@article{3cb69caf8d5a46a8958a9387029fa12a,
title = "Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer's disease",
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.",
keywords = "Alzheimer's disease, ECRG4, Genome-wide association study, HDAC9, Neuropathological traits, Pleiotropy analysis",
author = "Jaeyoon Chung and Xiaoling Zhang and Mariet Allen and Xue Wang and Yiyi Ma and Gary Beecham and Montine, {Thomas J.} and Younkin, {Steven G.} and Dickson, {Dennis W.} and Golde, {Todd E.} and Price, {Nathan D.} and Nil{\"u}fer Ertekin-Taner and Lunetta, {Kathryn L.} and Jesse Mez and Richard Mayeux and Haines, {Jonathan L.} and Pericak-Vance, {Margaret A.} and Gerard Schellenberg and Jun, {Gyungah R.} and Farrer, {Lindsay A.}",
note = "Funding Information: The Alzheimer's Disease Genetics Consortium supported the collection of samples used in this study through National Institute on Aging (NIA) grants U01-AG032984 and RC2AG036528. Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania and funded by NIA grant U24-AG041689-01. This work was also supported by NIA grants R01-AG048927 (to LAF), R01-AG032990 and RF-AG051504 (to NET), and U01-AG046139 (to NET, SGY, TEG, and NDP), as well as by National Institute of Neurological Disorders and Stroke (NINDS) grant R01-NS080820 (to NET). The Brain and Body Donation Program at Sun Health Research Institute (Sun City, AZ, USA) is supported by NINDS grant U24-NS072026 for the National Brain and Tissue Resource for Parkinson's Disease and Related Disorders; NIA grant P30-AG19610 for the Arizona Alzheimer's Disease Core Center; Arizona Department of Health Services contract 211002 for the Arizona Alzheimer's Research Center; Arizona Biomedical Research Commission contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson's Disease Consortium; and the Michael J. Fox Foundation for Parkinson's Research. Funding Information: The Alzheimer{\textquoteright}s Disease Genetics Consortium supported the collection of samples used in this study through National Institute on Aging (NIA) grants U01-AG032984 and RC2AG036528. Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer{\textquoteright}s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania and funded by NIA grant U24-AG041689-01. This work was also supported by NIA grants R01-AG048927 (to LAF), R01-AG032990 and RF-AG051504 (to NET), and U01-AG046139 (to NET, SGY, TEG, and NDP), as well as by National Institute of Neurological Disorders and Stroke (NINDS) grant R01-NS080820 (to NET). The Brain and Body Donation Program at Sun Health Research Institute (Sun City, AZ, USA) is supported by NINDS grant U24-NS072026 for the National Brain and Tissue Resource for Parkinson{\textquoteright}s Disease and Related Disorders; NIA grant P30-AG19610 for the Arizona Alzheimer{\textquoteright}s Disease Core Center; Arizona Department of Health Services contract 211002 for the Arizona Alzheimer{\textquoteright}s Research Center; Arizona Biomedical Research Commission contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson{\textquoteright}s Disease Consortium; and the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research. Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = feb,
day = "20",
doi = "10.1186/s13195-018-0349-z",
language = "English (US)",
volume = "10",
journal = "Alzheimer's Research and Therapy",
issn = "1758-9193",
publisher = "BioMed Central",
number = "1",
}