Genetics of dementia in a Finnish cohort

Pasanen, Petra; Myllykangas, Liisa; Pöyhönen, Minna; Kiviharju, Anna; Siitonen, Maija; Hardy, John; Brás, José; Paetau, Anders; Tienari, Pentti J.; Guerreiro, Rita; Verkkoniemi-Ahola, Auli

doi:10.1038/s41431-018-0117-3

Cited by 8 publications

(7 citation statements)

References 69 publications

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“…Some CNVs affected genes that are specifically expressed in the brain, and/or constrained against deletions and loss of function mutations, (Figure and Supplementary Information Appendix S1: list “constrains and expression”), identifying them as novel candidate genes for impulsive behavior. These genes included FBXL16 , PHACTR3, CDH20, FAM155A , DOK6, NKAIN2 , STXBP5L , or PCDH9 , UNC13C , and DPP10, C7orf26 , FSD1 , GLT8D1 , or GNL3. Other candidate genes included DNAJC15 and UBE2V2.…”

Section: Resultsmentioning

confidence: 99%

Rare copy number variation in extremely impulsively violent males

Vevera

Zarrei

Hartmannová

et al. 2018

Genes Brain and Behavior

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The genetic correlates of extreme impulsive violence are poorly understood, and there have been no studies that have systematically characterized a large group of affected individuals both clinically and genetically. We performed a genome‐wide rare copy number variant (CNV) analysis in 281 males from four Czech prisons who met strict clinical criteria for extreme impulsive violence. Inclusion criteria included age ≥ 18 years, an ICD‐10 diagnosis of Dissocial Personality Disorder, and the absence of an organic brain disorder. Participants underwent a structured psychiatric assessment to diagnose extreme impulsive violence and then provided a blood sample for genetic analysis. DNA was genotyped and CNVs were identified using Illumina HumanOmni2.5 single‐nucleotide polymorphism array platform. Comparing with 10851 external population controls, we identified 828 rare CNVs (frequency ≤ 0.1% among control samples) in 264 participants. The CNVs impacted 754 genes, with 124 genes impacted more than once (2‐25 times). Many of these genes are associated with autosomal dominant or X‐linked disorders affecting adult behavior, cognition, learning, intelligence, specifically expressed in the brain and relevant to synapses, neurodevelopment, neurodegeneration, obesity and neuropsychiatric phenotypes. Specifically, we identified 31 CNVs of clinical relevance in 31 individuals, 59 likely clinically relevant CNVs in 49 individuals, and 17 recurrent CNVs in 65 individuals. Thus, 123 of 281 (44%) individuals had one to several rare CNVs that were indirectly or directly relevant to impulsive violence. Extreme impulsive violence is genetically heterogeneous and genomic analysis is likely required to identify, further research and specifically treat the causes in affected individuals.

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Section: Resultsmentioning

confidence: 99%

Rare copy number variation in extremely impulsively violent males

Vevera

Zarrei

Hartmannová

et al. 2018

Genes Brain and Behavior

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“…ECSIT (down‐regulated with age) was the top‐ranked hub gene in the age transcriptome (Figure and Appendix ). Composed of 209 genes, the ECSIT network included CADM2, UNC13C and ST3GAL3 genes, with variants linked to cognition (Pasanen et al, ). ECSIT promotes NFκB activity (Wi et al, ), and in AD experimental models, repression of NFκB activity decreases BACE1 activity and both soluble and insoluble Aβ (Paris et al, ).…”

