CIRCUITS: Production Center for Reference and Variation Gene-Regulatory Maps

2019

Alzheimer’s disease is a devastating neurodegenerative disorder affecting 1 in 3 dying seniors and costing $236 billion annually in the United States alone. Its prevalence is increasing rapidly in an aging population, and there currently is no cure. Recent genetic studies provide new hope for therapeutic avenues, but translating genetic results into therapeutics has been remarkably difficult, due primarily to the fact that most genetic mutations do not alter protein function directly, but instead affect the expression of nearby genes in subtle ways.

Here, we seek to overcome this limitation by directly profiling changes in the circuitry of neurons and other brain cell types during Alzheimer’s disease, and how genetic variants are affecting that circuitry. In our initial efforts, we generated thousands of transcriptional and epigenomic maps of gene expression and control region activity by profiling post-mortem brains and in vitro differentiated brain cells from induced pluripotent cells across individuals at the tissue level, cell-type level and single-cell level.

We integrate the resulting datasets to decipher the mechanistic basis of genetic variants associated with disease, and to discover new therapeutic targets, and the pathways and cell types where they act. The resulting datasets and predictions will be disseminated broadly to the scientific community, and form the foundation for computational and experimental work by the broader Cure Alzheimer’s Fund CIRCUITS Consortium, in order to translate our datasets and predictions into mechanistic insights and new therapeutic avenues for Alzheimer’s disease.

2016

Alzheimer’s disease is a devastating neurodegenerative disorder, afflicting 1 in 3 dying seniors and costing $236 billion annually in the United States alone. Its prevalence is increasing rapidly in an aging population, and currently there is no cure. Recent genetic studies provide new hope for therapeutic avenues, but translating genetic results into therapeutics has been remarkably difficult, due primarily to the fact that most genetic mutations do not alter protein function directly, but instead affect the expression of nearby genes in subtle ways.

Here, we seek to overcome this limitation by directly profiling the gene-regulatory differences in Alzheimer’s patients, to understand the cell types, regulatory regions, target genes and upstream regulators whose function is affected in disease. We profile epigenomic differences in Alzheimer’s disease across 600 individuals, we dissect the cell-type-specific action of these differences in neurons, astrocytes and microglial cells, and we map the detailed circuitry of brain regulatory regions across Alzheimer’s patients and controls. The resulting datasets will be released broadly to the scientific community, and also form the foundation for computational and experimental work by the Cure Alzheimer’s Fund’s CIRCUITS consortium, in order to translate the resulting datasets into mechanistic insights and new therapeutic avenues for Alzheimer’s.