Challenging the Assumption of Genetic Homogeneity in European Ancestry

Previous studies studying the genomes of people with European heritage might have reported misleading results because they did not adequately account for population structure, according to a new study.

By incorporating the analysis of mixed genetic ancestries, scientists at the National Human Genome Research Institute (NHGRI), a division of the National Institutes of Health, have demonstrated that previously suggested connections between a genomic variant responsible for lactose digestion and characteristics like height and cholesterol levels may lack validity.

Their research, featured in a publication in Nature Communications, highlights the presence of mixed genetic ancestries, or admixture, in individuals of European descent, dispelling the assumption of genetic homogeneity in this population.

Consequently, the outcomes of prior large-scale genetic studies that neglected to address admixture when investigating individuals of European ancestry should undergo a reassessment.

By reading population genetics papers, we realized that the pattern of genetic makeup in Europe is too detailed to be viewed on a continental level.”

Daniel Shriner, PhD, Study Senior Author and Staff Scientist, Center for Research on Genomics and Global Health, National Institute of Health

Shriner added, “What is clear based on our analysis, is when data from genetic association studies of people of European ancestry are evaluated, researchers should adjust for admixture in the population to uncover true links between genomic variants and traits.”

In their examination of European genetic ancestry, the researchers aggregated data from previously published genetic association studies, constructing a comprehensive reference panel of genomic information comprising 19,000 individuals with European heritage hailing from 79 diverse populations in Europe and European Americans residing in the United States.

This reference panel encompasses a range of ancestral diversity not present in other extensive repositories of human genomic variation.

As an example, the researchers delved into the lactase gene, responsible for encoding a protein crucial for lactose digestion, displaying substantial variation across European populations.

Leveraging the novel reference panel, they scrutinized the relationship between a genomic variant within the lactase gene and traits like height, body mass index, and low-density lipoprotein cholesterol (commonly referred to as “bad cholesterol”).

When the researchers incorporated considerations of genetic admixture within the European population into their analysis, they discerned that the genomic variant responsible for lactose digestion was not associated with height or low-density lipoprotein cholesterol levels. However, this same variant did exert an influence on body mass index.

The findings of this study highlight the importance of appreciating that the majority of individuals in populations around the world have mixed ancestral backgrounds and that accounting for these complex ancestral backgrounds is critically important in genetic studies and the practice of genomic medicine.”

Charles Rotimi, PhD, Study Senior Author and Distinguished Investigator,andDirector, Center for Research on Genomics and Global Health, National Institute of Health

Although the lactase gene serves as just one example of a gene that may have been incorrectly associated with certain traits in prior analyses, the researchers suggest that it is plausible that other erroneous associations exist in scientific literature, and there are likely authentic associations yet to be uncovered.

Understanding the relationships between genomic variants and various traits aids researchers in estimating polygenic risk scores and offers insights into an individual’s potential responsiveness to drug treatments.

Even though the genetic variation between any two individuals’ genomes is minimal, accounting for less than 1%, this small fraction of genomic diversity can provide indications about the geographical origins of a person’s ancestors and familial relationships.

Information regarding an individual’s genetic ancestry, which reveals their biological lineage, can provide valuable insights into the genetic predisposition to common diseases.

Finding true genetic associations will help researchers be more efficient and careful with how further research is conducted. We hope that by accounting for mixed ancestries in future genomic analyses, we can improve the predictive value of polygenic risk scores and facilitate genomic medicine.”

Mateus Gouveia, PhD, Study First Author and Research Fellow, Center for Research on Genomics and Global Health, National Institute of Health

The reference panel created in this research is accessible to the scientific community for utilization in other investigations, and further details can be found in the published study.