TY - UNPB
T1 - Multi-ancestry polygenic risk scores for venous thromboembolism
AU - Lifelines Cohort Study
AU - INVENT Consortium
AU - Jee, Yon Ho
AU - Thibord, Florian
AU - Dominguez, Alicia
AU - Sept, Corriene
AU - Boulier, Kristin
AU - Venkateswaran, Vidhya
AU - Ding, Yi
AU - Cherlin, Tess
AU - Verma, Shefali Setia
AU - Faro, Valeria Lo
AU - Bartz, Traci M
AU - Boland, Anne
AU - Brody, Jennifer A
AU - Deleuze, Jean-Francois
AU - Emmerich, Joseph
AU - Germain, Marine
AU - Johnson, Andrew D
AU - Kooperberg, Charles
AU - Morange, Pierre-Emmanuel
AU - Pankratz, Nathan
AU - Psaty, Bruce M
AU - Reiner, Alexander P
AU - Smadja, David M
AU - Sitlani, Colleen M
AU - Suchon, Pierre
AU - Tang, Weihong
AU - Trégouët, David-Alexandre
AU - Zöllner, Sebastian
AU - Pasaniuc, Bogdan
AU - Damrauer, Scott M
AU - Sanna, Serena
AU - Snieder, Harold
AU - Kabrhel, Christopher
AU - Smith, Nicholas L
AU - Kraft, Peter
PY - 2024/1/10
Y1 - 2024/1/10
N2 - 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 GWAS meta-analyses of European- (71,771 cases and 1,059,740 controls) and African-ancestry samples (7,482 cases and 129,975 controls). We used LDpred2 and PRSCSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6,261 cases and 88,238 controls) and African-ancestry sample (1,385 cases and 12,569 controls). Multi-ancestry PRSs with weights tuned in European- and African-ancestry samples, respectively, outperformed ancestry-specific PRSs in European- (PRSCSX
EUR: AUC=0.61 (0.60, 0.61), PRSCSX_combined
EUR: AUC=0.61 (0.60, 0.62)) and African-ancestry test samples (PRSCSX
AFR: AUC=0.58 (0.57, 0.6), PRSCSX_combined
AFR: AUC=0.59 (0.57, 0.60)). 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 may be used to identify individuals at highest risk for VTE and provide guidance for the most effective treatment strategy across diverse populations.
AB - 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 GWAS meta-analyses of European- (71,771 cases and 1,059,740 controls) and African-ancestry samples (7,482 cases and 129,975 controls). We used LDpred2 and PRSCSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6,261 cases and 88,238 controls) and African-ancestry sample (1,385 cases and 12,569 controls). Multi-ancestry PRSs with weights tuned in European- and African-ancestry samples, respectively, outperformed ancestry-specific PRSs in European- (PRSCSX
EUR: AUC=0.61 (0.60, 0.61), PRSCSX_combined
EUR: AUC=0.61 (0.60, 0.62)) and African-ancestry test samples (PRSCSX
AFR: AUC=0.58 (0.57, 0.6), PRSCSX_combined
AFR: AUC=0.59 (0.57, 0.60)). 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 may be used to identify individuals at highest risk for VTE and provide guidance for the most effective treatment strategy across diverse populations.
U2 - 10.1101/2024.01.09.24300914
DO - 10.1101/2024.01.09.24300914
M3 - Preprint
C2 - 38260294
BT - Multi-ancestry polygenic risk scores for venous thromboembolism
PB - MedRxiv
ER -