IBD and the rare genetic lens on health disparities

Exploring admixture's role in rare variant contribution to IBD.


The use of advanced technology for sequencing entire genomes has led to a surge in research on how genetics relate to disease risk. However, most of this research has focused on people of European descent. Recognizing the need to address health disparities, researchers at Georgia Tech conducted a study to explore whether 25 rare gene variants linked to inflammatory bowel disease (IBD) also affect the risk for African Americans. 

These rare variants, discovered in individuals of European ancestry, contribute to around 15% of IBD cases. The study, led by Professor Greg Gibson, underscores the importance of considering genetic diversity and ancestry mix in research. The findings were published in the journal Genome Medicine.

Gibson, director of the Center for Integrative Genomics at Georgia Tech, said, “Because of major advancements in the last decade, we now know that most diseases are far more complex than we originally thought in genetics. Understanding whether genetic differences contribute to health disparities is a major focus for current genetics research, and we had an opportunity to test one idea with this study.”

While African Americans and European Americans show a similar rate of various types of inflammatory bowel disease (IBD) today, the progression is often more severe in African Americans, leading to a higher likelihood of requiring major interventions like colectomies. 

To understand if rare gene variants associated with IBD have a similar impact on both groups, Courtney Astore, a Ph.D. student in Professor Greg Gibson’s lab, analyzed over 3,000 genomes of African Americans, half with IBD. Surprisingly, she found a significant reduction in the prevalence of these rare variants in African Americans. Further analysis suggested that these variants only contribute a small amount to IBD risk in African Americans, about four times less than in Americans of European ancestry, indicating potential genetic differences in disease development.

Astore said, “Before our analysis, we suspected that admixture may play a role in the presence of IBD-associated rare variants in African Americans. When I saw the differences, I realized there was something important there that we needed to discover.”

In a nutshell, Astore used a method called chromosome painting to visualize where the rare gene variants in African Americans originated. She found that these variants mainly were located on segments of genomes with European ancestry. This indicated that the genes resulted from admixture, mixing genetic backgrounds throughout genealogy. 

The study concluded that the mutations had originated outside of Africa and began appearing in people of African ancestry over the last dozen generations. To reinforce their findings, Gibson and Astore also checked for other rare variants linked to various diseases, and the results confirmed that these variants generally contribute to African Americans through admixture.

These findings emphasize the importance of considering genetic diversity and admixture in genetics research, especially when studying rare gene variants and their links to complex diseases. While the study showed that rare European variants were not common in African Americans, it also suggests that there are likely other undiscovered rare variants specific to African Americans that contribute to inflammatory bowel disease (IBD) and may reveal important biological mechanisms.

Astore said, “Doing more genetic studies on diverse populations, especially those with admixture, will be pivotal for therapeutic discovery.”

Precision medicine is based on an individual’s genome. Knowing rare gene variants becomes crucial for guiding therapy. Understanding the context of ancestry is essential for effective treatment. The study underscores the need for more research on diverse ancestry groups. New treatments may only work for some if this is addressed. 

The team emphasizes that genetics is one factor in complex diseases like inflammatory bowel disease (IBD), and not all genetic discoveries apply universally. Professor Gibson stresses the importance of large-scale genetic sequencing for all ancestry groups to promote health equity, encouraging research on social determinants of health and IBD genetics across ancestries.

As precision medicine progresses toward personalized genomic therapy, understanding rare gene variants becomes pivotal for guiding treatment. The study sheds light on the importance of ancestry context. It highlights the necessity for broad-scale genetic sequencing across diverse populations. The researchers hope their work will drive more research on the social determinants of health and the genetics of IBD, fostering more significant health equity.

Journal reference:

  1. Astore, C., Sharma, S., Nagpal, S. et al. The role of admixture in the rare variant contribution to inflammatory bowel disease. Genome Medicine. DOI: 10.1186/s13073-023-01244-w.


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