Date Published: April 25, 2017
Publisher: Public Library of Science
Author(s): 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, Bruce L. Miller
Abstract: IntroductionThe 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 < 10−5, and nine independent loci met this threshold in eight distinct chromosomal regions. Three of the six genes within 100 kb of the lead SNP are expressed in the dorsolateral prefrontal cortex (DLPFC): UNC5C, ENC1, and TMEM106B. In the second step, in the subset of participants with DLPFC DNA methylation data (n = 648), we found that residual cognition was related to differential DNA methylation of UNC5C and ENC1 (false discovery rate < 0.05). In the third step, in the subset of participants with DLPFC RNA sequencing data (n = 469), brain transcription levels of UNC5C and ENC1 were evaluated for their association with residual cognition: RNA levels of both UNC5C (estimated effect = −0.40, 95% CI −0.69 to −0.10, p = 0.0089) and ENC1 (estimated effect = 0.0064, 95% CI 0.0033 to 0.0096, p = 5.7 × 10−5) were associated with residual cognition. In secondary analyses, we explored the mechanism of these associations and found that ENC1 may be related to the previously documented effect of depression on cognitive decline, while UNC5C may alter the composition of presynaptic terminals. Of note, the TMEM106B allele identified in the first step as being associated with better residual cognition is in strong linkage disequilibrium with rs1990622A (r2 = 0.66), a previously identified protective allele for TDP-43 proteinopathy. Limitations include the small sample size for the genetic analysis, which was underpowered to detect genome-wide significance, the evaluation being limited to a single cortical region for epigenetic and transcriptomic data, and the use of categorical measures for certain non-amyloid-plaque, non-neurofibrillary-tangle neuropathologies.ConclusionsThrough 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.
Partial Text: It is well known that cognitive impairment in older adults is only partially explained by common neuropathologies such as Alzheimer disease (AD), stroke, and Lewy body disease [1–4]. Previous studies have shown that the majority of the variability in cognitive decline is unexplained, even when quantitative indices of common neuropathologies and demographic variables are included in the model [1,2]. Although additional variability has been explained by traits such as depressive symptoms [2,5] and by neuroimaging measures of brain tissue integrity [6,7], a large part of the cognitive impairment in late life remains unexplained. Further disentangling this dissociation of pathological burden and cognitive outcome is of critical importance in understanding clinical heterogeneity in the patient population and in designing treatments that can prevent progression into dementia.
Leveraging two large community-based cohorts of older adults with genetic and phenotypic data, this study used a multistep process including genetic, epigenetic, and expression analyses to identify genes associated with the dissociation of cognitive function and neuropathological burden. Our results support a potential role of UNC5C and ENC1 in modulating differential neuronal susceptibility to pathological insults, and expand our understanding of TMEM106B, a gene known for its association with TDP-43 proteinopathy.