Human Genetic Studies of Disease Lack Diversity, Limiting Utility

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Big data-analysis of genome-wide association studies has enabled advances in precision medicine approaches to the diagnosis and treatment of a multitude of human diseases, but leave ethnic minorities behind, according to a commentary published in Cell on March 21.  The article by Girgio Sirugo and Sarah A. Tishkoff, both of the University of Pennsylvania, and Scott M. Williams of Case Western Reserve University, outlines how lack of diversity in these study populations translates into dangerously inferior care for under-represented populations around the globe.

Examining all genome-wide association studies (GWAS) up to 2018, the authors report that participants are 78% European, 10% Asian, 2% African and 1% Hispanic. “The under-representation of ethnically diverse populations impedes our ability to fully understand the genetic architecture of human disease and exacerbates health inequities,” says Sirugo. “Our ability to translate genetic research into clinical practice or public health policy may be dangerously incomplete, or worse, mistaken.”

In some cases, disease diagnoses may be overlooked in under-represented populations.  In particular, doctors may be looking for the wrong genetic target in patients of non-European decent, where different mutations may underlie a disease, or the prevalence of disease causing mutations differs drastically between ethnic groups. This is the explanation behind the under-diagnosis of cystic fibrosis in patients of African-decent who typically carry a different causative mutation than those of European ancestry.

Many such population-specific mutations are yet unknown. Characterizing the full spectrum of mutations, and their frequencies, across populations is critical to accurate diagnosis and implementing effective screening and treatment strategies. “Knowing and testing for specific pathogenic variants that vary in frequency across populations is crucial for appropriate clinical intervention,” says Sirugo.

In fact, applying precision medicine approaches derived from studying patients with European ancestry to patients across broad ethnicities can be downright dangerous. “Algorithms derived from Europeans do not translate into better and safer treatment across ethnic groups,” says Sirugo. For example, dosage calculations for the anticoagulant drug warfarin can be notoriously inaccurate in patients with non-European ancestry.  Apply European-derived algorithms puts these patients at higher risk of life-threatening strokes and hemorrhaging from incorrect dosing. “Identification of genetic variants that influence drug metabolism across global populations is needed to accurately predict drug responses in individuals of diverse ethnicities,” says Sirugo.

Similarly, disease-risk assessments can be way off. “Attempts to use estimates of genetic risk from European-based studies in non-Europeans may result in inaccurate assessment of risk and lack of intervention in under-studied populations,” says Sirugo.  These populations also have higher danger of adverse drug reactions and side effects, without adequate knowledge of ethnic genetic risk factors.  “Genetic variation can affect drug safety… In 2008 a failure to take (this) into account in Sub- Saharan Africa led to withdrawal of an effective antimalarial drug combination.”

Lack of understanding of ethnic genetic diversity in association with disease represents missed opportunities for diagnosing and treating specific populations, further perpetuation inequalities in medical care. But also, these are missed opportunities for understanding underlying disease etiology which may inform novel precision medicine approaches for a broader range of populations.  “(Population-specific) variants can provide important insights into gene function and pave the way to the discovery or validation of drug targets, as in the Human Knockout Project that focuses on Pakistanis,” says Sirugo. “They can also shed light on biological pathways that have relevance across populations, as has been the case with the discovery of PCSK9, an important gene for regulating LDL levels. This discovery was facilitated by studying people of African descent, … but the knowledge has translated into a drug with global utility.”

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