Section: Discussionmentioning

confidence: 99%

Longevity‐related molecular pathways are subject to midlife “switch” in humans

et al. 2019

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Emerging evidence indicates that molecular aging may follow nonlinear or discontinuous trajectories. Whether this occurs in human neuromuscular tissue, particularly for the noncoding transcriptome, and independent of metabolic and aerobic capacities, is unknown. Applying our novel RNA method to quantify tissue coding and long noncoding RNA (lncRNA), we identified ~800 transcripts tracking with age up to ~60 years in human muscle and brain. In silico analysis demonstrated that this temporary linear “signature” was regulated by drugs, which reduce mortality or extend life span in model organisms, including 24 inhibitors of the IGF‐1/PI3K/mTOR pathway that mimicked, and 5 activators that opposed, the signature. We profiled Rapamycin in nondividing primary human myotubes (n = 32 HTA 2.0 arrays) and determined the transcript signature for reactive oxygen species in neurons, confirming that our age signature was largely regulated in the “pro‐longevity” direction. Quantitative network modeling demonstrated that age‐regulated ncRNA equaled the contribution of protein‐coding RNA within structures, but tended to have a lower heritability, implying lncRNA may better reflect environmental influences. Genes ECSIT, UNC13, and SKAP2 contributed to a network that did not respond to Rapamycin, and was associated with “neuron apoptotic processes” in protein–protein interaction analysis (FDR = 2.4%). ECSIT links inflammation with the continued age‐related downwards trajectory of mitochondrial complex I gene expression (FDR < 0.01%), implying that sustained inhibition of ECSIT may be maladaptive. The present observations link, for the first time, model organism longevity programs with the endogenous but temporary genome‐wide responses to aging in humans, revealing a pattern that may ultimately underpin personalized rates of health span.

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“…It was reported as one of the hub genes in a genome-wide association study of post-traumatic stress disorder in Iraq-Afghanistan veterans [27]. Unc13c has also been found to be associated with neurodegeneration in a genetic dementia in Finland [28]. These studies suggested that Unc13c could be closely associated with the CNS, and it could be a target gene for reducing PND.…”

Section: Discussionmentioning

confidence: 99%

Identification of circRNA-miRNA-mRNA networks to explore the molecular mechanism and immune regulation of postoperative neurocognitive disorder

Bao

Liu

Peng

et al. 2022

Aging

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Postoperative neurocognitive disorder (PND) is a common complication in older patients. However, its pathogenesis has still remained elusive. Recent studies have shown that circular RNA (circRNA) plays an important role in the development of neurodegenerative diseases, such as PND after surgery. CircRNA, as a competitive endogenous RNA (ceRNA), mainly acts as a molecular sponge for miRNA to "adsorb" microRNA (miRNA) and to reduce the inhibitory effects of miRNAs on target mRNA. The sequencing data of circRNA were obtained from the Gene Expression Omnibus (GEO) database. By bioinformatic methods, circAtlas, miRDB, miRTarBase and miRwalk databases were applied to construct circRNA-miRNA-mRNA networks and screen differentially expressed mRNAs. To improve the accuracy of the data, we randomly divided aging mice into control (non-PND group) and PND groups, and used high-throughput sequencing to analyze their brain hippocampal tissue for analysis. Three key genes were cross-detected in the data of both groups, which were Unc13c, Tbx20 and St8sia2 (as hub genes), providing new targets for PND treatment. According to the results of the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, immune cell infiltration analysis, gene set enrichment analysis (GSEA), Connectivity Map (CMap) analysis, quantitative real-time polymerase chain reaction (qRT-PCR), the genes that were not related to the central nervous system were removed, and finally, mmu_circ_0000331/miR-1224-3p/Unc13c and mmu_circ_0000406/miR-24-3p/St8sia2 ceRNA networks were identified. In addition, the CMap method was used to select the top 4 active compounds with the largest negative correlation absolute values, including cimaterol, Rucaparib, FG-7142, and Hydrocortisone.

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Genetics of dementia in a Finnish cohort

Cited by 8 publications

References 69 publications

Rare copy number variation in extremely impulsively violent males

Rare copy number variation in extremely impulsively violent males

Longevity‐related molecular pathways are subject to midlife “switch” in humans

Identification of circRNA-miRNA-mRNA networks to explore the molecular mechanism and immune regulation of postoperative neurocognitive disorder

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