Genetic variation in individual brain cell types may predict disease risk

November 14, 2019

One might think that the primary cause of most genetically linked diseases comes from mutations in coding DNA -- alterations in coding regions of the genome that can lead directly to changes in the expression of particular proteins important for a healthy body. But the majority of human DNA is non-coding DNA -- regions of DNA that do not directly translate into functional proteins. These non-coding DNA regions contain functional elements, called enhancers, which can change the likelihood of a particular protein to be made.

Researchers are now finding particular genetic variations in some of these non-coding regulatory regions, called enhancers, determine whether or not proteins are expressed in specific cell types in the brain and may play a role in a person's risk of developing psychiatric or neurological conditions.

In a new study published November, 14, 2019 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, PhD, a postdoctoral fellow at UC San Diego School of Medicine Department of Cellular and Molecular Medicine. "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.

"Focusing on genetic variation associated with Alzheimer's disease (AD), we show preferential enrichment in disease risk variants in enhancers that are selectively active in microglia, the major immune cell in the brain," said senior author Christopher Glass, MD, PhD, professor of cellular and molecular medicine and professor of medicine at UC San Diego School of Medicine. "This finding substantially extends prior studies linking microglia to late-onset Alzheimer's disease."

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 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, MD, PhD, assistant adjunct professor of pediatrics, UC San Diego School of Medicine. "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."

Researchers say their findings will help inform future studies investigating genetic risk variants in many different neurological conditions. "In the immediate future, this work gives new targets, and tells us which cells to study them in," said co-first-author Alexi Nott, PhD, assistant project scientist in the Department of Cellular and Molecular Medicine at UC San Diego School of Medicine and a member of Glass' lab. "Going forward, our data sets can be used by others interested in studying many different brain disorders."

Nott said the research team plans to continue using the approach to generate even more targets of inquiry. "Because we studied healthy tissue, we may be missing some regulatory regions that are important in disease contexts. It may be that some of these elements are only altered in disease contexts. We also want to look at more cell types. But this work is a great starting point for furthering our understanding of how these cell-specific regulatory regions may be important for understanding disease risk."

Glass said the study represented a complex, massive team effort, with input from diverse scientists. "This breakthrough could not have been achieved without the application of a combination of multidisciplinary approaches and collaborative interactions involving neuroscientists, immunologists, stem cell biologists, geneticists, genomic scientists and neurosurgeons at UC San Diego, the Salk Institute and Rady Children's Hospital," he said.

"This is an exciting time in neuroscience because we are developing tools to understand the brain's remarkable complexity in entirely new ways," said co-author Fred "Rusty" Gage, PhD, professor and president of the Salk Institute. "The insights into brain health and disease gained from this study underscore the value of taking a multidisciplinary approach to biological research."
Co-authors include: Johannes C.M. Schlachetzki, Claudia Z. Han, Martina P. Pasillas, Christian K. Nickl, Zeyang Shen, James B. Brewer, and Michael G. Rosenfeld, UC San Diego; Miao Yu, Rong Hu and Bing Ren, UC San Diego and the Ludwig Institute for Cancer Research; Robert A. Rissman, UC San Diego and the Veterans Affairs San Diego Healthcare System; David Gosselin, UC San Diego and the Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval; David D. Gonda and Michael L. Levy, UC San Diego and Rady Children's Hospital-San Diego; Monique Pena, Jiayang Xiao, Yin Wu, Zahara Keuelen, Carolyn O'Connor, Simon T. Schafer, and Graham McVicker, The Salk Institute for Biological Studies.

The authors report the following disclosures: B.R. is co-founder of Arima Genomics, Inc, which sells Hi-C and PLAC-seq kits.

University of California - San Diego

Related Brain Articles from Brightsurf:

Glioblastoma nanomedicine crosses into brain in mice, eradicates recurring brain cancer
A new synthetic protein nanoparticle capable of slipping past the nearly impermeable blood-brain barrier in mice could deliver cancer-killing drugs directly to malignant brain tumors, new research from the University of Michigan shows.

Children with asymptomatic brain bleeds as newborns show normal brain development at age 2
A study by UNC researchers finds that neurodevelopmental scores and gray matter volumes at age two years did not differ between children who had MRI-confirmed asymptomatic subdural hemorrhages when they were neonates, compared to children with no history of subdural hemorrhage.

New model of human brain 'conversations' could inform research on brain disease, cognition
A team of Indiana University neuroscientists has built a new model of human brain networks that sheds light on how the brain functions.

Human brain size gene triggers bigger brain in monkeys
Dresden and Japanese researchers show that a human-specific gene causes a larger neocortex in the common marmoset, a non-human primate.

Unique insight into development of the human brain: Model of the early embryonic brain
Stem cell researchers from the University of Copenhagen have designed a model of an early embryonic brain.

An optical brain-to-brain interface supports information exchange for locomotion control
Chinese researchers established an optical BtBI that supports rapid information transmission for precise locomotion control, thus providing a proof-of-principle demonstration of fast BtBI for real-time behavioral control.

Transplanting human nerve cells into a mouse brain reveals how they wire into brain circuits
A team of researchers led by Pierre Vanderhaeghen and Vincent Bonin (VIB-KU Leuven, Université libre de Bruxelles and NERF) showed how human nerve cells can develop at their own pace, and form highly precise connections with the surrounding mouse brain cells.

Brain scans reveal how the human brain compensates when one hemisphere is removed
Researchers studying six adults who had one of their brain hemispheres removed during childhood to reduce epileptic seizures found that the remaining half of the brain formed unusually strong connections between different functional brain networks, which potentially help the body to function as if the brain were intact.

Alcohol byproduct contributes to brain chemistry changes in specific brain regions
Study of mouse models provides clear implications for new targets to treat alcohol use disorder and fetal alcohol syndrome.

Scientists predict the areas of the brain to stimulate transitions between different brain states
Using a computer model of the brain, Gustavo Deco, director of the Center for Brain and Cognition, and Josephine Cruzat, a member of his team, together with a group of international collaborators, have developed an innovative method published in Proceedings of the National Academy of Sciences on Sept.

Read More: Brain News and Brain Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to