Hussman Institute Prominent at World’s Largest Human Genetics Meeting
Article Summary
- Members of the Miller School’s John P. Hussman Institute for Human Genomics presented their research at The American Society of Human Genetics annual meeting.
- Dr. Margaret Pericak-Vance received the society’s highest honor, the Lifetime Achievement Award.
- Hussman Institute faculty presented on and moderated a featured symposium on the Alzheimer’s Disease Sequencing Project.
The world’s largest annual meeting in human genetics and genomics was a milestone event for the John P. Hussman Institute for Human Genomics at the University of Miami Miller School of Medicine.
Hussman Institute Director Margaret Pericak-Vance, Ph.D., also the Dr. John T. Macdonald Foundation Professor of Human Genetics at the Miller School, received the The American Society of Human Genetics’ (ASHG) highest honor, the ASHG Lifetime Achievement Award, at the society’s annual meeting.
Hussman Institute faculty presented on and moderated a featured symposium on the Alzheimer’s Disease Sequencing Project (ADSP). More than 30 Miller School faculty, medical students, residents, fellows and postdoctoral associates shared research during sessions and poster presentations at the event.
“ASHG is the largest society representing the global human genetics and genomics research and translation community. The society’s annual meeting attracts about 8,000 of these experts from around the world each year,” said Jeffery Vance, M.D., Ph.D., professor in the Dr. John T. Macdonald Foundation Department of Human Genetics and founding member of the Hussman Institute.
Alzheimer’s Disease Sequencing Project
Anthony Griswold, Ph.D., associate professor of human genetics at the Hussman Institute, moderated “The Alzheimer’s Disease Sequencing Project (ADSP): A Paradigm for Identifying Genetically Driven Therapeutics for a Global Complex Disease.” Biniyam Ayele, M.D., a neurologist from Ethiopia who is training in genomics at the Hussman Institute as part of the DAWN Alzheimer’s Research Study, co-moderated the session.
This session was one of 15 chosen from more than 300 applications.
“We discussed how ADSP can serve as a model for other consortia in identifying new therapeutic developments through international collaborations, inclusion of diverse ancestries in research, functional genomic analysis and exploration of clinical targets,” Dr. Griswold said.
The Hussman Institute has played key roles in the ADSP, a large-scale genetics effort to further fundamental understanding of Alzheimer’s disease and related disorders, with the goal to accelerate the development of effective treatments. In 2022, the National Institute on Aging (NIA) awarded Hussman Institute faculty $32.5 million to increase the diversity of the ADSP. Several Miller School faculty serve on ADSP committees and workgroups.
The informative session was among the first to bring a global audience of geneticists up to speed on what’s going on in the world of Alzheimer’s, according to Dr. Pericak-Vance, who delivered the ADSP overview to introduce the session.
“We were thrilled to put this great project front and center,” she said.
The ADSP, according to Dr. Pericak-Vance’s talk, has generated genome-wide association studies of single nucleotide polymorphism array data and whole genome sequencing on more than 36,000 individuals. Its goal is to provide detailed data from a highly diverse, combined dataset of more than 100,000 individuals. The data has been used to identify more than 100 loci associated with Alzheimer’s disease risk and has identified candidate causal genes in a number of these loci.
“Importantly, these genes and/or their effects are not consistent across diverse ancestral groups,” Dr. Pericak-Vance said.
This session highlighted ADSP’s history and emphasized current and future prospectives.
“The Hussman Institute has been one of the leaders of ADSP since it began about 12 years ago, ascertaining participants particularly from underrepresented populations, generating clinical, genomic and functional genomics data and leading analysis of the data,” Dr. Griswold said.
Genetics, Ancestry and Disease Status Interplay
Dr. Vance’s postdoctoral associate, Aura M. Ramirez, Ph.D., presented a platform talk on Miller School-led research investigating the impact of astrocytes from diverse ancestries on APOE expression and other Alzheimer’s disease risk genes.
“This research investigates how genetic risk variants related to late-onset Alzheimer’s disease may be influenced by an individual’s ancestry, potentially affecting the genomic regulatory architecture,” Dr. Ramirez said.
