scholarly journals Multi-tissue probabilistic fine-mapping of transcriptome-wide association study identifies cis-regulated genes for miserableness

2019 ◽  
Author(s):  
Calwing Liao ◽  
Veikko Vuokila ◽  
Alexandre D Laporte ◽  
Dan Spiegelman ◽  
Patrick A. Dion ◽  
...  
Keyword(s):  
Association Study ◽  
Fine Mapping ◽  
Brain Cortex ◽  
Common Variants ◽  
Inclusion Probability ◽  
Short Summary ◽  
Credible Sets ◽  
Functional Relevance ◽  
Negative Feelings ◽  
The Brain

AbstractMiserableness is a behavioural trait that is characterized by strong negative feelings in an individual. Although environmental factors tend to invoke miserableness, it is common to feel miserable ‘for no reason’, suggesting an innate, potential genetic component. Currently, little is known about the functional relevance of common variants associated with miserableness. To further characterize the trait, we conducted a transcriptome-wide association study (TWAS) on 373,733 individuals and identified 104 signals across brain tissue panels with 37 unique genes. Subsequent probabilistic fine-mapping prioritized 95 genes into 90%-credible sets. Amongst these prioritized hits, C7orf50 had the highest posterior inclusion probability of 0.869 in the brain cortex. Furthermore, we demonstrate that many GWAS hits for miserableness are driven by expression. To conclude, we successfully identified several genes implicated in miserableness and highlighted the power of TWAS to prioritize genes associated with a trait.Short summaryThe first transcriptome-wide association study of miserableness identifies many genes including c7orf50 implicated in the trait.

scholarly journals Intermittent Hypoxic Conditioning Rescues Cognition and Mitochondrial Bioenergetic Profile in the Triple Transgenic Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 22 (1) ◽  
pp. 461
Author(s):  
Sónia C. Correia ◽  
Nuno J. Machado ◽  
Marco G. Alves ◽  
Pedro F. Oliveira ◽  
Paula I. Moreira
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Brain Cortex ◽  
Neurodegenerative Disorder ◽  
Special Focus ◽  
Mitochondrial Bioenergetics ◽  
Related Phenotype ◽  
Brain Resilience ◽  
The Brain

The lack of effective disease-modifying therapeutics to tackle Alzheimer’s disease (AD) is unsettling considering the actual prevalence of this devastating neurodegenerative disorder worldwide. Intermittent hypoxic conditioning (IHC) is a powerful non-pharmacological procedure known to enhance brain resilience. In this context, the aim of the present study was to investigate the potential long-term protective impact of IHC against AD-related phenotype, putting a special focus on cognition and mitochondrial bioenergetics and dynamics. For this purpose, six-month-old male triple transgenic AD mice (3×Tg-AD) were submitted to an IHC protocol for two weeks and the behavioral assessment was performed at 8.5 months of age, while the sacrifice of mice occurred at nine months of age and their brains were removed for the remaining analyses. Interestingly, IHC was able to prevent anxiety-like behavior and memory and learning deficits and significantly reduced brain cortical levels of amyloid-β (Aβ) in 3×Tg-AD mice. Concerning brain energy metabolism, IHC caused a significant increase in brain cortical levels of glucose and a robust improvement of the mitochondrial bioenergetic profile in 3×Tg-AD mice, as mirrored by the significant increase in mitochondrial membrane potential (ΔΨm) and respiratory control ratio (RCR). Notably, the improvement of mitochondrial bioenergetics seems to result from an adaptative coordination of the distinct but intertwined aspects of the mitochondrial quality control axis. Particularly, our results indicate that IHC favors mitochondrial fusion and promotes mitochondrial biogenesis and transport and mitophagy in the brain cortex of 3×Tg-AD mice. Lastly, IHC also induced a marked reduction in synaptosomal-associated protein 25 kDa (SNAP-25) levels and a significant increase in both glutamate and GABA levels in the brain cortex of 3×Tg-AD mice, suggesting a remodeling of the synaptic microenvironment. Overall, these results demonstrate the effectiveness of the IHC paradigm in forestalling the AD-related phenotype in the 3×Tg-AD mouse model, offering new insights to AD therapy and forcing a rethink concerning the potential value of non-pharmacological interventions in clinical practice.

scholarly journals CAUSALdb: a database for disease/trait causal variants identified using summary statistics of genome-wide association studies

2019 ◽  
Author(s):  
Jianhua Wang ◽  
Dandan Huang ◽  
Yao Zhou ◽  
Hongcheng Yao ◽  
Huanhuan Liu ◽  
...  
Keyword(s):  
Fine Mapping ◽  
Genetic Variants ◽  
Association Studies ◽  
Complex Trait ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Genome Wide ◽  
Credible Sets ◽  
Causal Variants

