Genome-wide meta-analysis identifies ancestry-specific loci for Alzheimer's disease

Abstract

Introduction: Alzheimer's disease (AD) is a devastating neurological disease with complex genetic etiology. Yet most known loci have only identified from the late-onset type AD in populations of European ancestry.

Methods: We performed a two-stage genome-wide association study (GWAS) of AD totaling 6878 Chinese and 63,926 European individuals.

Results: In addition to the apolipoprotein E (APOE) locus, our GWAS of two independent Chinese samples uncovered three novel AD susceptibility loci (KIAA2013, SLC52A3, and TCN2) and a novel ancestry-specific variant within EGFR (rs1815157). More replicated variants were observed in the Chinese (31%) than in the European samples (15%). In combining genome-wide associations and functional annotations, EGFR and TCN2 were prioritized as two of the most biologically significant genes. Phenome-wide Mendelian randomization suggests that high mean corpuscular hemoglobin concentration might protect against AD.

Discussion: The current study reveals novel AD susceptibility loci, emphasizes the importance of diverse populations in AD genetic research, and advances our understanding of disease etiology.

Highlights: Loci KIAA2013, SLC52A3, and TCN2 were associated with Alzheimer's disease (AD) in Chinese populations. rs1815157 within the EGFR locus was associated with AD in Chinese populations. The genetic architecture of AD varied between Chinese and European populations. EGFR and TCN2 were prioritized as two of the most biologically significant genes. High mean corpuscular hemoglobin concentrations might have protective effects against AD.

Keywords: Alzheimer's disease; Asian; ancestry; genome‐wide association study; neurology.

FIGURE 1

Study workflow. Top left, we performed a two‐stage GWAS covering 70,804 participants. In Stage 1, GWASs of EOAD and LOAD in the discovery sample were performed and subsequently meta‐analyzed due to their observed genetic overlap. In Stage 2, replication and meta‐analyses were conducted among all variants that passed the suggestive threshold (p < 1 × 10⁻⁵) in Stage 1 in independent Chinese and European samples, respectively. Top right, we conducted validation and genetic overlap analyses to compare the genetic architecture of EOAD and LOAD. Bottom left, ancestry‐specific AD loci were identified by replication analyses in Chinese and European individuals. We also investigated the allele frequencies of top‐associated variants in different populations. Bottom right, to gain more insights into AD etiology, we further performed functional exploration analyses, developed a scoring system to prioritize genes, and conducted a phenome‐wide MR to identify potential causal factors on AD. EOAD, early‐onset Alzheimer's disease; GWAS, genome‐wide association study; LOAD, late‐onset Alzheimer's disease; MR, Mendelian randomization; SNP, single nucleotide polymorphism.

FIGURE 2

Manhattan plots of GWAS Stage 1 and Stage 1 + 2A. Manhattan plots display genome‐wide associations with AD in Stage 1 (A) and Stage 1 + 2A (B). The orange line denotes genome‐wide significance (P = 5 × 10⁻⁸), whereas the gray line represents the suggestive level (P = 1 × 10⁻⁵). The y‐axis is limited for better visualization of non‐APOE loci.

FIGURE 3

Functional exploration of candidate genes and gene prioritization. (A) Enriched gene ontologies of all candidate AD genes. (B), Relative expression levels in brain cell types of all candidate AD genes. The p‐values represent the significance of differential brain cell type expression between AD and controls. (C) Prioritization of candidate AD genes. Only genes with a priority score ≥5 are shown in this figure, and the full results can be found in Table S13. †Gene expression in human post‐mortem dorsolateral prefrontal cortex is correlated with the distribution and severity of neurofibrillary tangles (BRAAK), neuritic plaque density (CERAD), or final consensus cognitive diagnosis (COGDX) in the Agora database. ‡Gene expression is correlated with AD pathology in Aβ/tau line AD mouse models according to the AlzData database. BP, biological process; CC, cellular component; eQTL, expression quantitative trait loci; GO, gene ontology; MF, molecular function.

FIGURE 4

Differential expression of prioritized genes between human AD brains and controls. Meaningful differential expression is considered to be a log2 fold‐change value > 0.263, or < −0.263 according to the Agora database.