The frequency of pathogenic variation in the All of Us cohort reveals ancestry-driven disparities

Area of Science:

• Genomics
• Precision Medicine
• Population Health

Background:

• Disparities in clinical genomic interpretation data are a known issue, yet empirical evidence is limited.
• The All of Us Research Program is a large-scale initiative collecting diverse genomic and health data from over a million participants.
• Understanding variant frequencies across diverse populations is crucial for equitable healthcare.

Purpose of the Study:

• To examine pathogenic and likely pathogenic variants within the All of Us Research Program cohort.
• To identify and quantify disparities in variant frequencies across different ancestral groups.
• To inform targeted precision medicine strategies by revealing data biases.

Main Methods:

• Analysis of whole-genome sequencing data from the All of Us Research Program cohort.
• Identification and categorization of pathogenic and likely pathogenic variants.
• Comparison of variant frequencies across European, African, and Latino/Admixed American ancestry subgroups.
• Cross-referencing findings with the gnomAD database for validation and discrepancy analysis.

Main Results:

• The European ancestry subgroup exhibited the highest rate of pathogenic variation (2.26%).
• Lower rates were observed in the African ancestry group (1.62%) and Latino/Admixed American ancestry group (1.32%).
• Pathogenic variants were most commonly found in genes associated with Breast/Ovarian Cancer and Hypercholesterolemia.
• Variant frequencies largely aligned with gnomAD data, with some exceptions noted and resolved.

Conclusions:

• Observed differences in pathogenic variant frequencies between ancestral groups suggest ascertainment biases in current knowledge.
• Some deviations may indicate actual differences in disease prevalence across populations.
• This research provides critical insights into genomic data disparities, paving the way for more equitable precision medicine.