Scientists have compiled data from induced pluripotent stem cells to link genetic variants to many different diseases.
Researchers have found many genetic variants within the human genome that associate with specific diseases. Not all of these variants are located within protein-coding regions and instead impact gene regulation. Large population-scale gene expression studies have increasingly linked gene expression changes to the regulatory effects of common and rare variants. As a result, scientists are continually attempting to try and find out if, and in which tissues, these variants link to changes in specific gene activity.
Current methods to detect regulatory effects of variants, i.e., those focussed on blood and somatic tissue, are limited by tissue or cell accessibility. Induced pluripotent stem cells (iPSCs) are an established system to study the impact of genetic variants in derived cell types and developmental contexts. Pluripotent cells can also provide unique insights into regulation of gene expression in cell states that mimic early development. However, the regulatory landscape of genetic variation in human pluripotent cells and its relationship with common and rare diseases remains poorly understood.
Data on induced pluripotent stem cells
In this study, published in Nature Genetics, researchers integrated sequence and transcriptome data from 1,367 human iPSC lines to comprehensively map common and rare regulatory variants in human pluripotent cells.
For more than 67% of all genes active in iPSCs, the team found differential expression patterns depending on genetic variants. Many of these associations were novel and not previously described in somatic cell types. They also found for over 4,000 of these associations, that they could link the genetic variants responsible for altered expression to specific diseases. For example, variants associated with coronary heart disease, lipid metabolism disorders, or hereditary cancers.
Further investigation explored whether iPSCs were suitable for identifying the causative genes of rare genetic diseases. The team used iPSC lines from 65 patients with various rare diseases, whose causal gene variants were already known. Using transcriptome data, the researchers searched for outliers in the expression data, leading them to trace the genetic basis of the disease.
Marc Jan Bonder, Postdoctoral Fellow at EMBL, stated:
“Such screenings were previously impossible because there were simply no sufficiently large reference collections of iPSC transcriptomes.
We were surprised to find such a large number of disease-associated genetic variants that are already visible in the expression pattern at the earliest time point of cell differentiation, represented by the iPSCs.”
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