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

IF 11.1 1区医学 Q1 CLINICAL NEUROLOGY Alzheimer's & Dementia Pub Date : 2024-10-20 DOI:10.1002/alz.14128

Moonil Kang, John J. Farrell, Congcong Zhu, Hyeonseul Park, Sarang Kang, Eun Hyun Seo, Kyu Yeong Choi, Gyungah R. Jun, Sungho Won, Jungsoo Gim, Kun Ho Lee, Lindsay A. Farrer

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Abstract

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 = 2.71×10⁻⁸) among APOE ε4 non-carriers. A study-wide significant association was found with aggregated rare variants in MICALL1 (MICAL like 1) (p = 9.04×10⁻⁷). Several novel AD-associated genes, including ROCK2 and MICALL1, were differentially expressed in AD cases compared to controls (p < 3.33×10⁻³). ROCK2 was also differentially expressed between AD cases with and without dementia (p = 1.34×10⁻⁴).

DISCUSSION

Our results provide insight into genetic mechanisms leading to AD and cognitive resilience in East Asians.

Highlights

Novel genome-wide significant associations for AD identified with ROCK2 and MICALL1.
ROCK2 and MICALL1 are differentially expressed between AD cases and controls in the brain.
This is the largest whole-genome-sequence study of AD in an East Asian population.

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韩国人的全基因组测序研究确定了阿尔茨海默病的新基因位点

韩国人对阿尔茨海默病（AD）的遗传基础知之甚少。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.