Association of rare variants in neurodegenerative genes with familial Alzheimer's disease

Weiwei Zhang; Bin Jiao; Tingting Xiao; Xixi Liu; Xinxin Liao; Xuewen Xiao; Lina Guo; Zhenhua Yuan; Xinxiang Yan; Beisha Tang; Lu Shen

doi:10.1002/acn3.51197

Association of rare variants in neurodegenerative genes with familial Alzheimer's disease

Ann Clin Transl Neurol. 2020 Oct;7(10):1985-1995. doi: 10.1002/acn3.51197. Epub 2020 Sep 17.

Authors

Weiwei Zhang^{1

2}, Bin Jiao^{1

3

4}, Tingting Xiao¹, Xixi Liu¹, Xinxin Liao⁵, Xuewen Xiao¹, Lina Guo¹, Zhenhua Yuan¹, Xinxiang Yan¹, Beisha Tang^{1

3

4}, Lu Shen^{1

3

4

6}

Affiliations

¹ Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
² Molecular Imaging Center, Xiangya Hospital, Central South University, Changsha, China.
³ National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China.
⁴ Key laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China.
⁵ Department of Geriatric, Xiangya Hospital, Central South University, Changsha, China.
⁶ Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China.

Abstract

Objective: To investigate the impact of rare variants underlying neurodegenerative-related genes to familial Alzheimer's disease (AD).

Methods: We performed targeted sequencing of 277 neurodegenerative-related genes on probands from 75 Chinese AD families non-carrying causative mutation of dementia genes. Rare coding variants segregated in families were tested for association in an independent cohort of 506 patients with sporadic AD and 498 cognitively normal controls. East Asians data from the Exome Aggregation Consortium (ExAC) were used as a reference control.

Results: A novel rare variant, P410S of PLD3 was found in an early-onset AD family. LRRK2 I2012T, a causative mutation of Parkinson's disease, was identified in another early-onset AD family. Missense variants in ABCA7 (P143S and A1507T) and CR1(T239M) were significantly associated with familial AD (P = 0.005437, 0.001383, 0.000549), a missense variant in TREM2(S183C) was significantly associated with AD (P = 0.000396) when compared with the East Asian controls in ExAC database. A non-frameshift variant in FUS (G223del) was frequent in AD cases and significantly associated with familial AD (P = 0.008).

Interpretation: Multiple rare coding variants of causal and risk neurodegenerative genes were presented in clinically diagnosed AD families that may confer risk of AD. Our data supported that the clinical, pathological, and genetic architectures of AD, PD, and FTD/ALS may overlapping. We propose that targeted sequencing on neurodegenerative-related genes is necessary for genetically unclear AD families.

Publication types

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

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease / genetics*
Cohort Studies
Data Management / methods
Exome / genetics
Exome Sequencing / methods
Female
Genetic Predisposition to Disease / genetics*
Genetic Variation / genetics*
Humans
Male
Middle Aged
Mutation / genetics*

Grants and funding

This work was funded by National Natural Science Foundation of China grants 81671075, 81971029, and 81701134; National Key R&D Program of China grants 2017YFC0840100 and 2017YFC0840104; the Provincial Key Plan for Research and Development of Hunan grant 2017SK2031; Provincial Technology Innovation Guidance Plan Project of Hunan grant 2018SK52601; Youth Program of Science Foundation of Xiangya Hospital grant 2018Q017.