Integrating rare pathogenic variant prioritization with gene-based association analysis to identify novel genes and relevant multimodal traits for Alzheimer's disease

IF 11.1 1区医学 Q1 CLINICAL NEUROLOGY Alzheimer's & Dementia Pub Date : 2024-12-23 DOI:10.1002/alz.14444

Jixin Cao, Cheng Zhang, Chun-Yi Zac Lo, Qihao Guo, Jing Ding, Xiaohui Luo, Zi-Chao Zhang, Feng Chen, the ZIB Consortium, Tian-Lin Cheng, Jingqi Chen, Xing-Ming Zhao, for the Alzheimer's Disease Neuroimaging Initiative

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Abstract

INTRODUCTION

Increasing evidence has highlighted rare variants in Alzheimer's disease (AD). However, insufficient sample sizes, especially in underrepresented ethnic groups, hinder their investigation. Additionally, their impact on endophenotypes remains largely unexplored.

METHODS

We prioritized rare likely-deleterious variants based on whole-genome sequencing data from a Chinese AD cohort (n = 988). Gene-based optimal sequence kernel association tests were conducted between AD cases and normal controls to identify AD-related genes. Network clustering, endophenotype association, and cellular experiments were conducted to evaluate their functional consequences.

RESULTS

We identified 11 novel AD candidate genes, which captured AD-related pathways and enhanced AD risk prediction performance. Key genes (RABEP1, VIPR1, RPL3L, and CABIN1) were linked to cognitive decline and brain atrophy. Experiments showed RABEP1 p.R845W inducing endocytosis dysregulation and exacerbating toxic amyloid β accumulation, underscoring its therapeutic potential.

DISCUSSION

Our findings highlighted the contributions of rare variants to AD and provided novel insights into AD therapeutics.

Highlights

Identified 11 novel AD candidate genes in a Chinese AD cohort.
Correlated candidate genes with AD-related cognitive and brain imaging traits.
Indicated RABEP1 p.R845W as a critical AD contributor in the endocytic pathway.

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结合罕见致病变异优先排序和基于基因的关联分析，鉴定阿尔茨海默病的新基因和相关多模态特征

越来越多的证据强调了阿尔茨海默病（AD）的罕见变异。然而，样本量不足，特别是在代表性不足的族裔群体中，阻碍了他们的调查。此外，它们对内表型的影响在很大程度上仍未被探索。

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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.