Comparative Performance of Polygenic Risk Scores for Atherosclerotic Cardiovascular Disease Subtypes in theAll of UsResearch Program
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Abstract
Background Performance and portability of contemporary polygenic risk scores (PRS) for atherosclerotic cardiovascular disease (ASCVD) phenotypes vary based on different methods, training data, and trait ascertainment. Objectives We aimed to investigate performance and portability of contemporary PRS for ASCVD subtypes: coronary heart disease (CHD), abdominal aortic aneurysm (AAA), ischemic stroke (IS), and peripheral artery disease (PAD), using the All of Us Workbench which provides access to a large diverse cohort with phenotype and whole genome sequence data. We also developed and evaluated a multi-trait PRS for each subtype. Methods Performance of PRS for 4 ASCVD traits and related risk factors was compared across genetic ancestry groups in 245,388 All of Us participants. Genetic EUR, African (AFR), Admixed American (AMR), and remaining ancestry groups (combined as Other, OTH) were defined by All of Us based on principal components. PRS for CHD, IS, AAA, PAD, and multi-trait (combining PRS for the 4 traits as well as PRS for ASCVD risk factors) were assessed for portability across genetic ancestry groups using hazard ratios (HR) per SD increase. Results For CHD, CHD PGS003725 performed the best (HR for 1 SD increase [95% CI]), across 4 genetic ancestry groups (EUR: 1.72[1.67-1.78], AFR: 1.24[1.18-1.31], AMR: 1.48[1.37-1.59], OTH: 1.65[1.52-1.79]). The best performing PRS for AAA was AAA PGS003972 (EUR: 1.68[1.59-1.78], AFR: 1.29[1.13-1.48], AMR: 1.30[1.06-1.60], OTH: 1.45[1.20-1.75]). The best performing IS PRS was IS PGS000039 in AFR (1.12[1.06-1.17]), AMR (1.11[1.04-1.19]), and OTH (1.23[1.09-1.38]), and IS PGS004939 in EUR (1.16[1.12-1.20]). For PAD, PAD PGS004940 performed best in EUR (1.26[1.22-1.30]), AFR (1.11[1.05-1.18]), AMR (1.08[1.01-1.16]), and OTH (1.13[1.04-1.22]). Multi-trait PRS performed better than individual trait PRS for each ASCVD phenotype. Also, PRS derived from multi-ancestry cohorts performed better than those derived from single ancestry. Conclusions PRS for ASCVD developed from multi-ancestry cohorts and multiple related traits performed best across ancestrally diverse and admixed individuals. PRS for CHD and AAA performed better than those for IS and PAD.
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Abstract
Background Performance and portability of contemporary polygenic risk scores (PRS) for atherosclerotic cardiovascular disease (ASCVD) phenotypes vary based on different methods, training data, and trait ascertainment.
Objectives
We aimed to investigate performance and portability of contemporary PRS for ASCVD subtypes: coronary heart disease (CHD), abdominal aortic aneurysm (AAA), ischemic stroke (IS), and peripheral artery disease (PAD), using the All of Us Workbench which provides access to a large diverse cohort with phenotype and whole genome sequence data. We also developed and evaluated a multi-trait PRS for each subtype.
Methods
Performance of PRS for 4 ASCVD traits and related risk factors was compared across genetic ancestry groups in 245,388 All of Us participants. Genetic EUR, African (AFR), Admixed American (AMR), and remaining ancestry groups (combined as Other, OTH) were defined by All of Us based on principal components. PRS for CHD, IS, AAA, PAD, and multi-trait (combining PRS for the 4 traits as well as PRS for ASCVD risk factors) were assessed for portability across genetic ancestry groups using hazard ratios (HR) per SD increase.
Results
For CHD, CHDPGS003725 performed the best (HR for 1 SD increase [95% CI]), across 4 genetic ancestry groups (EUR: 1.72[1.67-1.78], AFR: 1.24[1.18-1.31], AMR: 1.48[1.37-1.59], OTH: 1.65[1.52-1.79]). The best performing PRS for AAA was AAAPGS003972 (EUR: 1.68[1.59-1.78], AFR: 1.29[1.13-1.48], AMR: 1.30[1.06-1.60], OTH: 1.45[1.20-1.75]). The best performing IS PRS was ISPGS000039 in AFR (1.12[1.06-1.17]), AMR (1.11[1.04-1.19]), and OTH (1.23[1.09-1.38]), and ISPGS004939 in EUR (1.16[1.12-1.20]). For PAD, PADPGS004940 performed best in EUR (1.26[1.22-1.30]), AFR (1.11[1.05-1.18]), AMR (1.08[1.01-1.16]), and OTH (1.13[1.04-1.22]). Multi-trait PRS performed better than individual trait PRS for each ASCVD phenotype. Also, PRS derived from multi-ancestry cohorts performed better than those derived from single ancestry.
Conclusions
PRS for ASCVD developed from multi-ancestry cohorts and multiple related traits performed best across ancestrally diverse and admixed individuals. PRS for CHD and AAA performed better than those for IS and PAD.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
T32 HL07111-45 NHGRI U01HG011710
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Institutional Review Board (IRB) of the All of Us Research Program gave ethical approval for this work. IRB 10-002758 of Mayo Clinic gave ethical approval for this work.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
Yes
Data Availability
All data produced in the present work are contained in the manuscript. Individual-level data is available upon request or application to All of Us Research Program.
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