By: Lisette Hilton | November 14, 2023 | 9 min. read| Share

Miller School-led studies on neurodegenerative disease chosen for platform presentations, poster awards and abstracts at American Society of Human Genetics annual meeting.

Many of the more than 8,000 international scientists attending the American Society of Human Genetics (ASHG) annual meeting learned about the latest neurodegenerative research at the John P. Hussman Institute for Human Genomics at the University of Miami Miller School of Medicine.

This has been a banner year for genetics research at the Hussman Institute and Miller School. We had three platform presentations, three poster awards and contributed to more than 60 featured abstracts. Were covering the gamut of human genetics, said Director Margaret Pericak-Vance, Ph.D.This acknowledges the work that were doing and the progress were making not only in neurodegenerative diseases like Alzheimers disease but in a number of different disorders, both rare and common in the population.

ASHG 2023, held November 1-4 in Washington, D.C., is the largest international human genetics conference, according to Stephan Zchner, M.D., Ph.D., professor, Dr. John T. Macdonald Foundation Department of Human Genetics and member of the Hussman Institute.

ASHG annual meetings get a lot of attention from a broad range of academic centers, National Institutes of Health leadership, industry, renowned international researchersThey all make it a point to be at the event, Dr. Zchner said.

Miller School researchers stand out globally for their work in studying diverse populations and pioneering work in long-read whole genome sequencing, which was among the highlights of this years meeting.

We are at the cusp of exploring with unprecedented precision the so-called noncoding space of the genome, Dr. Zchner said. Protein-coded segments make up less than 2% of the human genome. Researchers always had trouble interpreting the other 98%. The Hussman Institute is one of the first centers in the world to have acquired a new technology called long-read whole genome sequencing to better interpret the impact of the other 98%, or the noncoding space.

Dr. Zchners lab authored several abstracts on novel uses of the technology in neurodegenerative diseases. One example is a major, new type of ataxiaa brain disorder that can cause poor coordinationwhich lab researchers discovered as a noncoding element.

Three Hussman Institute studies on Alzheimers disease were featured as platform talks at ASHG:

Study: Assessing the functional effect of the Presenilin-1 G206A variant on age of onset of Alzheimer Disease in the Puerto Rican population

Presenilin is a known Alzheimers gene. It has several variants and is associated with early onset Alzheimersusually from 30- to 50-years-of-age, according to principal investigator Dr. Pericak-Vance.

We studied a variant pretty much found solely in the Puerto Rican population. Unlike some of forms of variants that you see with presenilin, this variant has a wide variety in the age of onset, from 30- to 90-years-of-age, Dr. Pericak-Vance said. We set out to better understand why this was.

Researchers screened 182 families for the presenilin mutation and identified 43 carriers of the mutation, called the G206A variant.

This mutation is unique, according to presenting author Katrina Celis, M.D., assistant scientist at the Hussman Institute.

There are other mutations that are in the same position as this mutation, but those other mutations are in Chinese, Korean or Swedish families, and they are all early onsetages 30- to 35-years-of-age, Dr. Celis said.

The Puerto Rican population is admixed, and their genomes have a combination of African, European and Amerindian ancestry. Dr. Celis and colleagues discovered the G206A variant falls in the African ancestry and has a founder effect, meaning the mutation arose in Puerto Rico, possible when an influx of people from Africa and Europe colonized the island.

We looked at individuals that primarily have African ancestry in their genome, like those from Nigeria and African Americans in the U.S., and none of them carried the mutation. That means the new mutation happened in Puerto Rico and only individuals that share that genetic background from Puerto Rico have it, Dr. Celis said.

The information could pave the way to better understand the protective phenomenon that some people with this variant seem to have and harness it to delay onset in the larger population, according to Dr. Pericak-Vance.

