Person: Yang, Hyun-Sik
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Yang
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Hyun-Sik
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Yang, Hyun-Sik
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Publication Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data(Public Library of Science, 2017) White, Charles C.; Yang, Hyun-Sik; Yu, Lei; Chibnik, Lori B.; Dawe, Robert J.; Yang, Jingyun; Klein, Hans-Ulrich; Felsky, Daniel; Ramos-Miguel, Alfredo; Arfanakis, Konstantinos; Honer, William G.; Sperling, Reisa; Schneider, Julie A.; Bennett, David A.; De Jager, PhilipIntroduction: 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 < 10−5, 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. Conclusions: 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.Publication Teaching NeuroImages: Brain mass with hilar adenopathy: The importance of histologic diagnosis(Ovid Technologies (Wolters Kluwer Health), 2014) Jordan, Justin; Yang, Hyun-Sik; Narendra, Derek; Plotkin, ScottPublication Cellular communities reveal trajectories of brain ageing and Alzheimer’s disease(Springer Science and Business Media LLC, 2024-08-28) Green, Gilad S.; Fujita, Masashi; Yang, Hyun-Sik; Taga, Mariko; Cain, Anael; McCabe, Cristin; Comandante-Lou, Natacha; White, Charles C.; Schmidtner, Anna K.; Zeng, Lu; Sigalov, Alina; Wang, Yanling; Regev, Aviv; Klein, Hans-Ulrich; Menon, Vilas; Bennett, David A.; Habib, Naomi; De Jager, Philip L.Alzheimer’s disease (AD) has recently been associated with diverse cell states, yet when and how these states affect the onset of AD remains unclear. Here we used a data-driven approach to reconstruct the dynamics of the brain’s cellular environment and identified a trajectory leading to AD that is distinct from other ageing-related effects. First, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.65 million single-nucleus RNA-sequencing profiles sampled from 437 older individuals, and identified specific glial and neuronal subpopulations associated with AD-related traits. Causal modelling then prioritized two distinct lipid-associated microglial subpopulations—one drives amyloid-β proteinopathy while the other mediates the effect of amyloid-β on tau proteinopathy—as well as an astrocyte subpopulation that mediates the effect of tau on cognitive decline. To model the dynamics of cellular environments, we devised the BEYOND methodology, which identified two distinct trajectories of brain ageing, each defined by coordinated progressive changes in certain cellular communities that lead to (1) AD dementia or (2) alternative brain ageing. Thus, we provide a cellular foundation for a new perspective on AD pathophysiology that informs personalized therapeutic development, targeting different cellular communities for individuals on the path to AD or to alternative brain ageing.