Addressing the challenges of polygenic scores in human genetic research

John Novembre; Catherine Stein; Samira Asgari; Claudia Gonzaga-Jauregui; Andrew Landstrom; Amy Lemke; Jun Li; Chloe Mighton; Matthew Taylor; Sarah Tishkoff

doi:10.1016/j.ajhg.2022.10.012

Addressing the challenges of polygenic scores in human genetic research

Am J Hum Genet. 2022 Dec 1;109(12):2095-2100. doi: 10.1016/j.ajhg.2022.10.012.

Authors

Affiliations

¹ Professional Practice and Social Implications Committee Polygenic Scores Guidance Writing Group, American Society of Human Genetics, Rockville MD, USA; Department of Human Genetics, University of Chicago, Chicago, IL, USA; Department of Ecology and Evolution, University of Chicago, Chicago, IL, USA. Electronic address: jnovembre@uchicago.edu.
² Professional Practice and Social Implications Committee Polygenic Scores Guidance Writing Group, American Society of Human Genetics, Rockville MD, USA; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA. Electronic address: cmj7@case.edu.
³ Professional Practice and Social Implications Committee Polygenic Scores Guidance Writing Group, American Society of Human Genetics, Rockville MD, USA; Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Professional Practice and Social Implications Committee Polygenic Scores Guidance Writing Group, American Society of Human Genetics, Rockville MD, USA; International Laboratory for Human Genome Research, Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, México.
⁵ Professional Practice and Social Implications Committee Polygenic Scores Guidance Writing Group, American Society of Human Genetics, Rockville MD, USA; Department of Pediatrics, Division of Cardiology, Duke University School of Medicine, Durham, NC, USA.
⁶ Professional Practice and Social Implications Committee Polygenic Scores Guidance Writing Group, American Society of Human Genetics, Rockville MD, USA; Norton Children's Research Institute, affiliated with the University of Louisville School of Medicine, Louisville, KY, USA.
⁷ Professional Practice and Social Implications Committee Polygenic Scores Guidance Writing Group, American Society of Human Genetics, Rockville MD, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
⁸ Professional Practice and Social Implications Committee Polygenic Scores Guidance Writing Group, American Society of Human Genetics, Rockville MD, USA; Genomics Health Services Research Program, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada; Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
⁹ Professional Practice and Social Implications Committee Polygenic Scores Guidance Writing Group, American Society of Human Genetics, Rockville MD, USA; Adult Medical Genetics Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁰ Professional Practice and Social Implications Committee Polygenic Scores Guidance Writing Group, American Society of Human Genetics, Rockville MD, USA; Department of Genetics, Center for Global Genomics and Health Equity, University of Pennsylvania, Philadelphia, PA, USA; Department of Biology, Center for Global Genomics and Health Equity, University of Pennsylvania, Philadelphia, PA, USA.

Abstract

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 by using genome-wide association studies (GWASs). The associations between phenotype and genotype found in GWASs make possible the construction of polygenic scores (PGSs), which aim to predict a trait or disease outcome in an individual on the basis of their genotype (in the disease case, the term polygenic risk score [PRS] is often used). PGSs have shown promise for studying the biology of complex traits and as a tool for evaluating individual disease risks in clinical settings. Although the quantity and quality of data to compute PGSs are increasing, challenges remain in the technical aspects of developing PGSs and in the ethical and social issues that might arise from their use. This ASHG Guidance emphasizes three major themes for researchers working with or interested in the application of PGSs in their own research: (1) developing diverse research cohorts; (2) fostering robustness in the development, application, and interpretation of PGSs; and (3) improving the communication of PGS results and their implications to broad audiences.

Publication types

Review

MeSH terms

Genetic Research
Genome-Wide Association Study*
Genotype
Humans
Multifactorial Inheritance* / genetics
Phenotype