The goal of generating the iPSCORE resource was to enable genotype-molecular phenotype correlation studies in iPSCs and iPSC-derived cell types.
The iPSCORE Resource contains 222 iPSC lines that were systematically derived and characterized and are publicly available through
WiCell. iPSCORE lines are pluripotent with high genomic integrity (no or low numbers of somatic CNVs) as determined using high-throughput RNA-seq and genotyping arrays, respectively. Participants were recruited to include 41 families, twins, and individuals of diverse ethnicity to enable genetic studies investigating the segregation of traits. Due to the fact that some of the individuals in the 41 families are only related by marriage, there are a total of 136 genetically unrelated individuals in the collection. Using whole genome sequence data generated from the blood of cardiac disease probands and their families, we examined genetic variation at candidate disease genes and identified four potentially disease-associated variants affecting two families and two singletons. The iPSCORE resource provides a powerful tool to examine how genetic variants influence molecular and physiological traits across a variety of derived cell types, as well as to functionally interrogate variants underlying a variety of GWAS phenotypes.
This CardiPS study, which was funded through the
CIRM, seeks to link cardiac phenotypes to genotypes through the generation of iPSC-derived cardiomyocytes (iPSC-CMs). While most participants in our collection do not have heart disease, there were 25 individuals with arrhythmia (some with multiple types), 13 with cardiomyopathy and one with structural cardiac malformations. We have successfully derived 147 iPSC-CMs and plan to use these samples to identify inherited coding and regulatory variants that influence cardiac molecular phenotypes (gene expression, epigenomic profiles, protein expression). CardiPS may provide insights into the role genetic variants play in the manifestation of cardiovascular disease and adverse drug reactions.
The Frazer lab is also involved in a NIDDK multi-PI study funded to link pancreatic beta cell phenotypes to genotypes through the generation of iPSC-derived pancreatic progenitors. We will derive pancreatic progenitors from 100 human iPSCs in the iPSCORE Resource and generate ATAC-seq, H3K27ac ChIP-seq, RNA-seq, DNA methylation and Hi-C chromatin conformation data, and combine with similar available datasets from human islets. These analyses will provide a comprehensive understanding of how genetic variants alter gene regulation and local chromatin states in islets and their precursors. This study may provide insights into the role genetic variants play in the manifestation of diabetes.
We are also generating epigenomic maps of retinal pigment epithelium (RPE) cells derived from 5 human iPSCs in the iPSCORE resource. We plan to generate ATAC-seq, H3K27ac ChIP-seq, RNA-seq, DNA methylation and Hi-C chromatin conformation data.
Gene Variants and Risk of Venous Thrombosis
In collaboration with Dr. John-Bjarne Hansen at the University of Tromsø (Norway), we are examining genetic risk factors for venous thromboembolism (VTE), a common disease encompassing deep-vein thrombosis and pulmonary embolism. It is potentially fatal, has a high recurrence rate, and serious short- and long-term complications. VTE is a multifactorial disease influenced by environmental exposures (e.g., cancer, immobilization, surgery, and pregnancy); genetic factors (e.g., FV-Leiden mutation); and interactions between genetics and the environment. A family history of VTE is a strong risk factor, but genes currently associated with VTE do not explain the increase in risk. Novel, rare genetic variation may be responsible.
To identify novel variants and genes associated with VTE, we have conducted targeted sequencing and array genotyping in coding genes in a large Norwegian cohort (600 VTE cases and 600 controls) and are evaluating the impact the variation identified on risk of VTE. We have identified genes that show an excess of rare variation in VTE cases and in collaboration with several international groups, are validating our findings. This work has the potential to identify new pathways involved in VTE pathogenesis and suggest novel routes for treatment, prevention, and prediction.
Investigators associated with this research project include:
John-Bjarne Hansen, MD, PhD
Initiated in 2010, this study is led by the University of Tromsø with funds obtained from the University of Tromsø Faculty of Health Sciences, the Northern Norway Regional Health Authority, and the K.G. Jebsen Foundation
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