Common and rare variants of EGF increase the genetic risk of Alzheimer's disease as revealed by targeted sequencing of growth factors in Han Chinese

Xiao Li; Min Xu; Rui Bi; Li-Wen Tan; Yong-Gang Yao; Deng-Feng Zhang

doi:10.1016/j.neurobiolaging.2022.10.009

Common and rare variants of EGF increase the genetic risk of Alzheimer's disease as revealed by targeted sequencing of growth factors in Han Chinese

Neurobiol Aging. 2023 Mar:123:170-181. doi: 10.1016/j.neurobiolaging.2022.10.009. Epub 2022 Nov 3.

Authors

Xiao Li¹, Min Xu¹, Rui Bi², Li-Wen Tan³, Yong-Gang Yao⁴, Deng-Feng Zhang⁵

Affiliations

¹ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Disease, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China.
² Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Disease, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China; CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
³ Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, China.
⁴ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Disease, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China; CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. Electronic address: yaoyg@mail.kiz.ac.cn.
⁵ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Disease, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China. Electronic address: zhangdengfeng@mail.kiz.ac.cn.

PMID: 36437134
DOI: 10.1016/j.neurobiolaging.2022.10.009

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease with high heritability. Growth factors (GFs) might contribute to the development of AD due to their broad effects on neuronal system. We herein aimed to investigate the role of rare and common variants of GFs in genetic susceptibility of AD. We screened 23 GFs in 6324 individuals using targeted sequencing. A rare-variant-based burden test and common-variant-based single-site association analyses were performed to identify AD-associated GF genes and variants. The burden test showed an enrichment of rare missense variants (p = 6.08 × 10^-4) in GF gene-set in AD patients. Among the GFs, EGF showed the strongest signal of enrichment, especially for loss-of-function variants (p = 0.0019). A common variant rs4698800 of EGF showed significant associations with AD risk (p = 3.24 × 10^-5, OR = 1.26). The risk allele of rs4698800 was associated with an increased EGF expression, whereas EGF was indeed upregulated in AD brain. These findings suggested EGF as a novel risk gene for AD.

Keywords: Alzheimer's disease; EGF; Growth factors; Targeted sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / genetics
East Asian People
Epidermal Growth Factor / genetics
Genetic Predisposition to Disease / genetics
Humans
Neurodegenerative Diseases*

Substances

Epidermal Growth Factor