Study: Haplotype characterization using short- and long-read sequencing data of a protective region of segmental duplication for Alzheimer disease in African carriers of APOE 4

This study helps to characterize a protective locus for Alzheimers APOE 4 carriers, which Miller School researchers discovered and published in 2022. The APOE-4 variant, discovered by Dr. Pericak-Vance, is the strongest known genetic risk factor for Alzheimers disease.

APOE 4 carriers are at an especially high risk of developing Alzheimers disease, according to study PI Jeffery M. Vance, M.D., Ph.D., professor and founding chair of the Dr. John T. Macdonald Foundation Department of Human Genetics and professor of neurology, Hussman Institute.

This protective locus is found only in people of African ancestry, and its very strong. Having the locus drops APOE 4 carriers risk of getting Alzheimers by 75%, according to Dr. Vance.

Basically, what weve seen is that lowering APOE 4 is good and increasing APOE 4 is bad, Dr. Vance said.

Presenting author Luciana Bertholim Nasciben, postdoctoral associate at the Hussman Institute, and coauthors studied data on 36,000 people from the Alzheimers Disease Sequencing Project. They analyzed the protective region, or haplotypes, in the nearly 2,000 people found to have the protective locus. The researchers further studied the locus in 16 brains from African American Alzheimers patients used for research at the Miller School with long-read sequencing to determine that the locus was not duplicated but rather had only one copy on the DNA.

The haplotype is found throughout African ancestry, so it has been around for a while, according to Dr. Vance. The mechanism explaining how the locus decreases APOE 4 is an important topic of future research.

There is a lot of interest in this novel finding and the clarity that weve provided in our research, Dr. Vance said.

Study: Neuropathology GWAS identifies novel genes involved in amyloid, vascular brain injury, and cerebrovascular disease from common variants

Dementia is ultimately a symptom of underlying damage to the brain.

This damage is commonly caused by Alzheimers disease, but there are other types of damage, like vascular, such as with a stroke, and Lewy bodies, which is the same damage underlying Parkinsons disease, according to study principal investigator Gary W. Beecham, Ph.D., director of research informatics in the Center for Genetic Epidemiology and Statistical Genetics at the Hussman Institute and associate professor, Dr. John T. Macdonald Foundation Department of Human Genetics.

There is increasing recognition that these diseases commonly co-occur, Dr. Beecham said.

This research presented at ASHG is one of the largest studies to date aimed at identifying genetic factors associated with Alzheimers disease neuropathology.

We analyzed brain autopsy data from over 10,000 participants from national and international collaborators. We identified new genetic factors that are linked to specific types of damage. We began looking at multiple types of damage simultaneously, which shows that genetics and differing types of damage interact to impact disease, Dr. Beecham said. We need to acknowledge the complex causes of dementia by studying different genetic factors and different pathological lesions that can impact the brain in unique and complex ways to affect disease.

Three Miller School abstracts were singled out for awards among thousands of abstracts at ASHG:

The awards give the abstracts additional visibility, according to Dr. Vance.

More people notice the work and realize whats going on at a center like the Hussman Institute, he said.

Participating in and attending the ASHG annual meeting is an important career event for faculty and students alike. Nasciben said she feels honored to present her work and represent the Hussman Institute at a meeting as important as ASHG.

As a postdoctoral research associate, the ASHG meeting is an excellent opportunity to show my most recent results and interact with the world community of geneticists, she said. This research theme is particularly inspiring for me because it contributes to finding mechanisms of the disease and potential cures for patients threatened by this devastating disease. The work also illustrates the importance of including diverse populations in genetic studies.

Tags: Alzheimer's & Dementia, Dr. Anthony Griswold, Dr. Derek Dykxhoorn, Dr. Gary Beecham, Dr. Jeffrey Vance, Dr. John T. Macdonald Foundation Department of Human Genetics, Dr. Karen Nuytemans, Dr. Katrina Celis, Dr. Margaret Pericak-Vance, Dr. Stephan Zuchner, Hussman Institute for Human Genomics, neurodegenerative diseases

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