Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations

Abstract

A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.

Fig. 1. Associations between the various PGSs and the risk of developing AD as a function of APOE status (25,782 AD cases and 35,280 controls).

a, The risk of developing AD, by PGS^ALZ stratum (0–2%, 2–5%, 10–20%, 20–40%, 60–80%, 80–90%, 90–95%, 95–98% and 98–100%). The 40–60% PGS^ALZ stratum was used as the reference. b, Risk of developing AD, by PGS^ALZ stratum (0–20%, 20–40%, 60–80% and 80–100%) and by APOE genotype (by grouping together the ε2ε2/ε2ε3, ε3ε3, ε2ε4/ε3ε4 and ε4ε4 carriers). The 40–60% PGS^ALZ stratum was used as the reference. OR per s.d. was calculated by logistic regression adjusted for age, gender, 14 first PCs and chip center if necessary. The lines indicate the 95% CI of each OR. ε2ε2/ε2ε3 carriers (960 AD cases and 3,604 controls), ε3ε3 (15,623 AD cases and 17,782 controls), ε2ε4/ε3ε4 (8,780 AD cases and 6,242 controls) and ε4ε4 carriers (2,309 AD cases and 479 controls).

Fig. 2. Association of PGS^ALZ with Aβ₄₂ and p-tau in cerebrospinal fluid.

a–c, Association of PGS^ALZ with the level of normalized Aβ₄₂ (a) and p-tau (b) in cerebrospinal fluid (n = 13,004) across European ancestry populations and according to PGS^ALZ strata (0–20%, 20–40%, 60–80% and 80–100%) (c); the 40–60% PGS^ALZ stratum was used as the reference. β values were calculated by general linear model and logistic regression adjusted for APOE, age, gender, ten first PCs and chip center if necessary. The horizontal lines in the forest plots indicate the 95% CI of each β value. If heterogeneity P (HetP) < 0.05, a random effect is shown for the meta-analysis results. I²; heterogeneity.

Fig. 3. Association of PGS^ALZ across multiancestry populations.

a, Association of PGS^ALZ with the risk of developing AD in multiancestry populations. The European ancestry meta-analysis includes MVP and Australia. The African American ancestry (more than 75% AA ancestry) meta-analysis includes MVP and ADSP. The East Asia meta-analysis includes China, Korea and Japan. The Latin American ancestry (self-reported) meta-analysis includes MVP and ADSP. The South America meta-analysis includes Argentina, Brazil, Chile and Colombia. b, The risk of developing AD, according to PGS^ALZ (logistic regression adjusted or not for APOE or included APOE variants) strata (0–20%, 20–40%, 60–80% and 80–100%) in multiancestry populations. The 40–60% PGS^ALZ stratum was used as the reference in each population, and results were meta-analyzed. The European ancestry meta-analysis includes MVP and Australia. The African American ancestry meta-analysis includes MVP and ADSP. The East Asia meta-analysis includes China, Korea and Japan. The Latin American ancestry meta-analysis includes MVP and ADSP. The South America meta-analysis includes Argentina, Brazil, Chile and Colombia. N_cases, number of cases; N_controls, number of controls. OR per s.d. was calculated by logistic regression adjusted for APOE, age, sex and specific PCs according to the study (Supplementary Table 2). The lines in the Forest plots indicate the 95% CI of each OR. If HetP < 0.05, a random effect is shown for the meta-analysis results. AA, African American; EUR, European; LA, Latin American.

Fig. 4. Comparison of the association of PGS^ALZ or PRS (excluding the APOE region) with the AD risk and the corresponding predictive values (adjusted Nagelkerke R² and liability R²).

All PGS^ALZ and PRS values were adjusted for interpopulation differences in distribution; PRS^EUR were generated by using only European ancestry summary statistics; PRS^COMB were generated by combining European, African American, Latin American and East Asian ancestry summary statistics. The sparseness parameter was set to 10⁻⁸, 10⁻⁷, 10⁻⁶, 10⁻⁵, 10⁻⁴, 10⁻² or 1. OR per s.d. was calculated by logistic regression adjusted for age, sex and specific PCs according to the study (Supplementary Table 2). MVP EUR (4,561 AD cases and 84,587 controls), MVP LA (375 AD cases and 7,166 controls), MVP AA (713 AD cases and 19,405 controls) and South Korea (1,119 AD cases and 1,172 controls).

