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Lack of Diversity in Genetic Datasets is Risky for Treating Disease

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Monday, March 25, 2019

Not too long ago, a couple came to see Neil Risch, a human geneticist at the University of California, San Francisco, in the hope that he could identify rare gene variants in their child, who had an undiagnosed disease. Not a problem, Risch thought. He’d sequence the exomes of the parents and child and run the data through a rare-variants database to identify the faulty genes underlying the child’s illness. The case wasn’t so straightforward, though. The parents didn’t have European ancestry but were descendants of a population not well represented in the database. 

“For individuals with genetic backgrounds not represented in [the database], there can be additional challenges in properly identifying genetic variants that cause the patient’s symptoms,” Risch says. Namely, it’s hard to identify any genetic link to symptoms, perhaps because the disease is caused by novel variants not yet identified as pathogenic. 

The case, Risch says, is not uncommon the clinical setting, where most of the data represents individuals with European ancestry. The same is true for the data that have, so far, been collected by the National Institutes of Health (NIH) and by companies such as 23andMe. In fact, a Nature comment published in 2016 estimated that about 80 percent of people in genetic studies were of European descent. And as of 2018, the proportions of individuals included in genome-wide association studies (GWAS) are 78 percent European, 10 percent Asian, 2 percent African, 1 percent Hispanic, with all other ethnicities representing less than 1 percent, University of Pennsylvania human geneticist Sarah Tishkoff and her colleagues write today (March 21) in a Cell commentary. That’s problematic, they write, because “the lack of ethnic diversity in human genomic studies means that our ability to translate genetic research into clinical practice or public health policy may be dangerously incomplete, or worse, mistaken.” 

At a very basic level, “if you really want to understand human biology, it makes sense to study the full breadth of human cultural and biological diversity,” Joanna Mountain, an anthropologist and senior director of research at 23andMe tells The Scientist. “If we can understand how [people have evolved culturally and biologically in their environment] around the world, we may be able to understand health and disease at a broader level. That’s one very, very core reason to diversify our genetic database.”

Others are doing the same, including scientists such as Tishkoff, clinical researchers such as Risch, and the National Institute of Health.

When it comes to Mendelian diseases, where one gene variant typically causes a disease, the pathogenic variant in one population should be pathogenic in other populations. But, that’s not always the case. In cystic fibrosis (CF), for example, the gene variant that most often causes CF in Europeans is ΔF508 in the CFTR gene. This mutation accounts for more than 70 percent of CF in Europeans, but only 29 percent of cases in people of the African diaspora. Another mutation, 3120+1GàA explains between 15 percent and 65 percent of CF in South African patients with African ancestry, Tishkoff and her colleagues explain. Each of these variants leads to somewhat different forms of the disease, and based on the population differences, treatments could be different for each group, a fact that becomes apparent only when genetic diversity is included in research datasets.

Another reason for prioritizing diversity in genetic studies, Tishkoff tells The Scientist, is that it can lead to a new understanding of genes that underlie disease or new therapeutics that may not be discoverable in populations that are already well studied. In 2017, for example, Tishkoff and her colleagues published a study in Science revealing novel gene variants and one novel gene associated with skin pigmentation in a sample of 1,600 individuals from diverse African populations. The novel gene MFSD12 “plays a critical role in melanocyte development and production of pigments, and a recent study indicates it plays a role in skin cancer,” Tishkoff says. But before her team’s study, “nothing was known about this gene.”

Another example is the development of PCSK9 inhibitors, new drugs that lower cholesterol. A study of genes related to cholesterol revealed that certain mutations in the PCSK9 genes in some individuals with African descent led them to have low LDL cholesterol. These mutations, however, are extremely rare in Americans with European ancestry, so without studying individuals of African descent, the new cholesterol-controlling drugs might not have been developed.

This is not to suggest that any given ethnicity is homogeneous, and diversity within groups is a critical consideration. Take, for instance, G6PD deficiency, which can lead to red blood cell destruction in response to taking antimalarial drugs. In sub-Saharan Africa, G6PD deficiency can reach a frequency of 25 percent, particularly when treatments for malaria are given. Because the illness was exacerbated by an effective antimalarial drug combination, called chlorproguanil-dapsone, it was pulled from use, even though it could have been used safely in malaria-infected patients not enzymatically deficient in G6PD, Tishkoff and her colleagues note. 

“Lots of populations have their own genetic profile,” Risch says, and there are “some we are clearly missing.”

Author: Ashley Yeager
Source: the-scientist
3.25
3.2 from 4 votes
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