Population structure and pharmacogenomic risk stratification in the United States

Abstract

Background Pharmacogenomic (PGx) variants mediate how individuals respond to medication, and response differences among racial/ethnic groups have been attributed to patterns of PGx diversity. We hypothesized that genetic ancestry (GA) would provide higher resolution for stratifying PGx risk, since it serves as a more reliable surrogate for genetic diversity than self-identified race/ethnicity (SIRE), which includes a substantial social component. We analyzed a cohort of 8628 individuals from the United States (US), for whom we had both SIRE information and whole genome genotypes, with a focus on the three largest SIRE groups in the US: White, Black (African-American), and Hispanic (Latino). Our approach to the question of PGx risk stratification entailed the integration of two distinct methodologies: population genetics and evidence-based medicine. This integrated approach allowed us to consider the clinical implications for the observed patterns of PGx variation found within and between population groups. Results Whole genome genotypes were used to characterize individuals’ continental ancestry fractions—European, African, and Native American—and individuals were grouped according to their GA profiles. SIRE and GA groups were found to be highly concordant. Continental ancestry predicts individuals’ SIRE with > 96% accuracy, and accordingly, GA provides only a marginal increase in resolution for PGx risk stratification. In light of the concordance between SIRE and GA, taken together with the fact that information on SIRE is readily available to clinicians, we evaluated PGx variation between SIRE groups to explore the potential clinical utility of race and ethnicity. PGx variants are highly diverged compared to the genomic background; 82 variants show significant frequency differences among SIRE groups, and genome-wide patterns of PGx variation are almost entirely concordant with SIRE. The vast majority of PGx variation is found within rather than between groups, a well-established fact for almost all genetic variants, which is often taken to argue against the clinical utility of population stratification. Nevertheless, analysis of highly differentiated PGx variants illustrates how SIRE partitions PGx variation based on groups’ characteristic ancestry patterns. These cases underscore the extent to which SIRE carries clinically valuable information for stratifying PGx risk among populations, albeit with less utility for predicting individual-level PGx alleles (genotypes), supporting the concept of population pharmacogenomics. Conclusions Perhaps most interestingly, we show that individuals who identify as Black or Hispanic stand to gain far more from the consideration of race/ethnicity in treatment decisions than individuals from the majority White population.

Evaluation of population‐level pharmacogenetic actionability in Alabama

“…Although it has been shown that self‐identified race ethnicity and genetic ancestry are highly concordant for PGx risk stratification, 48 we evaluated the ancestry composition of participants among self‐reported race groups to confirm these findings in our cohort prior to conducting the PGx assessment. Whereas the predominant ancestry fraction among each self‐reported race group was concordant, we present examples where the use of self‐reported race in lieu of PGx testing for variants that are thought to be unique to a specific ancestry group, may fail to identify participants who harbor the variant due to genetic admixture.…”

A Comprehensive Analysis of 21 Actionable Pharmacogenes in the Spanish Population: From Genetic Characterisation to Clinical Impact

“…In this sense, the Spanish population is very homogeneous between the different Spanish regions, and it has been described as similar to other European populations but more genetically diverse than Western and Northern Europeans [20]. This fact is mainly due to the fraction of North-West African ancestry (0-11%) in Spanish population, related to an admixture event occurring during the Muslim rule in Iberia [21]. Of note, we have already observed these differences in the Spanish population [22].…”

Rare Variants in Pharmacogenes Influence Clozapine Metabolism in Individuals with Schizophrenia

“…Given that individuals of other biogeographical ancestries are known to have different clozapine pharmacokinetic profiles 9 , our study cannot assess a potential rare variant contribution to those known ancestral differences, and its results might not be straightforwardly transferrable to non-European populations. We note, however, that consistency of variant effect sizes across populations is a reasonable assumption for pharmacogenes 52 and that the occurrence of deleterious variation in these gene sets is frequent (though individually rare) across continental ancestries 53 . Thus, the association between rare damaging burden and clozapine metabolism identified here could be of relevance beyond the European sample in which it was discovered.…”