@article{18f1d54da520487da06b941d73c9c7c4,
title = "Bayesian Genome-wide TWAS Method to Leverage both cis- and trans-eQTL Information through Summary Statistics",
abstract = "Transcriptome-wide association studies (TWASs) have been widely used to integrate gene expression and genetic data for studying complex traits. Due to the computational burden, existing TWAS methods do not assess distant trans-expression quantitative trait loci (eQTL) that are known to explain important expression variation for most genes. We propose a Bayesian genome-wide TWAS (BGW-TWAS) method that leverages both cis- and trans-eQTL information for a TWAS. Our BGW-TWAS method is based on Bayesian variable selection regression, which not only accounts for cis- and trans-eQTL of the target gene but also enables efficient computation by using summary statistics from standard eQTL analyses. Our simulation studies illustrated that BGW-TWASs achieved higher power compared to existing TWAS methods that do not assess trans-eQTL information. We further applied BWG-TWAS to individual-level GWAS data (N = ∼3.3K), which identified significant associations between the genetically regulated gene expression (GReX) of ZC3H12B and Alzheimer dementia (AD) (p value = 5.42 × 10−13), neurofibrillary tangle density (p value = 1.89 × 10−6), and global measure of AD pathology (p value = 9.59 × 10−7). These associations for ZC3H12B were completely driven by trans-eQTL. Additionally, the GReX of KCTD12 was found to be significantly associated with β-amyloid (p value = 3.44 × 10−8) which was driven by both cis- and trans-eQTL. Four of the top driven trans-eQTL of ZC3H12B are located within APOC1, a known major risk gene of AD and blood lipids. Additionally, by applying BGW-TWAS with summary-level GWAS data of AD (N = ∼54K), we identified 13 significant genes including known GWAS risk genes HLA-DRB1 and APOC1, as well as ZC3H12B.",
keywords = "Alzheimer dementia, Bayesian variable selection model, TWAS, cis-eQTL, summary statistics, trans-eQTL, transcriptome-wide association study",
author = "Luningham, {Justin M.} and Junyu Chen and Shizhen Tang and {De Jager}, {Philip L.} and Bennett, {David A.} and Buchman, {Aron S.} and Jingjing Yang",
note = "Funding Information: J.Y. was supported by the startup funding from Department of Human Genetics at Emory University School of Medicine. ROS/MAP study data were provided by the Rush Alzheimer{\textquoteright}s Disease Center, Rush University Medical Center, Chicago, IL. Data collection was supported through funding by NIA grants P30AG10161 , R01AG15819 , R01AG17917 , R01AG30146 , R01AG36836 , U01AG32984 , U01AG46152 , and U01AG61356 , the Illinois Department of Public Health , and the Translational Genomics Research Institute . The MCADGC led by Dr. Nil{\"u}fer Ertekin-Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL uses samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer disease Research Center, and the Mayo Clinic Brain Bank. MCADGC data collection was supported through funding by NIA grants P50 AG016574 , R01 AG032990 , U01 AG046139 , R01 AG018023 , U01 AG006576 , U01 AG006786 , R01 AG025711 , R01 AG017216 , and R01 AG003949 , NINDS grant R01 NS080820 , CurePSP Foundation , and support from Mayo Foundation . Funding Information: J.Y. was supported by the startup funding from Department of Human Genetics at Emory University School of Medicine. ROS/MAP study data were provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL. Data collection was supported through funding by NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, U01AG46152, and U01AG61356, the Illinois Department of Public Health, and the Translational Genomics Research Institute. The MCADGC led by Dr. Nil?fer Ertekin-Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL uses samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer disease Research Center, and the Mayo Clinic Brain Bank. MCADGC data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, and R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Publisher Copyright: {\textcopyright} 2020 American Society of Human Genetics",
year = "2020",
month = oct,
day = "1",
doi = "10.1016/j.ajhg.2020.08.022",
language = "English",
volume = "107",
pages = "714--726",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "4",
}