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Reviewing Genomic Research Through a Minority Lens_ Analysis of Inclusivity Policies – PDF VERSION
Emily Xiao1, Maya Vendhan2, Leigh Baratta3, Serena Yang4, Sabreen Alam5, Elizabeth Wang6, Brooke Ellison7
1Alexander Mackenzie High School, ON 14519, 2Colorado Academy, CO 80235, 3Smithtown High School East, NY 11780, 4Dougherty Valley High School, CA 94582, 5Portola High School, Irvine, CA 92618, 6BASIS Chandler, Chandler, AZ 85249, 7Center for Compassionate Care, Medical Humanities, and Bioethics, Health Science Center, Stony Brook University, Stony Brook, NY 11794
*Editors: Daniel Luo, Emily Zhou
Genetic research is important to understanding how the human body functions. These tests provide an awareness about population history, disease risk, etc., which is why the field of genetic testing has gained tremendous amounts of coverage in the past decade. Genome-wide association studies (GWAS), the most commonly used method to identify genetic mutations and/or variants that impact illnesses, involve single nucleotide polymorphisms (SNPs) to identify small variations within a population that indicate the presence of a particular disease.[9] However, these studies lack inclusivity. As shown in Figure 1, people of European descent were significantly more represented than those of Asian, Latin American, and African descent in the populations used for genomic studies done by Genome-Wide Association Study Catalog and the Genotypes and Phenotypes databases.[1, 4, 8] Various data types and disease areas all showed similar findings.[4] This lack of diversity impacts prognosis and treatment, precision medicine, and knowledge of diseases prevalent in minority populations. To combat these challenges, genomic research needs to include more minority populations.
Figure 1. The distribution of ethnic populations represented in genome-wide association studies (GWAS) based on studies (left) and based on the total number of individuals (right).[8]
Cystic fibrosis diagnosis statistics are an example of how the effectiveness of precision medicine is compromised due to lack of diversity in gene pools tested to examine the cause of the disease. Cystic fibrosis is a common disease known to affect many Europeans; current research states that 1 in every 2000 Europeans are afflicted, while only 1 in every 17000 Africans are afflicted.[8] This statistic seemingly indicates that cystic fibrosis does not significantly affect Africans, but these numbers are a result of cystic fibrosis being often underdiagnosed in Africans. In Europeans, over 70% of the cases are caused by an allele in the CFTR gene, ΔF508, yet this same allele causes less than 30% of the African cases.[8] The current medication (Ivacaftor) commonly used to treat cystic fibrosis selectively targets ΔF508, but there are over 2000 rare mutations in the CFTR gene that require different treatment.
Another problem of the lack of diversity in genetic research is that there are population-specific mutations in underrepresented populations. In the United States, the transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a hereditary heart disease that both disproportionately affects and often goes undiagnosed in Black Americans.[7] The TTR pathogenic missense mutation (V122I) is highly prevalent in older Black Americans, with 3.43% carrying the mutation.[8] However, studies on the clinical symptoms of cardiac amyloidosis are restricted to areas where subjects with V122I are few, resulting in skewed data of patients presenting features of late-stage disease. Genetic testing, though, offers a solution as it can allow for early identification of at-risk or affected individuals and can determine whether the TTR amyloidosis is hereditary.[7] Furthermore, genetic screening can provide crucial information about diagnostic accuracy and therapy, which are pertinent to precision medicine.[8]
On the opposite end, a genetic test in 2005 incorrectly concluded that many patients with African ancestry had a high risk of developing hypertrophic cardiomyopathy. The test was based on data from those of European ancestry, and the variants TNNI3 P82S and MYBPC3 G278E were labeled as pathogenic.[5] Black Americans had significantly greater frequency of the variants of this disease than white Americans. Black Americans had a genotype frequency ranging from 2.9% to 27.1% while for white Americans, it was only 0.02% to 2.9%.[5] Due to lack of data, many black Americans were misdiagnosed as pathogenic when in actuality, the alleles were benign. This misdiagnosis creates a potentially dangerous environment of uncertainty amongst clinicians and patients.
