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Researchers set out to build polygenic risk scores using association data from multiple populations in Mount Sinai’s BioMe Biobank. BioMe is a system-wide effort to revolutionize diagnosis and classification of diseases according to a patient’s molecular profile.
Researchers calculated these polygenic risk scores using IBD association data from cohorts with European, African American, and Ashkenazi Jewish backgrounds. The risk scores represented an estimate of overall risk based on the sum of an individual’s many genetic variants.
Researchers also evaluated rare variants in genes associated with very early-onset IBD within each population and found that African American carriers of uncommon LRBA variants showed reduced expression of both proteins LRBA and CTLA-4.
LRBA deficiency increases susceptibility to IBD and results in lower CTLA-4 expression, which can be reversed with the commonly prescribed antimalarial drug chloroquine. Going forward, the research team plans to focus on which subsets of patients may benefit from this pathway.
“Since lowered LRBA and CTLA-4 expression can lead to IBD, it’s encouraging that chloroquine is able to partially recover expression,” said the study’s first author Kyle Gettler, PhD, postdoctoral fellow in the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai.
The results showed that risk scores calculated from integrating data significantly improved predictions among individuals with European, Ashkenazi Jewish, and Hispanic ancestry in BioMe.
The team stated that predictive power was lower for people of African ancestry, most likely because of substantially smaller reference datasets and substantially greater genetic diversity within populations of African descent.
The study demonstrates the importance of studying multi-ethnic populations to better understand disease risk and treatment, the group said.
“The ability to accurately predict genetic disease risk in individuals across ancestries is a critical avenue that may positively affect patient outcomes, as early interventions and even preventive measures are being considered and developed,” said the study’s senior author Judy H. Cho, MD, Dean of Translational Genetics and Director of The Charles Bronfman Institute for Personalized Medicine at the Icahn School of Medicine at Mount Sinai.
“These findings support a need for greater genetic diversity, including more data on African American populations, to enhance disease risk predictions and reduce health disparities for all populations.”
Researchers at the Perelman School of Medicine are also leveraging data from diverse populations to better understand the role of genetics in disease. The team recently received a $4.8 million grant from the National Institute on Aging (NIA) to study the genetics of Alzheimer’s disease in people of Asian ancestry.
The project, called the Asian Cohort for Alzheimer’s Disease (ACAD) aims to enroll a population of at least 5,000 participants of Asian ancestry in the US and Canada.
“This is an extremely important project. There is currently a major bias towards inclusion of people of European ancestry in human genetics studies,” said Sarah Tishkoff, PhD, professor of genetics and biology and ACAD scientific advisory board member.
“The Asian Cohort for Alzheimer’s Disease study is critically important for making sure that a more diverse set of ethnic groups, with a focus on Asian Americans and Canadians, will benefit from human genetics research studies to understand risk factors for Alzheimer’s disease and to develop diagnostics and therapeutics that are move effective in all ethnic groups.”
By Jessica Kent