Researchers used induced pluripotent stem cell (iPSC)-derived neural spheroids from people of African, Amerindian and European ancestries. Focusing on astrocytes, the researchers identified 60 Alzheimer’s disease genome-wide association study (GWAS) genes that were differentially expressed across these ancestries, including key genes such as APOE, ABCA1 and CLU. Notably, they found that astrocytes from individuals with different APOE genotypes exhibited varying levels of APOE expression.
“ASHG serves as a vital platform for presenting this research because it brings together experts in human genetics and genomics, fostering collaboration and discussion that can lead to impactful advancements in our understanding of genetic influences on health,” Dr. Ramirez said.
Inner Ear Models and DNA Variants
Faraz Zafeer, Ph.D., a postdoctoral associate of Mustafa Tekin, M.D., professor of Human Genetics and chair of the Dr. John T. Macdonald Department of Human Genetics, presented a poster discussing human inner ear organoids and cochlear malformations.
Researchers create organoids—tiny models of body parts—by using three-dimensional tissue cultures derived from stem cells. Miller School researchers assessed the utility of human inner ear organoids to validate coding and no-coding DNA variants linked with deafness and cochlear malformations. They found human inner ear organoids are a useful model in which to rapidly validate coding and non-coding DNA variants in hereditary deafness.
“This is a novel approach to understand the cochlear development in humans and also leading to discovery of regulatory non-coding sites in embryonic development,” Dr. Tekin said.
Genetic Changes in Spinocerebellar Ataxia 27B
Guinevere Spurdens, a postdoctoral student working with Stephan Züchner, M.D., Ph.D., presented research on adult-onset spinocerebellar ataxia 27B (SCA27B).
Spinocerebellar ataxia 27B is a rare, neurodegenerative condition that causes uncoordinated movements, balance problems, vertigo, double vision and other issues. Spinocerebellar ataxia 27B (SCA27B) involves an expansion of repeated DNA sequences in the fibroblast growth factor 14 (FGF14) gene.
Researchers tried to determine if this genetic change is similar to what occurs in another disorder, Friedreich’s ataxia.
“We took skin cells from SCA27B patients, turned them into stem cells and then developed them into specific types of brain cells called GABAergic neurons. These neurons help us better understand how SCA27B affects the cerebellum, the part of the brain involved in movement,” said Dr. Züchner, chief genomics officer for the Miller School, professor of human genetics and neurology and member of the Hussman Institute.
They looked for “R-loop” structures, which the researchers hypothesize might interfere with gene function by reducing the production of FGF14.
The research is ongoing but, if their hypothesis is correct, will have uncovered a new way that SCA27B affects the brain. This could pave the way for new avenues for treating diseases caused by these types of repeat expansions.
A Year To Celebrate
ASHG 2024 was also a time to celebrate Dr. Pericak-Vance’s ASHG Lifetime Achievement Award, her field’s highest honor. After receiving the award, Dr. Pericak-Vance addressed the entire society and discussed the path that brought her to this moment, messaging the next generation of scientists. The Miller School hosted a reception in Dr. Pericak-Vance’s honor after her award.
“We moved from Duke University with about 70 faculty and staff in 2007 to build a world-class genetics institute at the Miller School,” Dr. Pericak-Vance said. “I’m so proud of what we’ve accomplished as a team to make impactful change to the lives of people around the world with life-altering diagnoses. Our extensive participation at ASHG helps to put that success on display and this lifetime achievement award further shows that we’ve delivered on the promise to build an institute that truly is world-class.”
Tags: Alzheimer's disease, Alzheimer’s Disease Sequencing Project, DAWN Alzheimer's Research Study, Dr. Anthony Griswold, Dr. Jeffery Vance, Dr. John T. Macdonald Foundation Department of Human Genetics, Dr. Margaret A. Pericak-Vance, Dr. Mustafa Tekin, Dr. Stephan Zuchner, genetics, genome editing, genome research, John P. Hussman Institute for Human Genomics