Transferability of Alzheimer Disease Polygenic Risk Score Across Populations and Its Association With Alzheimer Disease-Related Phenotypes

Abstract

ImportancePolygenic risk scores (PRSs), which aggregate the genetic effects of single-nucleotide variants identified in genome-wide association studies (GWASs), can help distinguish individuals at a high genetic risk for Alzheimer disease (AD). However, genetic studies have predominantly focused on populations of European ancestry.ObjectiveTo evaluate the transferability of a PRS for AD in the Korean population using summary statistics from a prior GWAS of European populations.Design, Setting, and ParticipantsThis cohort study developed a PRS based on the summary statistics of a large-scale GWAS of a European population (the International Genomics of Alzheimer Project; 21 982 AD cases and 41 944 controls). This PRS was tested for an association with AD dementia and its related phenotypes in 1634 Korean individuals, who were recruited from 2013 to 2019. The association of a PRS based on a GWAS of a Japanese population (the National Center for Geriatrics and Gerontology; 3962 AD cases and 4074 controls) and a transancestry meta-analysis of European and Japanese GWASs was also evaluated. Data were analyzed from December 2020 to June 2021.Main Outcomes and MeasuresRisk of AD dementia, amnestic mild cognitive impairment (aMCI), earlier symptom onset, and amyloid β deposition (Aβ).ResultsA total of 1634 Korean patients (969 women [59.3%]), including 716 individuals (43.6%) with AD dementia, 222 (13.6%) with aMCI, and 699 (42.8%) cognitively unimpaired controls, were analyzed in this study. The mean (SD) age of the participants was 71.6 (9.0) years. Higher PRS was associated with a higher risk of AD dementia independent of APOE ɛ4 status in the Korean population (OR, 1.95; 95% CI, 1.40-2.72; P < .001). Furthermore, PRS was associated with aMCI, earlier symptom onset, and Aβ deposition independent of APOE ɛ4 status. The PRS based on a transancestry meta-analysis of data sets comprising 2 distinct ancestries showed a slightly improved accuracy.Conclusions and RelevanceIn this cohort study, a PRS derived from a European GWAS identified individuals at a high risk for AD dementia in the Korean population. These findings emphasize the transancestry transferability and clinical value of PRSs and suggest the importance of enriching diversity in genetic studies of AD.

2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association

“…A PRS for AD developed from GWASs in a European population was associated with risk of AD in a sample of 1634 Korean participants, of whom 716 had AD (OR of AD per increment in PRS, 1.95 [95% CI, 1.40–2.72]), suggesting that GRSs for AD may be transferable across different ethnic populations. 151…”

Improving genetic risk modeling of dementia from real-world data in underrepresented populations

“…These finding further reinforces the limitations of standard PRS when applied to non-European populations, in which attempting to transfer GWAS effect size from one GIA to another GIA, or when using matched genetic ancestry GWAS with smaller sample size, as demonstrated in several AD and other phenotype studies. 75–78…”

Polygenic risk scores validated in patient-derived cells stratify for mitochondrial subtypes of Parkinson’s disease

“…To determine whether the OXPHOS-PRS could represent a pathophysiology relevant tool to stratify iPD patients based on mitochondrial dysfunction, we sought to functionally validate predicted phenotypes in patient-derived cellular models. Participants were arbitrary grouped into low-, medium-, or high-risk groups according to the PRS distribution in lower and higher deciles [33,34]. Decile cut-offs of 10% and 90%, corresponding to the lowest and highest PD odds ratios, have been chosen for the subsequent functional studies (Supplementary Fig.…”