Multi-ancestry polygenic risk scores for venous thromboembolism

Jun 16, 2024Human molecular genetics

Genetic risk scores for blood clots across different ancestry groups

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Abstract

The highest fifth percentile of the best-performing polygenic risk score was associated with a 1.9-fold increased risk for venous thromboembolism among European-ancestry subjects.

Multi-ancestry polygenic risk scores constructed from diverse training data may enhance predictive ability for venous thromboembolism across different populations.
In European-ancestry test samples, the area under the receiver operating curve for the combined multi-ancestry polygenic risk score was 0.609.
Ancestry-specific polygenic risk scores showed slightly lower performance compared to multi-ancestry scores in both European- and African-ancestry samples.
The highest fifth percentile of the best-performing polygenic risk score was associated with a 1.68-fold increased risk for venous thromboembolism among African-ancestry subjects.
Findings indicate that multi-ancestry polygenic risk scores could be utilized to better identify individuals at highest risk for venous thromboembolism.

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Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations. We developed PRSs for VTE using summary statistics from the International Network against Venous Thrombosis (INVENT) consortium genome-wide association studies meta-analyses of European- (71 771 cases and 1 059 740 controls) and African-ancestry samples (7482 cases and 129 975 controls). We used LDpred2 and PRS-CSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6781 cases and 103 016 controls) and African-ancestry sample (1385 cases and 12 569 controls). Multi-ancestry PRSs with weights tuned in European-ancestry samples slightly outperformed ancestry-specific PRSs in European-ancestry test samples (e.g. the area under the receiver operating curve [AUC] was 0.609 for PRS-CSx_combinedEUR and 0.608 for PRS-CSxEUR [P = 0.00029]). Multi-ancestry PRSs with weights tuned in African-ancestry samples also outperformed ancestry-specific PRSs in African-ancestry test samples (PRS-CSxAFR: AUC = 0.58, PRS-CSx_combined AFR: AUC = 0.59), although this difference was not statistically significant (P = 0.34). The highest fifth percentile of the best-performing PRS was associated with 1.9-fold and 1.68-fold increased risk for VTE among European- and African-ancestry subjects, respectively, relative to those in the middle stratum. These findings suggest that the multi-ancestry PRS might be used to improve performance across diverse populations to identify individuals at highest risk for VTE.

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