Miller School Shares Important Genetic Research at ASHG Conference

Researchers present data on complex conditions like Alzheimer’s disease and rare genetic variations.

Dr. Katrina Celia at ASHG session, "Averting Alzheimer's as soon as possible."
Dr. Katrina Celia (center, seated) served as a session moderator at an ASHG session, “Averting Alzheimer’s as soon as possible.” Dr. Jeffery Vance was the session’s program committee liaison.

The American Society for Human Genetics (ASHG) recently held its first in-person conference since 2019, and University of Miami Miller School of Medicine researchers were major participants. In all, Miller School and University scientists and physicians contributed to 65 research abstracts at the conference.

“The research we presented at ASHG represented years of study to gain a better understanding of complex conditions, such as Alzheimer’s, and rare genetic diseases,” said Stephan Züchner, M.D., Ph.D., chief genomics officer for the Miller School. “By interrogating the genetic variations that can cause disease, we come measurably closer to finding new therapies and improving care.”

One of the most important topics at ASHG was diversity — specifically, studying diverse genomes. In the 20-plus years since the human genome was first sequenced, the vast majority of participants have had European ancestry, which excludes an enormous amount of genetic diversity.

“This can really exacerbate health disparities,” said Margaret Pericak-Vance, Ph.D., director of  the John P. Hussman Institute for Human Genomics, who was instrumental in discovering that the APOE4 gene can increase the risk of developing Alzheimer’s disease. “Besides identifying ancestry-specific genetic factors increasing risk, diversifying these studies helps us uncover important protective mechanisms.”

The Hussman Institute has been actively working with the African American and Hispanic/Latino communities to make sure they are included in genomic studies, to ensure they will benefit from ongoing research toward therapeutics. This effort has recently been expanded to several diverse community studies, with collaborators in nine African countries and Peru, that will globally benefit patients with African ancestry as well as Hispanic/Latino individuals in the U.S.

In one important study by Hussman Institute researchers and others showed that the APOE4 gene can have different consequences in European and African ancestry populations. The gene is the same; however, the associated regulatory mechanisms can be different. As a result, African communities have reduced APOE4 expression, which can lower their risk of developing Alzheimer’s disease.

“If you have APOE4 with an African genome surrounding it, you have a lower risk,” said Jeffery Vance, M.D., Ph.D., professor of neurology and professor and founding chair of the Dr. John T. Macdonald Foundation Department of Human Genetics. “If you have APOE4 with a European genome surrounding it, you have a much higher risk.” These differences in risk between ancestries can illuminate potential therapeutic strategies.

Studying Amish Genomes for Alzheimer’s Risk

Researchers at Hussman are also investigating genomes in Midwestern Amish communities, which lend themselves to these studies because of their shared ancestral background and homogeneous lifestyles.

“We’re turning the tables,” said William K. Scott, Ph.D., a principal investigator of the study at the Hussman Institute and professor in the Dr. John T. Macdonald Foundation Department of Human Genetics. “Instead of looking at what causes the disease, we’re looking at people who are cognitively intact to see how they’re protected against developing Alzheimer’s disease.”

In another abstract presented at ASHG, Miller School and other researchers investigated whether blood biomarkers in Amish participants could be used to detect Alzheimer’s disease early, when it is more treatable. The research points to the potential to create a genomic risk score that predicts an individual’s genetic risk to develop Alzheimer’s disease; however, much more work needs to be done.

Genomic Sequencing in Rare Genetic Diseases

Mustafa Tekin, M.D., professor in the Dr. John T. Macdonald Foundation Department of Human Genetics and co-director of the Hussman Institute, whose work focuses on rare genetic diseases, shared his excitement that genomic sequencing is becoming both cheaper and more comprehensive.

“Now, we are talking about large projects, like All of Us, that aim to collect samples from a million people and look at their health data and genomes,” Dr. Tekin said. “We are seeing more refined and advanced analysis, which will help with research and patient care.”

More comprehensive information is already paying dividends. Quite often, because of cost, researchers have only sequenced the relatively small parts of the genome that codes for proteins (the exome). However, as whole genome sequencing (WGS) becomes more accessible, it is revealing information exome studies have missed.

Dr. Tekin co-authored a study, presented at ASHG, that used WGS to identify unknown variants associated with hereditary deafness. The study found 14 novel variants, identifying the underlying mechanisms that caused hearing loss in several families.

In addition, long-read sequencing technologies, which can also capture hidden genomic information, are coming down in price and showing increased accuracy and speed. Dr. Tekin believes these approaches will reveal important data.

“Short-read whole genome sequencing can miss important regions because they’re repetitive and difficult to read,” said Dr. Tekin. “These areas can contain genetic variations that could explain human disease. Long reads have been around for a while, but they’ve been expensive and throughput was low. Now, technologies are advancing, and that’s going to help us see even more of the genome in our studies.”

Other Research Highlights at ASHG Conference

Charcot-Marie-Tooth Disease, type 4B3, can cause intellectual disabilities and other issues in young children. The condition is caused by mutations in a single gene, making it potentially amenable to gene therapy. However, because the gene is particularly large, it will not fit into current gene delivery approaches (AAVs). Researchers are exploring how “minigenes” might overcome this problem.

Short tandem genome repeats are responsible for around 50 known diseases, primarily affecting the nervous system. There may be many more conditions, but tandem repeats are difficult to detect. Miami researchers have developed an algorithm called RExPRT that detects these variations and ranks them by their ability to cause disease.

Researchers identified a mutation that turns off one of the cell’s most important quality control mechanisms: the misfolded protein response, which eliminates aberrant molecules. The study found that variations in the FICD enzyme shut down activity in a protein called BiP, leading to bad proteins accumulating. These findings could lead to new therapeutic strategies.

Education has long been thought to be protective against Alzheimer’s, but it may not be that simple. In a study of 537 African American participants, UM researchers found that those with low genetic risk for Alzheimer’s were protected by education. However, those with high genetic risk benefited from a smaller protective effect from education.

Tags: Alzheimer's disease, Dr. John T. Macdonald Foundation Department of Human Genetics, Dr. Stephan Zuchner, genetics, Hussman Institute, Miller School of Medicine