Genome-wide association studies of Alzheimer's disease and related disorders stratified by sex, onset age, and Apolipoprotein E genotype reveal novel risk loci in African Americans

Abstract

Background: Alzheimer's disease (AD) risk variants have been identified in European ancestry cohorts that have stronger effects at certain ages, in individuals with a specific sex, or in those with specific isoforms of APOE, the strongest AD risk locus. However, sample sizes in African ancestry (AA) cohorts have been underpowered to perform stratified analyses.

Methods: We generated genome-wide association study datasets stratified by sex, age at onset (< 75 vs ≥ 75), and APOE-ε4 carrier status in AA cohorts from MVP and the Alzheimer's Disease Genetics Consortium (ADGC). Outcomes in MVP were AD and related dementias (ADRD; n = 4073 cases and 19,648 controls) and proxy dementia (i.e., reported dementia in a parent, n = 6216 cases and 21,566 controls) while ADGC analyses examined AD (n = 2425 cases and 5069 controls). The proxy dementia GWASs were included in the sex-stratified meta-analysis corresponding to the sex of the affected parent. The top genes were tested for differential expression in AA brain tissue.

Results: In addition to the APOE region, genome-wide significant associations were observed in an intergenic region near the EPHA5 gene (rs141838133, p = 2.19 × 10^-8) in individuals with onset < 75 years, in GRIN3B near the known AD risk gene ABCA7 (rs115882880, p = 3.83 × 10^-8) in females, and near TSPEAR (rs139130053, p = 4.27 × 10^-8) in APOE-ε4 non-carriers. EPHA5 regulates glucose homeostasis, and ephrin receptors modify the strength of existing synapses in the brain and in pancreatic islets. It is unclear whether GRIN3B represents a locus distinct from ABCA7. Rs115882880 was a significant eQTL for GRIN3B but not ABCA7 in AA brain samples. TSPEAR regulates Notch signaling but has not been linked to neuronal function.

Conclusions: Age, sex, and APOE-stratified analyses of dementia in AA participants from two cohorts revealed potential new associations. Stratified analyses may yield critical information about the genetic heterogeneity underlying dementia risk and lead to advances in precision medicine.

Keywords: African Ancestry; Alzheimer’s disease; Genome-wide association study; RNA-sequencing; Stratified.

Fig. 1

Regional Manhattan plots showing the genome wide significant associations: The EPHA4 region on chromosome 4 identified in individuals with ADRD onset less than 75 years (A). The GRIN3B-ABCA7 region on chromosome 19 identified in females (B). The TSPEAR region on chromosome 21 identified in individuals without an APOE-ε4 allele (C). Chromosomal position in GRCh38 is on the X axis and the Y axis shows the -log10 p-values for each SNP in the region. The degree of linkage disequilibrium with the peak SNP (purple diamonds) is indicated by the color of the point on the plot in the 1000 Genomes Project AFR reference panel

Fig. 2

Forest plot showing the effect sizes (odds ratios) and 95% confidence intervals for the MVP/ADGC meta-analysis results for the genome-wide significant SNPs in both the stratum in which the association was identified and the opposite stratum. The green points show the effect of rs139130053 in APOE-ε4 negative individuals (upper green point) and APOE-ε4 positive individuals (lower green point). The pink points show the effect of rs115882880 in females (upper pink point) and males (lower pink point). The blue points show the effect of rs141838133 in individuals with onset age ≥ 75 years (upper blue point) and individuals with onset age < 75 years (lower blue point)

Fig.3

Expression levels (Y axis) of ABCA7 (first column), GRIN3B (second column), and WDR18 (third column) by imputed rs115882880 dosage (X axis) in African American brain tissue in females (A), males (B), and unstratified (C). The red points represent AD cases, and the blue dots represent cognitively normal controls