Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional Data

Charles C. White, Hyun-Sik Yang, Lei Yu, Lori B. Chibnik, Robert J. Dawe, Jingyun Yang, Hans-Ulrich Klein, Daniel Felsky, Alfredo Ramos-Miguel, Konstantinos Arfanakis, William G. Honer, Reisa A. Sperling, Julie A. Schneider, David A. Bennett, Philip L. De Jager



The molecular underpinnings of the dissociation of cognitive performance and neuropathological burden are poorly understood, and there are currently no known genetic or epigenetic determinants of the dissociation.

Methods and findings

“Residual cognition” was quantified by regressing out the effects of cerebral pathologies and demographic characteristics on global cognitive performance proximate to death. To identify genes influencing residual cognition, we leveraged neuropathological, genetic, epigenetic, and transcriptional data available for deceased participants of the Religious Orders Study (n = 492) and the Rush Memory and Aging Project (n = 487). Given that our sample size was underpowered to detect genome-wide significance, we applied a multistep approach to identify genes influencing residual cognition, based on our prior observation that independent genetic and epigenetic risk factors can converge on the same locus. In the first step (n = 979), we performed a genome-wide association study with a predefined suggestive p < 10 xss=removed xss=removed xss=removed xss=removed xss=removed xss=removed xss=removed>


Through a multistep analysis of cognitive, neuropathological, genomic, epigenomic, and transcriptomic data, we identified ENC1 and UNC5C as genes with convergent genetic, epigenetic, and transcriptomic evidence supporting a potential role in the dissociation of cognition and neuropathology in an aging population, and we expanded our understanding of the TMEM106B haplotype that is protective against TDP-43 proteinopathy.

Citation: White CC, Yang H-S, Yu L, Chibnik LB, Dawe RJ, Yang J, et al. (2017) Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data. PLoS Med 14(4): e1002287. doi:10.1371/journal.pmed.1002287

Academic Editor: Bruce L. Miller, University of California San Francisco Memory and Aging Center, UNITED STATES

Received: October 24, 2016; Accepted: March 17, 2017; Published: April 25, 2017

Copyright: © 2017 White et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: ROS/MAP/ROS and MAP data are at the Rush Alzheimer’s Disease Center Research Resource Sharing Hub. Researchers may apply for data access at (

Funding: The study was funded by National Institute of Health grants P30AG10161, R01AG17917, R01AG34374, R01AG036836, R01AG042210, RF1AG15819, U01AG046152, and UH2 NS100599. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: WGH is on the Scientific Advisory Board of In Silico Biosciences, and served as a consultant to Roche, MDH Consulting Ltd, Lundbeck, Otsuka, and Eli Lilly; and received an honorarium from Rush University (as part of the National Institute of Aging (NIA) grant held by DAB) related to the study. RAS served as a consultant to and received honorarium from Abbvie, Biogen, Genentech, Bracket, Roche, Sanofi, Lundbeck, Otsuka, and Merck, all of which were under $5,000; and received clinical research funding from Eli Lilly and Janssen; and is a research grant site principal investigator for the NIA; and reports the following financial relationship for her spouse, all of which were under $5,000: Lundbeck, Piramal Healthcare, Siemens, and Novartis. DAB receives many grants from the NIH; and serves on numerous external advisory boards for AD centers and other NIH grants; and serves on the adjudication committee for a clinical trial by Takeda; and serves on the data monitoring committee for a clinical trial by AbbVie. In the past, DAB received an unrestricted educational grant from Zinfandel Pharmaceuticals, Inc.; and was a US PI for a clinical trial funded by Nutricia, which also funded a travel grant to the XXV Brazil Neurological Congress to present the clinical trials program; and has served as a paid consultant for Eli Lilly, Inc. and Enzymmotic, Ltd; and was provided a travel grant and honoraria from Sun Pharmaceuticals to speak at a neurology course in India; and was funded by Elsevier for a travel to London to present at a Lancet Neurology conference; and served as a consultant for the India Institute of Science.

Abbreviations: AD, Alzheimer disease;CAA, cerebral amyloid angiopathy;cis-eQTL, cis-expression quantitative trait locus;DLPFC, dorsolateral prefrontal cortex;FDR, false discovery rate;FPKM, fragments per kilobase of transcript per million fragments mapped;FTLD, frontotemporal lobar degeneration;GTEx, Genotype-Tissue Expression;GWAS, genome-wide association study;LD, linkage disequilibrium;MAF, minor allele frequency;MAP, Rush Memory and Aging Project;QC, quality control;RNA-Seq, RNA sequencing;ROS, Religious Orders Study;SNP, single nucleotide polymorphism;TSS, transcription start site.

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