Cross-ancestry genome-wide association study identifies implications of SORL1 in cerebral beta-amyloid deposition

Abstract

GWAS of Alzheimer's disease have been predominantly based on European ancestry cohorts with clinically diagnosed patients. Increasing the ancestral diversity of GWAS and focusing on imaging brain biomarkers for Alzheimer's disease may lead to the identification of new genetic loci. Here, we perform a GWAS on cerebral β-amyloid deposition measured by PET imaging in 3,885 East Asians and a cross-ancestry GWAS meta-analysis with data from 11,816 European participants. Our GWAS analysis replicates known loci (APOE4, CR1, and FERMT2) and identifies a novel locus near SORL1 that is significantly associated with β-amyloid deposition. Single-nucleus expression analysis shows that SORL1 is differentially expressed according to β-amyloid positivity in microglia. Our joint association analysis using the SORL1 lead variant (rs76490923) and the APOE4 allele demonstrates that the risk of β-amyloid deposition is reduced by up to 43.5% in APOE4 non-carriers and up to 55.6% in APOE4 carriers, according to the allelic dosage of the rs76490923 T allele. Our findings suggest that SORL1 may play an important role in the pathogenesis of Alzheimer's disease, particularly in relation to β-amyloid deposition.

Fig. 1. Manhattan plots of EAS and cross-ancestry meta-GWASs for Aβ deposition.

a Manhattan plot of the GWAS meta-analysis for Aβ deposition in EAS (stage 1, n = 3855). b Manhattan plot of the cross-ancestry GWAS meta-analysis for Aβ deposition in EAS and EUR populations (n = 15,701). p values for GWASs were calculated using a fixed-effect inverse variance-weighted meta-analysis. The x-axis represents chromosomal position, and the y-axis represents the −log₁₀(p value) for the association of variants with Aβ deposition. Reported p values are two-sided and not corrected for multiple testing. The light green dots represent the genome-wide significant lead variants. The red text highlights previously unreported loci along with their mapped genes, while the black text indicates previously reported loci. The pink and blue horizontal dashed lines indicate the genome-wide significance level (p value = 5.00 × 10⁻⁸) and the genome-wide suggestive level (p value = 1.00 × 10⁻⁵), respectively. EAS East Asian, EUR European, GWAS genome-wide association study.

Fig. 2. Regional plots for SORL1 signals associated with Aβ deposition.

a Regional plot for SORL1 signals from the East Asian GWAS. b Regional plot for SORL1 signals from the European GWAS. c Regional plot for SORL1 signals from the cross-ancestry meta-GWAS. p values for GWASs were calculated using a fixed-effect inverse variance-weighted meta-analysis. Each dot is colored by r² of linkage disequilibrium with the purple-colored lead SNPs indicated with texts. Reported p values are two-sided and not corrected for multiple testing. The x-axis represents chromosomal position, and the y-axis represents the −log₁₀(p value) for the association of variants with Aβ deposition. EAS East Asian, EUR European, GWAS genome-wide association study, SE standard error, MAF minor allele frequency, gnomAD Genome Aggregation Database.

Fig. 3. Forest plots of risk of Aβ deposition according to the APOE4 and SORL1 status.

a Aβ deposition risk between APOE4 carriers and non-carriers. b Aβ deposition risk according to APOE4 status and SORL1/rs76490923 genotype. c Aβ deposition risk according to SORL1/rs76490923 genotype stratified by APOE4 status. The joint association analyses were conducted on 4042 study samples, combining data from stage 1 and stage 2 datasets. The number of Aβ-positive cases represents participants classified as Aβ-positive according to the CERAD neuropathological category. Boxes represent the adjusted odds ratio, with horizontal lines around the boxes indicating 95% confidence intervals. The odds ratios were estimated using logistic regression models, adjusted for age, sex, cohort type, and the first five principal components of ancestry. p values were determined using a Wald test. p values for the trend were calculated using the Cochran-Armitage trend test. All p values were derived from two-sided tests. Exact statistical values are provided as a Source Data file. OR odds ratio, CI confidence interval, CERAD Consortium to Establish a Registry for Alzheimer’s disease.

Fig. 4. Brain cell-type specific expression of the SORL1 from Korean single-nucleus RNA-seq.

a UMAP colored by major brain single-cell types. b UMAP plot colored by Aβ positivity across single-cell types. The red represents Aβ-positive and blue represents Aβ-negative. c SORL1 gene expression across single-cell types colored by z-scored expression levels. The red indicates higher gene expression, and the blue indicates lower expression. d Box plots for differential gene expression of SORL1 by Aβ positivity in single-cell types. Aβ positivity was defined based on the CERAD neuropathological category. Differential gene expression analysis was performed using MAST (v1.16.0) and brain cell-type-specific gene expression data from 15 Korean individuals (nine Aβ-positive and six Aβ-negative individuals). The asterisk indicates a significant result obtained from the likelihood ratio test that meets the threshold of a false discovery rate-corrected p value < 0.05, calculated using the Benjamini–Hochberg correction from two-sided tests. This box plot illustrates the differential expression of SORL1 across major brain cell types, grouped by Aβ positivity (positive in red and negative in blue). On the box plots, the horizontal line indicates the median, the box indicates the first to third quartile of expression and whiskers indicate 1.5 × the interquartile range. The x-axis represents various cell types, and the y-axis represents SORL1 log normalization expression. Source data are provided as a Source Data file. UMAP uniform manifold approximation, and projection, UMI unique molecular identifiers, MG microglia, OD oligodendrocytes, IN inhibitory neurons, OPC oligodendrocyte precursor cells, End endothelial cells, Ast astrocytes, Ext excitatory neurons, ns non-significant, CERAD Consortium to Establish a Registry for Alzheimer’s disease.