Genetic Variations Associated with Brain Diseases Examined

In a study published yesterday in Science, a team of researchers at University of California San Diego School of Medicine and the Salk Institute for Biological Studies used healthy tissue isolated from six patients to isolate four different kinds of brain cells—neurons, microglia, oligodendrocytes, and astrocytes—then looked at genetic variation associated with disease in the non-coding enhancer regions of each cell type, searching for variations that might be linked to disease risk.

Using novel molecular techniques, they were able to further map the connections between enhancer regions and their target genes, providing insights into how variations in enhancer regions can affect downstream gene expression in specific cell types.

"The brain is very complex, with lots of different cell types in different brain regions," said co-first-author Inge Holtman, Ph.D. "Currently, our understanding of the regulatory landscape in the brain is largely unclear. Past research has tried to generate a consensus regulatory landscape of the whole brain, but until now we didn't really know what it looked like in individual cell types. This work gives us a much better understanding of how genes are being regulated, which enhancers are there, and which enhancers are looping back to particular genes and affecting their expression, in particular cell types in the brain."

The findings showed that while many genes are expressed in many different cell types, the enhancer regions differ between cells—and that disease risk is often linked to specific enhancer regions in specific cell types.

Beyond identifying genetic risk variants, the researchers validated their findings using pluripotent human stem cells. By targeting a particular enhancer region close to BIN1, a gene that has previously been linked to Alzheimer’s disease (AD), they found that deleting that enhancer region led to a dramatic reduction in expression of BIN1 in microglia, but not in neurons or astrocytes, indicating that this BIN1-associated risk allele lies within a microglia-specific enhancer region.

"Often, it's hard to know in what cell type particular genes are important because they're expressed in all cell types in the brain," said co-first-author Nicole Coufal, M.D., Ph.D. "In Alzheimer's disease, it was previously assumed that BIN1 was most important in neurons, but this study indicates that it may actually be more important to understand the role of BIN1 in microglia."