A large-scale biobank study at the University of California Los Angeles has uncovered previously unknown differences in disease risk, genetic associations, and treatment response across diverse ancestry groups. Among other findings, the researchers report the first evidence of a genetic link between variants of the PTPRU gene and response to GLP-1 drugs, with mixed-raced Americans experiencing lower weight loss effects.
Published today in Cell, these findings were based on the analysis of data from nearly 94,000 participants in the UCLA ATLAS Community Health Initiative Biobank, which encompasses genetic information and electronic health records (EHR) across five continental and 36 fine-scale ancestry groups.
“Although many other efforts to integrate electronic health records with genetic data have advanced genetic and biomedical discovery, they’ve often had a heavy concentration of homogeneous populations of European ancestry, limiting generalizability,” said Roni Haas, PhD, assistant project scientist at UCLA Health and lead author of the study.
What makes this study stand out is that the entire population is served by a single health system within the Los Angeles County, which is one of the world’s most diverse metropolitan areas. This allowed Haas and colleagues to study a broad range of ancestries while minimizing differences in clinical care across health systems, which is a common limitation of nationwide biobank programs.
“ATLAS represents a sweeping cross-section of real patients, making its discoveries directly translatable to the groups of people medicine has historically left behind,” said Daniel H. Geschwind, MD, PhD, senior associate dean and associate vice chancellor of Precision Health at UCLA, who developed and oversees the ATLAS program.
Some of the findings include a link between the ANKZF1 gene and peripheral vascular diseases in individuals of African ancestry, as well as a link between the EPG5 gene and HDL cholesterol and triglyceride levels in Ashkenazi Jews. In South American and Mexican populations, an increased susceptibility to the side effects of hormonal therapy was found.
Using longitudinal EHR data, the researchers looked at patient response to the GLP-1 drug semaglutide as a case study for the identification of genetic factors that influence drug efficacy. Results found reduced weight loss effects in mixed-race Americans and a slower rate of weight loss both in mixed-race Americans and East Asian populations.
Using whole exome sequencing, a significant association was found between the weight loss effects of semaglutide with the PTPRU gene, which encodes for a protein that is linked with a higher risk of type 2 diabetes. Overall, higher PTPRU expression was associated with lower weight loss rates in patients taking semaglutide, and multiple variants of the gene were found to appear at different frequencies in each ancestry group.
“These findings showcase how UCLA Health’s unique patient populations add significantly to understanding the genetic basis of medical disorders across the spectrum of disease and ancestry,” said Geschwind. “Although this is one of the first concrete results at the research end of our efforts, we have pilot studies underway that we hope and expect will soon show the immediate clinical impact that this work has the potential to deliver.”
