Genetic Variants Associated with Alzheimer's disease and Related Dementias

National Institute On Aging

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Abstract

In this project, we plan to generate 200 new induced pluripotent stem cells (IPSCs) from donors whose whole genome sequence is already known. Due to the scale of this project, we have started to introduce laboratory automation in order to be able to handle and maintain a large number of cell lines. We have also identified donors from appropriate clinical sources and started to generate IPSC lines. We will test that the produced lines have the same genetic background as the original donors in the next few months to guard against sample mixups and genetic drift in the lines due to, for example, selection for cells that might have acquired oncogenic mutations. We have generated all planned IPSC cell lines, confirmed identity and were able to show that the cells were fully epigenetically reprogrammed. By comparing DNA methylation with donor cells were could show that age-associated DNA methylation was reset to a naive state, which we will follow up by evaluating methylation as a quantitative trait in the absence of such non-genetic variants. Furthermore, we demonstrated the ability of these cells to be differentiated into both neurons and microglia that we were able to show transcriptionally matched human brain cell types. Having this resource, we have analyzed the correlational relationships between genetic variation, chromatin accessibility and gene expression. We have found so far that microglia have more genetically determined quantitative traits than neurons. Additionally, we have confirmed recently published associations seen in microglia using this independent series. Future work will evaluate how inflammatory signaling modifies expression quantitative traits.