When studying the genetics of the Indigneous Maori population in New Zealand, researchers identified a variant of the monoamine oxidase (MAO-A) gene which caused aggressive behaviour in monkeys. The variant was identified as the warrior gene, which is present in all populations but at different frequencies. Although it may not have been the researchers’ intention, the discovery created an inaccurate association that labelled the Indigenous Maori population as genetically aggressive.[2] This example is just one of the many negative experiences of an indigenous community because of genomic researchers, leading to mistrust between the two groups. Indigenous populations are widely underrepresented in genome-wide association studies, estimated at 0.02% of the total number of people whom research was conducted on in 2019. Furthermore, the Genome Aggregation Database, which is often utilized for genomic variant analysis, lacks abundant information about indigenous people.[2] Negative socioeconomic factors and historical experiences that have created tension between these minority groups and genomic researchers have fueled this underrepresentation.
The lack of minority representation in genomic research is clearly problematic, posing life-threatening risks for various demographics. Developing therapeutics that only cater towards a specific portion of our population is dangerous and blatantly ignores the disproportionately adverse impacts on minorities. Possible solutions to this issue include redefining genomic research by specifically examining the previously-ignored demographics. A consortium of researchers referred to as PAGE (Population Architecture using Genomics and Epidemiology) developed a Multi-Ethnic Genotyping Array (MEGA), which allowed for a deeper analysis of a wide variety of diseases in minority groups. They analyzed populations included 22,216 Hispanic/Latinos, 17,299 African Americans, 4,680 Asians, 3,940 Native Hawaiians, and 652 Native Americans.[4] Dr. Ulrike Peters, senior scientist at PAGE, concluded that “by examining previously underrepresented populations, we found new ancestry-specific associations, which furthers our understanding of the genetic architecture of traits and underscores the importance of including diverse populations in these studies”.[4] Supporting the work of PAGE and other groups with similar endeavors is critical to maintaining the integrity and effectiveness of genomic research and subsequent drugs and therapies. By funding research focused on bridging the racial gap in genetic data, redirecting efforts in universities and private sectors towards this cause, and allocating resources at the federal level to contribute towards diverse genomic research, we can develop safer and more effective therapeutics for all individuals regardless of race or ethnic background.
As a result of the differences in representation for European and minority populations, there have been many medicinal challenges. This lack of diversity has advanced health disparities, furthering misdiagnoses and inadequate treatment. Studies have indicated that 80% of the genomic database is European, suggesting that data acquired may not translate to minority populations. Therapeutics and treatments should be designed to cater toward any type of population, so it is of utmost importance to increase the amount of diversity in genomic databases such as GWAS. Through funding and support, minority populations can be equally represented in genetic research, improving the quality of care they receive.
References
[1] Benetti, Elisa et al. “ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population.” European journal of human genetics : EJHG vol. 28,11 (2020): 1602-1614. doi:10.1038/s41431-020-0691-z
[2] Garrison, Nanibaa’ A et al. “Genomic Research Through an Indigenous Lens: Understanding the Expectations.” Annual review of genomics and human genetics vol. 20 (2019): 495-517. doi:10.1146/annurev-genom-083118-015434
[3] “Lack of Diversity in Genetic Research a Problem.” Fred Hutch, 19 June 2019, www.fredhutch.org/en/news/center-news/2019/06/lack-diversity-genetic-research-problem.html
[4] Landry, Latrice G., et al. “Lack of Diversity in Genomic Databases Is a Barrier to Translating Precision Medicine Research into Practice.” Health Affairs, vol. 37, no. 5, 2018, pp. 780–785., doi:10.1377/hlthaff.2017.1595.
[5] Manrai, Arjun K et al. “Genetic Misdiagnoses and the Potential for Health Disparities.” The New England journal of medicine vol. 375,7 (2016): 655-65. doi:10.1056/NEJMsa1507092
[6] McGuire, Amy L. et al. , “The Road Ahead in Genetics and Genomics.” Nature Reviews 21 (2020): 581- 596.
[7] Shah, Keyur B., et al. “Transthyretin Cardiac AMYLOIDOSIS in Black Americans.” Circulation: Heart Failure, vol. 9, no. 6, 2016, doi:10.1161/circheartfailure.115.002558.
[8] Sirugo, Giorgio, et al. “The Missing Diversity in Human Genetic Studies.” Cell, vol. 177, no. 1, 21 Mar. 2019, pp. 26–31., doi:10.1016/j.cell.2019.04.032.
[9] “What Are Genome-Wide Association Studies?: MedlinePlus Genetics.” MedlinePlus, U.S. National Library of Medicine, 18 Sept. 2020, medlineplus.gov/genetics/understanding/genomicresearch/gwastudies/.