Genetic Research Inaccuracies Revealed by NIH European Ancestors Under the Microscope

NIH study finds that not accounting for mixed genetic lineages can lead to inaccuracies.

The researchers found that previous studies that analyzed the genomes of people of European descent could have produced inaccurate results by not fully accounting for population structure. Considering mixed genetic lineages, researchers at the National Human Genome Research Institute (NHGRI) National Institutes of Health (NIH), showed that previously inferred links between a genomic variant that helps digest lactose and traits such as human height and cholesterol levels may not be valid.

Genetic mix

The study, published today (November 7). Communications of nature, shows that people of European descent, previously treated as a genetically homogeneous group in large-scale genetic studies, have clear evidence of mixed genetic ancestry, known as admixture. As such, the results of previous genome-wide association studies that do not account for the admixture of people of European ancestry in their studies should be re-evaluated.

The researchers found that previous studies that analyzed the genomes of people of European descent could have produced inaccurate results by not fully accounting for population structure. Credit: Daryl Leja, National Human Genome Research Institute

Results of the study

By reading population genetics papers, we realized that the pattern of genetic makeup in Europe is too detailed to be observed at the continental level, says Daniel Schreiner, PhD, of the NIH Center for Genomics and Global Health and Global Health Research. senior author of the study. What is clear from our analysis is that when evaluating data from genetic association studies in people of European descent, researchers must adjust for admixture in the population to reveal true associations between genomic variants and traits.

To look at European genetic ancestry, the scientists collected data from published genetic association studies and created a reference panel of genomic data that includes 19,000 individuals of European ancestry in 79 populations in Europe and European Americans in the United States, capturing a diversity of ancestry not seen in other countries. large catalogs of human genomic variation.

As an example, the researchers looked at the lactase gene, which codes for a protein that helps digest lactose and is highly diverse across Europe. Using the new reference panel, they analyzed how the genomic variant of the lactase gene was associated with traits such as height, body mass index and low-density lipoprotein cholesterol, also known as bad cholesterol.

When the researchers looked at the genetic mix of the European population in their analysis, they found that the genomic variant that gives people the ability to digest lactose was not associated with high or low-density lipoprotein cholesterol levels. In contrast, the same variant affects body mass index.

Implications for genomic research

The results of this study underscore the importance of appreciating that the majority of the world’s population has mixed ancestry, and that accounting for this complex ancestry is critical to the practice of genetic studies and genomic medicine, said Charles Rotimi, Ph.D. .D., NIH Distinguished Investigator, director of the Center for Genomics and Global Health Research, and senior author of the study.

Although the lactase gene is an example of a gene that may be falsely associated with certain traits based on previous analyses, the researchers believe it is likely that there are other spurious associations in the literature and that some true associations have yet to be discovered. Information about how genomic variants are associated with different traits helps researchers estimate polygenic risk scores and can provide clues about a person’s ability to safely respond to drug treatment.

Although the differences between the genomes of any two peoples are less than 1%, the small percentage of genomic variation can provide clues about where people’s ancestors may have come from and how different families may be related. Information about a person’s biological ancestry, known as genetic ancestry, can provide important clues about genetic risks for common diseases.

Finding true genetic associations will help researchers be more efficient and careful in future studies, says Matheus Gouveia, Ph.D., a research fellow at the Center for Genomics and Global Health Research and first author of the study. We hope that by accounting for admixed ancestry in future genomic analyses, we can improve the predictive value of polygenic risk estimates and facilitate genomic medicine.

The dashboard created in this study is available to the scientific community for use in other research with additional information provided in the paper.

Reference. Underestimated subcontinental admixture in Europeans and European Americans. implications for genetic epidemiology studies November 7, 2023 Communications of nature.
DOI: 10.1038/s41467-023-42491-0