Whole-genome sequencing study in Koreans identifies novel loci for Alzheimer's disease

초록

INTRODUCTION The genetic basis of Alzheimer's disease (AD) in Koreans is poorly understood. METHODS We performed an AD genome-wide association study using whole-genome sequence data from 3540 Koreans (1583 AD cases, 1957 controls) and single-nucleotide polymorphism array data from 2978 Japanese (1336 AD cases, 1642 controls). Significant findings were evaluated by pathway enrichment and differential gene expression analysis in brain tissue from controls and AD cases with and without dementia prior to death. RESULTS We identified genome-wide significant associations with APOE in the total sample and ROCK2 (rs76484417, p = 2.71x10(-8)) among APOE epsilon 4 non-carriers. A study-wide significant association was found with aggregated rare variants in MICALL1 (MICAL like 1) (p = 9.04x10(-7)). Several novel AD-associated genes, including ROCK2 and MICALL1, were differentially expressed in AD cases compared to controls (p < 3.33x10(-3)). ROCK2 was also differentially expressed between AD cases with and without dementia (p = 1.34x10(-4)). DISCUSSION Our results provide insight into genetic mechanisms leading to AD and cognitive resilience in East Asians.