Basic Science and Pathogenesis

Background: With a rapidly aging population, South Korea anticipates a surge in Alzheimer disease (AD). However, the genetic basis of AD in Koreans is not well understood.

Method: We sequenced the genomes of 3,540 Koreans (1,583 AD cases and 1,957 controls) older than age 60 and performed a genome-wide association study (GWAS) of AD using logistic regression models that included covariates for age, sex, five ancestry principal components, and an empirical genetic relationship matrix. We also conducted association tests in subgroups stratified by APOE ε4 status or sex. Findings from the Korean sample were combined with results from two Japanese GWAS datasets using the inverse-variance meta-analysis method. We also performed gene-based tests of aggregated rare variants in the Korean dataset. Novel findings were evaluated by pathway enrichment analysis and by differential gene expression analysis in brain tissue from controls and AD cases who were either cognitively impaired or healthy prior to death.

Result: We identified genome-wide significant (GWS) associations (P < 5.0 × 10^-8) with two well-established AD loci (APOE and SORL1) in the total sample and with one novel locus, ROCK2 (rs76484417, P = 2.71 × 10^-8) among APOE ε4 non-carriers. Another novel study-wide significant association (P < 2.47 × 10^-6) was found with aggregated rare variants in MICALL1 (P = 9.04 × 10^-7). We also observed suggestive associations (P < 1.0 × 10^-6) with 14 novel loci (MSX1, BCL11A, ARMH3, CTNNA3, YTHDF1P1, GRM3, LINC02479, LRCH1, COL9A1, TTC8, MCTP2, DLGAP2, TBC1D32, and EXD2). Expression of several novel genes, including ROCK2 and MICALL1, was significantly different in multiple cortical regions in AD cases compared to controls (P < 3.33 × 10^-3). ROCK2 was also differentially expressed between AD cases with and without cognitive impairment (P = 1.34 × 10^-4).

Conclusion: We identified GWS and suggestive association for AD with several loci in Koreans and Japanese not previously observed in other populations. Our results provide additional insight into genetic mechanisms leading to AD and cognitive resilience, as well as emphasize the need for further genetic studies of East Asian populations.