ASHG Issues New Guidance on Addressing the Challenges of Polygenic Scores in Human Genetic Research

The American Society of Human Genetics (ASHG) today published a new Guidance on the challenges in the development and application of polygenic scores (PGS) in human genetic research. Appearing in today’s issue of the American Journal of Human Genetics (AJHG), this new resource was developed by a writing group led by members of the ASHG Professional Practice and Social Implications Committee (PPSI). It was approved by the ASHG Board of Directors for publication in October 2022.

The genotyping of millions of human samples has made it possible to evaluate variants across the human genome for their possible association with risks for numerous diseases and other traits using genome-wide association studies (GWAS). The association between a person’s genome and health outcomes has led to the development and application of polygenic scores (PGS), often called polygenic risk scores (PRS) in the context of disease. This statistical tool has shown promise for studying the biology of complex traits and for evaluating individual disease risks in clinical settings. However, there are challenges in the application of PGS, particularly for individuals whose backgrounds are underrepresented in genomics research, potentially leading to misrepresentation of disease risk and exacerbation of health inequities. The vision of ASHG is that people everywhere will realize the benefits of human genetics and genomics ( Ensuring that the benefits of human genetics and genomics research are realized in ways that minimize harms and maximize benefits is a goal that can only be achieved through focused efforts to address health inequities and increase representation in research.

This ASHG Guidance emphasizes three major recommendations to address the current limitations of PGS for researchers working with or interested in the application of PGS in their own research: 1) develop diverse research cohorts across multiple dimensions, 2) foster robustness in the development, application, and interpretation of PGS, and 3) improve the communication of PGS results, including limitations, and their implications to broad audiences. As work continues in this area, it is critical for researchers to pro-actively consider, apply, and build upon these recommendations in order to avoid misapplication of PGS.

Catherine Stein, PhD, Polygenic Scores Guidance Writing Group Co-Chair and one of the corresponding authors on this Guidance, said, “With the increasing use of polygenic scores both for research and clinical applications, it is important to consider the methodologic limitations and ethical implications in these scores.  This ASHG Guidance provides a critical first step in tackling these issues as researchers.” John Novembre, PhD, Polygenic Scores Guidance Writing Group Co-Chair and co-corresponding author, added, “The challenges of polygenic scores in research are multi-dimensional.  As the report highlights, we need more diverse cohorts, more robust polygenic score methods, and improved communication of results.”

Recognizing that researchers do not always have formal training on specific ethical or social implications, ASHG sees the creation of each Guidance as a tangible and constructive step in responsible application of research. The committee aims to engage the research community further on this topic, including with a webinar in 2023.

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