McGovern, professor of Medicine and Biomedical Sciences, was a co-senior author and co-organizer ofthe study, along with Subra Kugathasan, MD, Marcus professor of Pediatrics and Human Geneticsat Emory University School of Medicine in Atlanta; and Steven Brant, MD, from Rutgers University in New Jersey.
IBD causes inflammation of the intestines. It can produce diarrhea abdominal cramps, bloody stool, blocked bowels, fever, loss of body fluids and appetite, extreme weight loss and anemia, among other conditions.
As part of their analysis, the investigators developed an algorithm that corrects for ancestry when calculating an IBD polygenic risk score. Polygenic risk scores are tools for calculating gene-based risk for a disease.
"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 author Kugathasan. "It shows that you can't develop a polygenic risk score based on one population and apply it to another."
Having a first-degree relative with a form of IBD confers a greater risk than any known environmental factor. African Americans are conventionally thought to be less at risk for IBD, but Kugathasan said that view may reflect disparities in diagnosis and access to healthcare.
The study showed that the most important genetic risk locus for IBD in African Americans—known as PTGER4—is relatively minor in European ancestry population. By contrast, two gene loci that are major in Europeans—NOD2 and IL23R—play smaller roles in African Americans.
There is some overlap in genetic risk factors based on the African American population historically having about 20% European genetic background, with known IBD risk factors such as IL23R coming from the European side.
The current study also identified rare genetic variants conferring IBD risk that are specific to African Americans and which had not been observed in previous studies. The variants are connected to the gene encoding calbindin2 (CALB2), a protein involved in nervous system signaling.
What the study did not find were a host of rare genetic variants that explain the “missing heritability” in IBD among African Americans. In genome-wide association studies, missing heritability refers to disease risk that is not accounted for by common gene variants.
The primary sites to recruit study participants were Cedars-Sinai, Emory and Rutgers, along with Johns Hopkins and Washington University at SaintLouis.
Funding: This research was supported by the Rutgers Health Crohn's and Colitis Center of New Jersey and grants from three institutes of the National Institutes of Health: the Institute of Diabetes and Digestive and Kidney Diseases under award numbers DK062431, DK087694, DK062413, DK046763, DK062429, DK062422, DK062420, DK062432 and DK062423, the National Institute of Allergy and Infectious Diseases under award number AI067068 and the National Institute of Dental and Craniofacial Research under award number U54DE023789.