The small variations in the genome that lead to differences in biology, including risk for diseases, can't be assumed to be the same for different populations, new work has shown. Genome-wide association studies should include people with varied ancestry. For example, the genetic risk factors that affect the development of inflammatory bowel disease (IBD) in African Americans are not the same as those in people of European ancestry.
Reporting in the American Journal of Human Genetics, researchers looked at the whole genome sequences from 1,700 Crohn's disease and ulcerative colitis patients and around 1,600 unaffected individuals. The work showed that IBD studies should account for ancestry.
"Even though the disease destination looks the same, the populations look very different, in terms of what specific genes contribute to risk for IBD," said lead study author Subra Kugathasan, M.D., the Marcus professor of pediatrics and human genetics at Emory University School of Medicine among other appointments. "It shows that you can't develop a polygenic risk score based on one population and apply it to another."
Polygenic risk scores are used to describe how likely a person is to develop a complex disease like heart disease based on their genes. As we learn more about the genome, they become more useful.
The biggest risk factor for IBD is having a first-degree relative with a form of IBD, moreso than any environmental factor. This research suggested that for African Americans, the more significant risk locus is PTGER4, a minor one in European populations, noted Kugathasan. But the two primary European gene loci, NOD2 and IL23R, have smaller roles in African Americans. There is overlap in some genetic risk factors, such as IL23R, because there is some European ancestry in the African-American genetic background.
"One of our goals in treating IBD is to move toward a more personalized approach," said Dermot McGovern, M.D., Ph.D., the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics at Cedars-Sinai. "Deciphering the genetic architecture is an important part of this effort. Studies such as this one are vital to ensure that diverse populations, including African-Americans, benefit from the tremendous advances promised by genomic medicine."
Kugathasan noted that there is a therapy being developed for IBD that targets the IL23 receptor pathway, in part because of the risk factor; as such, work on PTGER4 should expand.
This work also revealed some rare genetic variants that are associated with IBD and have not been found in other populations. These variants were linked to a gene involved in nervous system signaling, CALB2.
The researchers were disappointed that they did not discover more variants that can adequately explain IBD risk in African-Americans that is likely to come from the genome, but is not explained by known variants.
Additional research investigating how IBD may be affected by the interaction between genes and environmental factors like diet, toxins, or the microbiome will be needed and may reveal more, suggested Kugathasan.