Polygenic Risk Score for Alzheimer's Disease in Caribbean Hispanics
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abstract
ObjectivePolygenic risk scores (PRSs) assess the individual genetic propensity to a condition by combining sparse information scattered across genetic loci, often displaying small effect sizes. Most PRSs are constructed in European‐ancestry populations, limiting their use in other ethnicities. Here we constructed and validated a PRS for late‐onset Alzheimer's Disease (LOAD) in Caribbean Hispanics (CH).MethodsWe used a CH discovery (n = 4,312) and independent validation sample (n = 1,850) to construct an ancestry‐specific PRS (“CH‐PRS”) and evaluated its performance alone and with other predictors using the area under curve (AUC) and logistic regression (strength of association with LOAD and statistical significance). We tested if CH‐PRS predicted conversion to LOAD in a subsample with longitudinal data (n = 1,239). We also tested the CH‐PRS in an independent replication CH cohort (n = 200) and brain autopsy cohort (n = 33). Finally, we tested the effect of ancestry on PRS by using European and African American discovery cohorts to construct alternative PRSs (“EUR‐PRS”, “AA‐PRS”).ResultsThe full model (LOAD ~ CH‐PRS + sex + age + APOE‐ɛ4), achieved an AUC = 74% (ORCH‐PRS = 1.51 95%CI = 1.36–1.68), raising to >75% in APOE‐ɛ4 non‐carriers. CH‐PRS alone achieved an AUC = 72% in the autopsy cohort, raising to AUC = 83% in full model. Higher CH‐PRS was significantly associated with clinical LOAD in the replication CH cohort (OR = 1.61, 95%CI = 1.19–2.17) and significantly predicted conversion to LOAD (HR = 1.93, CI = 1.70–2.20) in the longitudinal subsample. EUR‐PRS and AA‐PRS reached lower prediction accuracy (AUC = 58% and 53%, respectively).InterpretationEnriching diversity in genetic studies is critical to provide an effective PRS in profiling LOAD risk across populations. ANN NEUROL 2021;90:366–376
