Genetically regulated expression in late-onset Alzheimer’s disease implicates risk genes within known and novel loci

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作者
Hung-Hsin Chen
Lauren E. Petty
Jin Sha
Yi Zhao
Amanda Kuzma
Otto Valladares
William Bush
Adam C. Naj
Eric R. Gamazon
Jennifer E. Below
机构
[1] Vanderbilt University Medical Center,Vanderbilt Genetics Institute and Division of Genetic Medicine, Department of Medicine
[2] University of Pennsylvania,Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine
[3] University of Pennsylvania,Department of Pathology and Laboratory Medicine, Perelman School of Medicine
[4] Case Western Reserve University,Department of Population & Quantitative Health Sciences, School of Medicine
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Translational Psychiatry | / 11卷
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摘要
Late-onset Alzheimer disease (LOAD) is highly polygenic, with a heritability estimated between 40 and 80%, yet risk variants identified in genome-wide studies explain only ~8% of phenotypic variance. Due to its increased power and interpretability, genetically regulated expression (GReX) analysis is an emerging approach to investigate the genetic mechanisms of complex diseases. Here, we conducted GReX analysis within and across 51 tissues on 39 LOAD GWAS data sets comprising 58,713 cases and controls from the Alzheimer’s Disease Genetics Consortium (ADGC) and the International Genomics of Alzheimer’s Project (IGAP). Meta-analysis across studies identified 216 unique significant genes, including 72 with no previously reported LOAD GWAS associations. Cross-brain-tissue and cross-GTEx models revealed eight additional genes significantly associated with LOAD. Conditional analysis of previously reported loci using established LOAD-risk variants identified eight genes reaching genome-wide significance independent of known signals. Moreover, the proportion of SNP-based heritability is highly enriched in genes identified by GReX analysis. In summary, GReX-based meta-analysis in LOAD identifies 216 genes (including 72 novel genes), illuminating the role of gene regulatory models in LOAD.
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