Polygenic risk, population structure and ongoing difficulties with race in human genetics

Area of Science:

• Human Population Genetics
• Genomics
• Bioethics

Background:

• Richard Lewontin's 1972 work established that race has little genetic significance.
• The biomedical community still debates incorporating race/ancestry in research.
• Translating genetic associations into polygenic risk scores (PRS) for clinical use is a current challenge.

Purpose of the Study:

• To examine challenges in developing and applying PRS in diverse cohorts.
• To analyze how population structure influences PRS and health disparities.
• To revisit Lewontin's findings in the context of modern PRS development.

Main Methods:

• Perspective piece analyzing current literature and debates.
• Tracing the historical context from Lewontin's "The Apportionment of Human Diversity".
• Critically evaluating the application of population structure in PRS.

Main Results:

• Despite analytical advances, PRS development faces difficulties in accounting for relevant population structure.
• There are ongoing struggles in deciding which population structure facets matter for health.
• Skepticism remains regarding PRS's ability to effectively address health disparities.

Conclusions:

• Lewontin's work suggests caution in using population structure for PRS.
• Current PRS approaches may not adequately identify or intervene on health disparities.
• Further critical evaluation is needed for equitable application of genetic risk prediction.