Редактирование: UNC5C

Netrin receptor UNC5C precursor (Protein unc-5 homolog 3) (Protein unc-5 homolog C) [UNC5H3]

==Publications==

{{medline-entry
|title=Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28441426
|abstract=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. "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. 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.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alleles
* Alzheimer Disease
* Brain
* Cognition
* Cognition Disorders
* DNA Methylation
* Depression
* Epigenesis, Genetic
* Female
* Genome-Wide Association Study
* Genotype
* Humans
* Linkage Disequilibrium
* Male
* Membrane Proteins
* Memory
* Microfilament Proteins
* Nerve Tissue Proteins
* Netrin Receptors
* Neuropeptides
* Nuclear Proteins
* Polymorphism, Single Nucleotide
* RNA
* Receptors, Cell Surface
* TDP-43 Proteinopathies

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404753
}}