of 862 individuals from 374 families. Families consist of combinations of both MZ and DZ twin pairs, their siblings and for 72 families their parents. Whole blood for expression profiling was collected directly into PAXgene tubes and total RNA was extracted using the WB gene RNA purification kit. RNA from all samples was run on an Agilent Bioanalyzer to assess quality.
2013-12-11 | E-GEOD-53195 | biostudies-arrayexpress
Project description:Seed quality traits of oilseed rape, Brassica napus (B. napus), exhibit quantitative inheritance determined by its genetic makeup and the environment via the mediation of a complex genetic architecture of hundreds to thousands of genes. Thus, instead of single gene analysis, network-based systems genomics and genetics approaches that combine genotype, phenotype, and molecular phenotypes offer a promising alternative to uncover this complex genetic architecture. In the current study, systems genetics approaches were used to explore the genetic regulation of lignin traits in B. napus seeds. Four QTL (qLignin_A09_1, qLignin_A09_2, qLignin_A09_3, and qLignin_C08) distributed on two chromosomes were identified for lignin content. The qLignin_A09_2 and qLignin_C08 loci were homologous QTL from the A and C subgenomes, respectively. Genome-wide gene regulatory network analysis identified eighty-three subnetworks (or modules); and three modules with 910 genes in total, were associated with lignin content, which was confirmed by network QTL analysis. eQTL (expression quantitative trait loci) analysis revealed four cis-eQTL genes including lignin and flavonoid pathway genes, cinnamoyl-CoA-reductase (CCR1), and TRANSPARENT TESTA genes TT4, TT6, TT8, as causal genes. The findings validated the power of systems genetics to identify causal regulatory networks and genes underlying complex traits. Moreover, this information may enable the research community to explore new breeding strategies, such as network selection or gene engineering, to rewire networks to develop climate resilience crops with better seed quality.
2024-06-04 | GSE268725 | GEO
Project description:Determining the genetic architecture of complex traits is challenging because phenotypic variation arises from interactions between multiple, environmentally sensitive alleles. We quantified genome-wide transcript abundance and phenotypes for six ecologically relevant traits in D. melanogaster wild-derived inbred lines. We observed 10,096 genetically variable transcripts and high heritabilities for all organismal phenotypes. The transcriptome is highly genetically intercorrelated, forming 241 transcriptional modules. Modules are enriched for transcripts in common pathways, gene ontology categories, tissue-specific expression and transcription factor binding sites. The high degree of transcriptional connectivity allows us to infer genetic networks and the function of predicted genes from annotations of other genes in the network. Regressions of organismal phenotypes on transcript abundance implicate several hundred candidate genes that form modules of biologically meaningful correlated transcripts affecting each phenotype. Overlapping transcripts in modules associated with different traits provide insight into the molecular basis of pleiotropy between complex traits.
| S-EPMC2752214 | biostudies-literature