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Alzheimer's Research & Therapy
Published in: Alzheimer's Research & Therapy 1/2018

Open Access 01-12-2018 | Research

Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease

Authors: Jaeyoon Chung, Xiaoling Zhang, Mariet Allen, Xue Wang, Yiyi Ma, Gary Beecham, Thomas J. Montine, Steven G. Younkin, Dennis W. Dickson, Todd E. Golde, Nathan D. Price, Nilüfer Ertekin-Taner, Kathryn L. Lunetta, Jesse Mez, Richard Mayeux, Jonathan L. Haines, Margaret A. Pericak-Vance, Gerard Schellenberg, Gyungah R. Jun, Lindsay A. Farrer, Alzheimer’s Disease Genetics Consortium

Published in: Alzheimer's Research & Therapy | Issue 1/2018

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Abstract

Background

Simultaneous consideration of two neuropathological traits related to Alzheimer’s disease (AD) has not been attempted in a genome-wide association study.

Methods

We conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data.

Results

Genome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10−8) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10−8). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10−6) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10−3), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10−3) and visual (P = 5.6 × 10−4) cortices.

Conclusions

Our findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.
Appendix
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Metadata
Title
Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease
Authors
Jaeyoon Chung
Xiaoling Zhang
Mariet Allen
Xue Wang
Yiyi Ma
Gary Beecham
Thomas J. Montine
Steven G. Younkin
Dennis W. Dickson
Todd E. Golde
Nathan D. Price
Nilüfer Ertekin-Taner
Kathryn L. Lunetta
Jesse Mez
Richard Mayeux
Jonathan L. Haines
Margaret A. Pericak-Vance
Gerard Schellenberg
Gyungah R. Jun
Lindsay A. Farrer
Alzheimer’s Disease Genetics Consortium
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Alzheimer's Research & Therapy / Issue 1/2018
Electronic ISSN: 1758-9193
DOI
https://doi.org/10.1186/s13195-018-0349-z

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