SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians

To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values ,261025 were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P=7.3361027 in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P=1.7761029) and rs3781834 (P=1.0461028). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P=1.7161025) and rs744373 near BIN1 (P = 1.3961024). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations

Top-ranked genome-wide association results in the Japanese discovery (Stage 1) sample (P<2.5×10⁻⁵) and their replication in Japanese (Stage 2).

<p>CH:MB, chromosome:position (in megabasepairs, build 19); MA, minor allele; MAF, minor allele frequency; # SNPs, the number of SNPs for which P≤1×10⁻⁴ in the discovery (Stage 1) sample; OR, odds ratio; <i>P</i> P-value;</p><p>Selected SNPs represent the strongest association within each locus.</p

Meta-analysis of top-ranked association results with <i>SORL1</i> in Japanese, Korean, and Caucasian datasets.

<p>CH:MB, chromosome:position (in megabase pairs, build 19); MA, minor allele; MAF, minor allele frequenc; OR, odds ratio; <i>P</i> P-value.</p

Sample size and characteristics of the discovery and replication datasets.

<p>Sample size and characteristics of the discovery and replication datasets.</p

Forest plots of the two most strongly associated SNPs, rs3781834 (A) and rs11218343 (B), in the <i>SORL1</i> region showing the strength and pattern of significance in the Japanese discovery and each replication dataset in the model of adjusting for population structure, age, and sex.

<p>Forest plots of the two most strongly associated SNPs, rs3781834 (A) and rs11218343 (B), in the <i>SORL1</i> region showing the strength and pattern of significance in the Japanese discovery and each replication dataset in the model of adjusting for population structure, age, and sex.</p

Regional association plot for the <i>SORL1</i> region on chromosome 11 in the three-stage design.

<p>For each SNP, the chromosomal location is shown on the x-axis and the significance level for association with LOAD is indicated by a –log₁₀P value on the y-axis. P-values are expressed as –log₁₀(P) (y-axis) for every tested SNP ordered by chromosomal location (x-axis). Genomic position was determined using the NCBI database (Build 37.1). Computed estimates of linkage disequilibrium (LD; r²) between SNPs in this region with the top-ranked SNP (rs3781834) in the Japanese discovery (J1) dataset are shown as red circles for r²≥0.8, orange circles for 0.5≤r²<0.8, light blue circles for 0.2≤r²<0.5, and dark blue circles for r²<0.2 using hg19/1000 Genomes of Asian populations (ASN; release on November 2010) combined from Han Chinese (CHB) and Japanese (JPT). Meta-analysis <i>P</i>-values are shown as purple diamonds for the Japanese datasets (J1+J2) and all datasets (J1+J2+K+C) including Japanese, Korean (K), and Caucasians (C). Two genome-wide significant SNPs in the final stage (rs3781834 and rs11218343) are presented. The gene structure and reading frame are shown below the plot. Exons are denoted with vertical bars. The LD between rs3781834 and rs11218343 is 0.57 in the ASN reference population.</p