Fig. 5. Association of PRS (including the APOE region) with the AD risk and the corresponding predictive values (adjusted Nagelkerke R² and liability R²).

All PRS were adjusted for interpopulation differences in distribution; PRS^EUR were generated by using only European ancestry summary statistics; PRS^COMB were generated by combining European, African American, Latin American and East Asian ancestry summary statistics. The sparseness parameter was set to 10⁻⁸, 10⁻⁷, 10⁻⁶, 10⁻⁵, 10⁻⁴, 10⁻² or 1. OR per s.d. was calculated by logistic regression adjusted for age, sex and specific PCs according to the study (Supplementary Table 2). MVP EUR (4,561 AD cases and 84,587 controls), MVP LA (375 AD cases and 7,166 controls), MVP AA (713 AD cases and 19,405 controls) and South Korea (1,119 AD cases and 1,172 controls).

Fig. 6. Association of PGS^ALZ or PRS^COMB (excluding the APOE region) with AD, AD and related dementia (ADRD) and dementia in MVP, and the corresponding predictive values (adjusted Nagelkerke R² and liability R²).

PGS^ALZ and PRS^COMB were adjusted for interpopulation differences in distribution; PRS^COMB were generated by combining European, African American and Latin American and East Asian ancestry summary statistics. The sparseness parameter was set to 10⁻⁸ and 10⁻⁶. OR per s.d. was calculated by logistic regression adjusted for age, sex and specific PCs according to the study (Supplementary Table 2). MVP EUR (4,561 AD, 17,519 ADRD, 26,473 dementia cases and 84,587 controls), MVP LA (375 AD; 1,527 ADRD; 1,981 dementia cases and 7,166 controls), MVP AA (713 AD; 4,016 ADRD; 4,702 dementia cases and 19,405 controls).

Extended Data Fig. 1. Association of PGS^ALZ with the risk of developing AD (a) in 17 European countries and (b) in Men and Women.

Ncases, number of cases; Ncontrols, number of controls; OR, Odds ratio per Standard deviation were calculated using logistic regressions adjusted for age, gender and PCs according to the population studied (Supplementary Table 2). The lines in the Forest plots indicate the 95% confidence interval for the ORs.

Extended Data Fig. 2. Associations between (a) PGS^ALZ or (b) PGS^ALZ adjusted for APOE and age at onset of AD in European countries.

N_cases, the number of cases. Since HetP <0.05, the random effect is shown for the meta-analysis results. βs were calculated using a general linear model adjusted for APOE, gender and PCs according to the population studied (Supplementary Table 2).

Extended Data Fig. 3. Distribution and association of APOE ε2/ε3/ε4 alleles with AD risk worldwide.

(a) World map showing the populations analyzed. A color gradient indicates the strength of the association between APOE ε2/ε3/ε4 alleles and the risk of developing AD in different countries (b) frequencies of APOE ε2/ε3/ε4 alleles in case and controls as well association of APOE ε4 alleles with the risk of developing AD in different countries. OR, Odds ratio were calculated using logistic regressions adjusted for age, gender and PCs according to the population studied (Supplementary Table 2). Sample sizes are reported in Supplementary Table 2. The map was generated using ggplot2 and royalty-free data from rnaturalearth (https://www.naturalearthdata.com/about/terms-of-use/).

Extended Data Fig. 4. Association between (a) PGS^ALZ or (b) PGS^ALZ (adjusted for APOE) and age at onset of AD in multi-ancestry populations.

N_cases, number of cases. The African-American-ancestry meta-analysis (more than 75% of the population with African-American ancestry) included the MVP and ADSP datasets. The East Asia meta-analysis included datasets from China, Korea, and Japan. The Latin American (LA) ancestry (self-reporting) meta-analysis included the MMVP and ADSP datasets. The South America meta-analysis included the datasets from Argentina, Brazil, Chile, and Colombia. * not used in the meta-analysis. βs were calculated using a general linear model adjusted for gender and PCs according to the population studied (Supplementary Table 2).