Clinical use of current polygenic risk scores may exacerbate health disparities

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Abstract

Polygenic risk scores (PRS) are poised to improve biomedical outcomes via precision medicine. However, the major ethical and scientific challenge surrounding clinical implementation of PRS is that those available today are several times more accurate in individuals of European ancestry than other ancestries. This disparity is an inescapable consequence of Eurocentric biases in genome-wide association studies, thus highlighting that-unlike clinical biomarkers and prescription drugs, which may individually work better in some populations but do not ubiquitously perform far better in European populations-clinical uses of PRS today would systematically afford greater improvement for European-descent populations. Early diversifying efforts show promise in leveling this vast imbalance, even when non-European sample sizes are considerably smaller than the largest studies to date. To realize the full and equitable potential of PRS, greater diversity must be prioritized in genetic studies, and summary statistics must be publically disseminated to ensure that health disparities are not increased for those individuals already most underserved.

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The personal and clinical utility of polygenic risk scores

Eric Topol, Nathan Wineinger, Ali Torkamani (2018)

Initial expectations for genome-wide association studies were high, as such studies promised to rapidly transform personalized medicine with individualized disease risk predictions, prevention strategies and treatments. Early findings, however, revealed a more complex genetic architecture than was anticipated for most common diseases - complexity that seemed to limit the immediate utility of these findings. As a result, the practice of utilizing the DNA of an individual to predict disease has been judged to provide little to no useful information. Nevertheless, recent efforts have begun to demonstrate the utility of polygenic risk profiling to identify groups of individuals who could benefit from the knowledge of their probabilistic susceptibility to disease. In this context, we review the evidence supporting the personal and clinical utility of polygenic risk profiling.

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Understanding associations among race, socioeconomic status, and health: Patterns and prospects.

David R. Williams, Naomi Priest, Norman B. Anderson (2016)

Race/ethnicity and socioeconomic status (SES) are social categories that capture differential exposure to conditions of life that have health consequences. Race/ethnicity and SES are linked to each other, but race matters for health even after SES is considered. This commentary considers the complex ways in which race combines with SES to affect health. There is a need for greater attention to understanding how risks and resources in the social environment are systematically patterned by race, ethnicity and SES, and how they combine to influence cardiovascular disease and other health outcomes. Future research needs to examine how the levels, timing and accumulation of institutional and interpersonal racism combine with other toxic exposures, over the life-course, to influence the onset and course of illness. There is also an urgent need for research that seeks to build the science base that will identify the multilevel interventions that are likely to enhance the health of all, even while they improve the health of disadvantaged groups more rapidly than the rest of the population so that inequities in health can be reduced and ultimately eliminated. We also need sustained research attention to identifying how to build the political support to reduce the large shortfalls in health. (PsycINFO Database Record

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Fine-mapping inflammatory bowel disease loci to single variant resolution

Hailiang Huang, Ming Zhu Fang, Luke Jostins … (2017)

Summary The inflammatory bowel diseases (IBD) are chronic gastrointestinal inflammatory disorders that affect millions worldwide. Genome-wide association studies have identified 200 IBD-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 IBD loci using high-density genotyping in 67,852 individuals. We pinpointed 18 associations to a single causal variant with >95% certainty, and an additional 27 associations to a single variant with >50% certainty. These 45 variants are significantly enriched for protein-coding changes (n=13), direct disruption of transcription factor binding sites (n=3) and tissue specific epigenetic marks (n=10), with the latter category showing enrichment in specific immune cells among associations stronger in CD and in gut mucosa among associations stronger in UC. The results of this study suggest that high-resolution fine-mapping in large samples can convert many GWAS discoveries into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.