New Insights Into How Genetic Variants Impact Gene Expression

The Department of Biomedical Informatics (DBMI) at the University of Colorado School of Medicine, in collaboration with the University of California San Francisco and Stanford University, has recently published a study that is the largest of its kind to focus on ancestry correlations with biomedical traits.

It is also the first study to look at the role of genetic variants across various ancestries in regulating gene expression.

We are trying to understand how genetic variability around the world allows us to gain a deeper understanding of the relationship between genetics and RNA levels and then protein levels and physiology. The genome and gene expression each on their own only tells us so much. Having these layers coming together helps us a lot more.”

Chris Gignoux, Ph.D., Study Co-Senior Author and Associate Professor, Department of Biomedical Informatics, School of Medicine, University of Colorado

Gignoux compares the genetic regulation of gene expression to a dial that regulates how much of the gene is translated into RNA and protein, eventually affecting function in a variety of ways.

The study's sample consisted of children with African American and Latino ethnicity, with researchers conducting whole genome and RNA sequencing. Since gene expression can vary significantly depending on ancestry, researchers say their findings highlight the value of measuring gene expression across various populations.

They also suggest that doing so can result in discoveries that could help close healthcare disparities for historically underrepresented groups.

Data from the Population Architecture using Genomics and Epidemiology (PAGE) Study and the Trans-Omics for Precision Medicine (TOPMed) collaboration, both supported by the National Human Genome Research Institute, were utilized in Gignoux’s study.

To investigate changes in the genetic architecture of whole blood gene expression associated with ancestry and heterozygosity, they examined whole genome and RNA sequencing data from 2,733 African American and Latino children.

Gignoux added, “The ultimate goal was that we learn by looking at gene expression patterns in populations that came from the same ethnic group. Individuals from across Latin America do not reflect one homogeneous population, so that was part of the reason why it was important to not just look at Hispanics in one group, but to highlight what we can learn from studying Mexican Americans and Puerto Ricans, specifically. We’re able to leverage some of that diversity to understand some of these patterns.”

Understanding the link between genetics and heritage is extremely hard, and it can vary considerably across people, as ethnicity is a sociopolitical identity. This is valid even for members of certain groups, such as those of Puerto Rican origin.

There has historically been a dearth of genetics research, including individuals of non-European heritage, yet understanding the connection between genetic diversity and gene expression can help advance research into a wide range of health problems.

This has been demonstrated in instances like the medical community’s understanding of heart attacks, which for many years was restricted to men alone. Further study revealed that women have quite distinct risk factors and symptoms.

It is practically difficult to predict how a disease would manifest in a different demographic without examining other groups.

The research carried out by Gignoux and his colleagues, including those from the many cultures represented, could help in the identification of additional risk factors for heart attacks in women in addition to other findings that are important to varied populations.

“We are not going to know what we don’t know unless we look, and that has the potential to impact how we think about individuals’ risk factors for a number of different conditions and traits. It is also important to look in the right kind of ways and develop the methodologies so that we can leverage these kinds of diversity-focused efforts. The hope is that as these kinds of initiatives move forward in genetic and non-genetic disciplines there's an opportunity to improve our understanding of biomedical traits for anyone who walks into the clinic,” Gignoux concluded.