The first genome-wide association study in the Argentinian and Chilean populations identifies shared genetics with Europeans in Alzheimer's disease

Abstract

Introduction: Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities.

Methods: We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta-analysis and tested their genetic risk score (GRS) performance in this admixed population.

Results: We detected apolipoprotein E ε4 as the single genome-wide significant signal (odds ratio = 2.93 [2.37-3.63], P = 2.6 × 10^-23 ). The meta-analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD-GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose.

Discussion: We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations.

Highlights: This is the first genome-wide association study on Alzheimer's disease (AD) in a population sample from Argentina and Chile. Trans-ethnic meta-analysis reveals four new loci involving lysosomal function in AD. This is the first independent replication for TREM2L, IGH-gene-cluster, and ADAM17 loci. A genetic risk score (GRS) developed in Europeans performed well in this population. The higher the Native American ancestry the lower the GRS values.

Keywords: Hispanic; Latin America; Native-American ancestry; South America; admixture; genetic risk score; genetics; genome-wide association study.

FIGURE 1

Ancestry analysis of the Argentinian and Chilean populations. A, Principal component analysis (PCA) of ancestry results for the Argentinian sample (ARG, black) and the Chilean sample (CHI, gray). Ancestral populations are Caucasians (CEU, blue), Yoruba (YRI, red), and Native Americans (NAM, green). B, Bar‐plots of each sample (x‐axis) versus their respective percent of Caucasian (CEU, blue), African (YRI, red), and Native American (NAM, green) ancestry (y‐axis).

FIGURE 2

GRS performance and its association with NAM ancestry. GRSs of the samples from Argentina and Chile were split into five groups (quintiles) depending on their proportion of NAM ancestry. A, Boxplot of GRSs in cases (AD) and cognitively normal individuals (CN) present in each quintile (1 to 5). The dot color represents the degree of NAM ancestry of the sample, the lighter the higher the proportion of NAM ancestry. B, Quantitative information of the quintiles. NAM range (%), proportion of NAM ancestry range; CN, number of control samples; AD, number of cases samples; OR [95% CI], GRS effect expressed as odds ratio and 95% confidence interval; P, OR associated P‐value; GRS mean [range], mean value of GRSs and its respective range. At the right of the table, differences among GRS values estimated by two‐way analysis of variance (Tukey's multiple comparisons test) are represented; ns, not significant; *, P < 0.05; ***, P < 0.001. AD, Alzheimer's disease; CI, confidence interval; EADB, European Alzheimer and Dementia Biobank; GRS, genetic risk score; NAM, Native American; OR, odds ratio