Genetic Variants Associated with Alzheimer's disease and Related Dementias

National Institute On Aging

Investigators

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Abstract

In this project, we have now generate 200 new induced pluripotent stem cells (IPSCs) from donors whose whole genome sequence is already known. The donors for these lines were largely healthy human donors who represent a breadth of the US population and whose genetic makeup is already known. We confirmed that each line was adequately reprogrammed using multiple measures including pluripotency. Importantly, we also confirmed that each line was genetically identical to the original donor, thus providing us with a resource with which to examine the effects of natural genetic variation in the population to phenotypes of cells in culture. Genetic variation has a widespread influence on epigenetic markers, leading to the identification of abundant methylation quantitative trait loci (methQTL) across the genome. However, methylation is influenced by additional factors, including environmental exposures, cell type and aging. Here, we established a cohort of 100 induced pluripotent stem cells (iPSCs) from diverse and healthy individuals enrolled in the Genetic and Epigenetic Signatures of Translation Aging Laboratory Testing (GESTALT) study to evaluate methQTL in the absence of confounding factors such as age and variable environments. After quality control, we used genome-wide DNA methylation arrays to show that the methylation clock is largely reset to an early methylation age after conversion of peripheral blood mononuclear cells (PBMCs) to iPSCs. Mapping the relationship of genetic variants to CpG methylation in both PBMC and iPSC, we identified many unique methQTL in each cell type. This resource of lines and associated data indicates that methylation is strongly influenced by cell type, independent of aging or environment. We have also taken the same set of lines and differentiated them into microglia and neurons to examine the relationship between genetic variation, gene expression and a second type of epigenetic modification, chromatin accessibility. In these experiments, we used single cell approaches combined with pooling of genetically distinct lines to be able to rapidly generate a large dataset. Current analysis indicates that microglia contain many more genetically defined traits than neurons with specific enrichments for genes linked to age-associated neurodegenerative diseases. This effort parallels similar approaches we have used for Parkinson's disease (PD) where dopamine neurons were the major focus of study.