Abstract Genome-wide association studies (GWASs) have revolutionized the field of complex trait genetics over the past decade, yet for most of the significant genotype-phenotype associations the true causal variants remain unknown. Identifying and interpreting how causal genetic variants confer disease susceptibility is still a big challenge. Herein we introduce a new database, CAUSALdb, to integrate the most comprehensive GWAS summary statistics to date and identify credible sets of potential causal variants using uniformly processed fine-mapping. The database has six major features: it (i) curates 3052 high-quality, fine-mappable GWAS summary statistics across five human super-populations and 2629 unique traits; (ii) estimates causal probabilities of all genetic variants in GWAS significant loci using three state-of-the-art fine-mapping tools; (iii) maps the reported traits to a powerful ontology MeSH, making it simple for users to browse studies on the trait tree; (iv) incorporates highly interactive Manhattan and LocusZoom-like plots to allow visualization of credible sets in a single web page more efficiently; (v) enables online comparison of causal relations on variant-, gene- and trait-levels among studies with different sample sizes or populations and (vi) offers comprehensive variant annotations by integrating massive base-wise and allele-specific functional annotations. CAUSALdb is freely available at http://mulinlab.org/causaldb.

scholarly journals Characterization of calcium-dependent membrane binding proteins of brain cortex

1985 ◽  
Vol 229 (3) ◽  
pp. 587-593 ◽  
Author(s):  
A R Rhoads ◽  
M Lulla ◽  
P B Moore ◽  
C E Jackson
Keyword(s):  
Brain Cortex ◽  
Peptide Mapping ◽  
Bovine Brain ◽  
Particulate Fraction ◽  
Structural Homology ◽  
One Dimensional ◽  
Calcium Dependent ◽  
Stokes Radius ◽  
The Brain

Proteins of Mr 68 000, 34 000 and 32 000 were selectively extracted by EGTA from brain cortex. The three proteins that were extracted along with calmodulin were acidic, monomeric, and did not exhibit structural homology, as demonstrated by one-dimensional peptide mapping. The Mr-68 000 protein was purified to homogeneity and had a Stokes radius of 3.54 nm and S20,W value of 5.1S. Purified calmodulin, Mr-68 000 protein and two proteins of Mr 34 000 and Mr 32 000, interacted with the brain particulate fraction, with half-maximal binding occurring at 3.5 microM, 8.3 microM and 150 microM-Ca2+ respectively. Proteins were bound independently of each other and calmodulin. Pretreatment of the particulate fraction with trypsin prevented the Ca2+-dependent binding of calmodulin; however, the binding of the Mr-68 000 protein or the Mr−32 000 and −34 000 proteins was unaffected. The Mr-68 000 protein of bovine brain did not cross-react immunologically with Mr-67 000 calcimedin from chicken gizzard.

Well-Preserved Cholinergic Neuronal Activity in the Brain Cortex of the Severely Uremic Rats

Renal Failure ◽  
1999 ◽  
Vol 21 (5) ◽  
pp. 551-554
Author(s):  
Hiroshi Tanaka ◽  
Hideki Hirakata ◽  
Hidetoshi Kanai ◽  
Itsuko Ishida ◽  
Masatoshi Fujishima
Keyword(s):  
Neuronal Activity ◽  
Brain Cortex ◽  
The Brain

Physiology and pathophysiology of the RANKL/RANK system

2010 ◽  
Vol 391 (12) ◽  
Author(s):  
Reiko Hanada ◽  
Toshikatsu Hanada ◽  
Josef M. Penninger
Keyword(s):  
Body Temperature ◽  
Mammary Gland Development ◽  
Basal Body Temperature ◽  
Central Nervous Systems ◽  
Rank System ◽  
Functional Relevance ◽  
Rank Signaling ◽  
Gland Development ◽  
The Brain ◽  
Node Formation

Abstract The TNF family molecule RANKL and its receptor RANK are key regulators of bone remodeling, lymph node formation, and mammary gland development during pregnancy. RANKL and RANK are also expressed in the central nervous systems (CNS). However, the functional relevance of RANKL/RANK in the brain was entirely unknown. Recently, our group reported that the RANKL/RANK signaling pathway has an essential role in the central regulation of body temperature via the prostaglandin axis. This review discusses novel aspects of the RANKL/RANK system as key regulators of fever and female basal body temperature in the CNS.

An accurate 3-D model for magnetic stimulation of the brain cortex

1995 ◽  
Vol 19 (1) ◽  
pp. 7-16 ◽  
Author(s):  
G. Cerri ◽  
R. De Leo ◽  
F. Moglie ◽  
A. Schiavoni
Keyword(s):  
Magnetic Stimulation ◽  
Brain Cortex ◽  
D Model ◽  
The Brain ◽  
Stimulation Of
Sign in / Sign up

Export Citation Format

Share Document