Study Highlights Need for Population-to-Individual Transition in Genomic Medicine – ScienceDaily


Polygenic scores — estimates of an individual’s susceptibility to complex traits and diseases — hold promise for identifying patients at disease risk and guiding early personalized treatments, but UCLA experts found that the scores fail to account for the wide range of genetic variation across individuals in all ancestors.

“Polygene scores can estimate the likelihood of an individual having a particular trait by summing and analyzing small effects of thousands to millions of common genetic variants in a single score, but their performance among individuals of diverse genetic backgrounds is limited,” Bogdan said. Pasaniuc, PhD, a UCLA health expert in statistical and computational methods for understanding genetic risk factors for common diseases.

The researchers’ analysis published in natureshows that the accuracy of polygenic scores (PGSs) varies between individuals along a continuum of genetic ancestry—and this is true even in populations traditionally considered ‘homogeneous’, (eg, Europeans) said Pasaniuk, senior author of the paper.

The authors said that assessment of PGS performance is most commonly performed at the ‘population’ level, as in ‘Europeans’, where individuals of similar ancestry cluster together in the genetic lineage group.

“Imposing artificial boundaries on this continuum and ignoring diversity, or ‘heterogeneity’ within groups can obscure intra-group variation, mask similarities that individuals in different groups may have, and exclude individuals who do not fit neatly into a given group,” Ye said. Ding, a UCLA bioinformatics graduate student, member of the Bassanyuk Lab, and first author of the paper: “Genetic origin.”

To provide a more accurate estimate of the accuracy of PGS, researchers have developed a method for assessing the accuracy of PGS at the individual level. To test it, they applied PGSs for 84 complex traits to data from more than 35,000 individuals at the UCLA ATLAS Precision Health Biobank, one of the most diverse biobanks in the world, in part because the Los Angeles area is home to one of the most ancestrally diverse populations in the world. .

The ‘training’ data for the new tool came from a subset of individuals at the UK Biobank in the United Kingdom. As an alternative to separate genetic origins, a continuous measure of ‘genetic distance’ was used to locate each individual in the ATLAS database in a genetic lineage, essentially showing how similar or different an individual’s genome is (ATLAS). To that of the UK population training.

“We found that the more divergent – or genetically distant – the genome of a target individual was from the UK Biobank training data, the lower the accuracy of PGS,” said Ding.

The accuracy of PGSs decreased as the genetic distance became larger even when the researchers looked specifically at genetic ancestry groups that were considered homogeneous, such as individuals of European genetic ancestry. Conversely, some unspecified individuals of European ancestry could have higher levels of genetic similarity, demonstrating that PGS performance can differ between two individuals of the same ancestry but comparable to two individuals of different ancestry – depending on their genetic similarity. .

“Our measure of genetic distance outperformed separate groups in identifying individuals who could benefit from PGSs,” said Pasaniuk, a researcher at UCLA’s David Geffen School of Medicine and UCLA’s Precision Health Institute.

The research team identified several factors — topics for ongoing and future studies — that could influence the accuracy and usefulness of PGS, particularly in people of “mixed” ancestry. These are usually defined as individuals of recent ancestry from two or more continental origins – such as African Americans and Hispanics.

These individuals have “mosaic” genomes, with parts of different continental ancestry in each region, said Basanyuk, whose research focuses on improving predictors of genetic risk factors for people of mixed ancestry. With different parts contributed by different ancestors, it is very difficult to accurately classify these individuals using traditional pedigree nomenclature.

“For PGSs to be used equitably, assessment of PGS accuracy must consider the full spectrum of genetic variation,” he said.


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