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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This post is Copyright: 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 | December 23, 2024