Nav: Home

Study merges big data and zebrafish biology to reveal mechanisms of human disease

April 24, 2019

In a series of studies that volleyed between large databases and research in zebrafish, Vanderbilt investigators have discovered a link between vascular biology and eye disease.

The research uncovered an unexpected role for the gene GRIK5, and it showcases a new paradigm for using biobanks, electronic health records and zebrafish to discover the genetic mechanisms that contribute to human disease. The findings were reported in the American Journal of Human Genetics.

The back-and-forth approach primarily involved two teams of investigators in the Division of Genetic Medicine: Eric Gamazon, PhD, and Nancy Cox, PhD, using computational genetics and large databases, and Gokhan Unlu, PhD, and Ela Knapik, MD, studying gene function in zebrafish.

"This iteration between statistical genetics analyses and biobanks and studies in animal models provides a framework that can be used to understand what a gene does within the context of the human phenome -- all the diseases and traits included in electronic health records," said Gamazon, research instructor in Medicine.

The studies had their start several years ago when Gamazon and Cox, Mary Phillips Edmonds Gray Professor of Genetics and director of the Vanderbilt Genetics Institute, developed a computational method called PrediXcan that correlates genetically regulated gene expression with phenotypes. In the current work, they applied PrediXcan to BioVU, Vanderbilt's DNA biobank and de-identified electronic health records, to generate a comprehensive catalog of associations between gene expression and clinical traits.

Among the associations in this catalog, which they call PredixVU, the gene GRIK5 stood out. Reduced expression of GRIK5, which encodes a glutamate receptor subunit, was associated with 18 different eye diseases ranging from retinal detachment to cataract to glaucoma.

"This was very unusual -- the expectation was that a gene might be associated with four or five disease phenotypes," said Knapik, associate professor of Medicine and Cell and Developmental Biology.

The relationship of GRIK5 to eye phenotypes was also unexpected, Knapik added. GRIK5 has mostly been studied for its role in brain signaling and cognition.

To explore the role of GRIK5 in zebrafish, Unlu used two approaches (CRISPR gene editing and morpholino oligonucleotides) to delete or reduce expression of GRIK5. The most striking finding in the zebrafish with reduced or no GRIK5 was bleeding.

"This was a complete surprise. There was no previous knowledge that GRIK5 had anything to do with the blood or vasculature," Knapik said.

Gamazon and Cox returned to the databases to search for evidence of patients who have both eye and vascular diseases.

They analyzed electronic health records for more than 2.6 million Vanderbilt subjects and found significant comorbidity of eye and vascular diseases, and they confirmed this comorbidity using an insurance claims dataset of 150 million individuals. Unlu and Knapik continued their studies in zebrafish. They used the morpholino approach to reduce expression of GRIK5 in a zebrafish line with glowing green blood vessels and found reduced numbers of blood vessels and other vascular abnormalities in the eye, brain and trunk. They labeled the plasma with nanobeads and found leaking blood vessels in the eye, brain and ear.

"Our studies show that not only the architecture of the vasculature but also the function -- keeping the blood inside -- is compromised in zebrafish with reduced GRIK5 expression," said Unlu, research fellow in Genetic Medicine.

In further computational studies of genotyped BioVU participants, Gamazon and Cox demonstrated an association of reduced genetically predicted GRIK5 expression with comorbid vascular and eye diseases.

The researchers propose that reduced GRIK5 expression compromises vascular perfusion to the eye, leading to late-onset diseases like cataracts and glaucoma.

Further studies are needed to understand the precise role of GRIK5 in the vasculature -- and how defects lead to eye diseases, but the framework from these studies can be broadly applied, Knapik said.

"I am a developmental geneticist. We do forward genetics in zebrafish: we make changes in the genome and study the phenotypes that result," she said. "On the human side, Mother Nature has made changes in our genomes. And the health care system is phenotyping every day and keeping the results in electronic health records. Scientists can now use the approach we've demonstrated to understand the mechanisms of human disease."
-end-
Additional contributing authors from Vanderbilt included Xinzi Qi, Daniel Levic, PhD, Lisa Bastarache, MS, Joshua Denny, MD, MS, Dan Roden, MD, Max Breyer, Xue Zhong, PhD, MS, and Anuar Konkashbaev. This research was supported by the National Institutes of Health (grants MH113362, HG009086, GM115305, LM010685, DE022226, HD007502), Vanderbilt International Scholar Program and American Heart Association.

Vanderbilt University Medical Center

Related Blood Vessels Articles:

3D printing, bioinks create implantable blood vessels
A biomimetic blood vessel was fabricated using a modified 3D cell printing technique and bioinks.
When blood vessels are overly permeable
In Germany alone there are around 400,000 patients who suffer from chronic inflammatory bowel diseases.
Nicotine-free e-cigarettes can damage blood vessels
A Penn study reveals single instance of vaping immediately leads to reduced vascular function.
Creating blood vessels on demand
Researchers discover new cell population that can help in regenerative processes.
Self-sustaining, bioengineered blood vessels could replace damaged vessels in patients
A research team has bioengineered blood vessels that safely and effectively integrated into the native circulatory systems of 60 patients with end-stage kidney failure over a four-year phase 2 clinical trial.
Found: the missing ingredient to grow blood vessels
Researchers have discovered an ingredient vital for proper blood vessel formation that explains why numerous promising treatments have failed.
How sickled red blood cells stick to blood vessels
An MIT study describes how sickled red blood cells get stuck in tiny blood vessels of patients with sickle-cell disease.
Like a zipper -- how cells form new blood vessels
Blood vessel formation relies on the ability of vascular cells to move while remaining firmly connected to each other.
Blood vessels instruct brain development
The group of Amparo Acker-Palmer (Buchmann Institute of Molecular Life Sciences and the Institute of Cell Biology and Neuroscience, Goethe University) reported in a Research Article in the last issue of the journal Science a novel function of blood vessels in orchestrating the proper development of neuronal cellular networks in the brain.
Texas A&M team develops new way to grow blood vessels
Formation of new blood vessels, a process also known as angiogenesis, is one of the major clinical challenges in wound healing and tissue implants.
More Blood Vessels News and Blood Vessels Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Risk
Why do we revere risk-takers, even when their actions terrify us? Why are some better at taking risks than others? This hour, TED speakers explore the alluring, dangerous, and calculated sides of risk. Guests include professional rock climber Alex Honnold, economist Mariana Mazzucato, psychology researcher Kashfia Rahman, structural engineer and bridge designer Ian Firth, and risk intelligence expert Dylan Evans.
Now Playing: Science for the People

#540 Specialize? Or Generalize?
Ever been called a "jack of all trades, master of none"? The world loves to elevate specialists, people who drill deep into a single topic. Those people are great. But there's a place for generalists too, argues David Epstein. Jacks of all trades are often more successful than specialists. And he's got science to back it up. We talk with Epstein about his latest book, "Range: Why Generalists Triumph in a Specialized World".
Now Playing: Radiolab

Dolly Parton's America: Neon Moss
Today on Radiolab, we're bringing you the fourth episode of Jad's special series, Dolly Parton's America. In this episode, Jad goes back up the mountain to visit Dolly's actual Tennessee mountain home, where she tells stories about her first trips out of the holler. Back on the mountaintop, standing under the rain by the Little Pigeon River, the trip triggers memories of Jad's first visit to his father's childhood home, and opens the gateway to dizzying stories of music and migration. Support Radiolab today at Radiolab.org/donate.