Researchers
at the University of Delaware, working with colleagues at the Kaiser
Permanente Division of Research and 23andMe Inc., have found 54
locations on the human genome that are associated with the risk of
age-related cataracts, the leading cause of blindness worldwide.
The research, published June 14 in the journal Nature Communications,
represents the largest and most ethnically diverse genetic study of
cataracts. Scientists looked at genetic information from more than 3.8
million people — obtained from the Kaiser Permanente Northern California
health care system, UK Biobank in the United Kingdom and the genetic
testing company 23andMe — all of whom volunteered their genetic and
medical information for research.
The study identifies new locations on the genome that could relate to
an increased risk of cataracts, including one location that seems to be
specific to women, who develop the condition more often than men. That
finding especially “highlights the need to include sex as a biological
variable in future studies,” said Salil Lachke, Alumni Distinguished
Early Career Professor of Biology and associate chair of the Department of Biological Sciences at UD, the joint senior author of the paper, which was also co-authored by UD postdoctoral researcher Deepti Anand.
“There are so many aspects to this multi-ethnic study that are
important,” Lachke said. “It represents a critical first step toward
addressing this very significant human eye disease associated with aging
… and makes a case for inclusion and diversity in these studies.”
Lead author Hélène Choquet, a research scientist at the Kaiser
Permanente Division of Research, said that identifying individuals who
are at higher risk of developing cataracts could lead to earlier
treatments and possible lifestyle changes to reduce their risk.
Cataracts, defined as clouding of the lens of the eye, generally develop
with age, but such factors as smoking and certain medications can
increase the risk.
About half of Americans age 80 or older are impacted by cataracts,
according to the National Eye Institute. Currently, the only treatment
for cataracts is surgery, which is estimated to cost $3.4 billion
annually and is projected to increase over the next 25 years as the U.S.
population ages. For those reasons, understanding the genetic,
biological and environmental basis of the disease remains critical, the
researchers said.
“This [study] is the first step, and we can use this information
along with other factors to build predictive models to identify people
more likely to develop cataracts,” Choquet said. “If we can screen
people before they develop a disease, that would help them and their
doctors be vigilant to rapidly identify when a cataract is forming or
perhaps help them make lifestyle changes.”
Choquet and colleagues conducted the population-genetics research,
identifying the 54 locations associated with the risk of cataracts.
After analyzing the genetic data, a separate database, developed at UD
by Lachke, was used to confirm the results, finding that many of the
genes at the newly discovered locations were abundantly present in the
lens. Their levels were also found to be affected in other models of
cataract, suggesting their importance in ensuring a healthy lens tissue.
“Finding the [genetic] locations is the first step,” Lachke said.
“But it is critical to also find the biological connections to
understand the basis of the pathology of the disease.”
The database used for that part of the research is known as Integrated Systems Tool for Eye gene discovery (iSyTE),
a bioinformatics-based tool that predicts the genes associated with eye
development and defects. The interactive tool is available to all
clinicians, scientists and anyone who is interested in studying eye
development and disorders, Lachke said. His own work as a developmental
biologist focuses on interdisciplinary genetic research involving the
eye and its associated defects, including a particular interest in
pediatric cataracts.
Over the past decade, iSyTE has led to the identification of several
new genes and regulatory pathways linked to pediatric cataract, but this
is the first time the database was successfully applied in the study of
genes associated with age-related cataract. Lachke said his laboratory
has “invested considerable effort in updating and expanding iSyTE by
including gene expression data using different technologies and on
different stages of the lens,” which allowed it to be used successfully
in the new study.
“The use of iSyTE to show gene expression was an important part of
the new study,” Choquet said. “If a gene is expressed in the tissue,
that means its perturbations could have a direct relationship to the
development of a cataract.”
These findings have initiated a long-term collaboration between
Choquet and Lachke, who are applying for grants to support future work
in understanding the mechanisms of how genetic changes affect
susceptibility to cataracts.
More about this study
The study was funded by several grants from the National Institutes of Health, particularly the National Eye Institute.
The paper was authored by researchers from the University of
California San Francisco and King’s College London, in addition to those
from Kaiser Permanente Northern California, UD and the 23andMe Research
Team.
Genetic data was examined for association with cataract risk in
67,844 people with cataract and 517,399 people without cataract from the
Kaiser Permanente Research Bank and UK Biobank. Those findings were
then replicated using data from 347,209 people with cataract and more
than 2.8 million without cataract from the 23andMe research cohort.
Article by Ann Manser, with information from the Kaiser Permanente Division of Research; photo by Evan Krape
Published July 22, 2021
