scholarly journals GWAS and translating genetic associations to molecular mechanisms - far from the nearest gene: Commentary on "Regulatory genomic circuitry of human disease loci by integrative epigenomics" by C. Boix et al.2021, Nature volume 590, pages 300-307

2021 ◽  
Author(s):  
Julien Barc ◽  
Jason C Kovacic
2021 ◽  
Vol 22 (9) ◽  
pp. 4617
Author(s):  
Styliana Kyriakoudi ◽  
Anthi Drousiotou ◽  
Petros P. Petrou

Mitochondria are dynamic organelles, the morphology of which is tightly linked to their functions. The interplay between the coordinated events of fusion and fission that are collectively described as mitochondrial dynamics regulates mitochondrial morphology and adjusts mitochondrial function. Over the last few years, accruing evidence established a connection between dysregulated mitochondrial dynamics and disease development and progression. Defects in key components of the machinery mediating mitochondrial fusion and fission have been linked to a wide range of pathological conditions, such as insulin resistance and obesity, neurodegenerative diseases and cancer. Here, we provide an update on the molecular mechanisms promoting mitochondrial fusion and fission in mammals and discuss the emerging association of disturbed mitochondrial dynamics with human disease.


2012 ◽  
Vol 19 (18) ◽  
pp. 2901-2917 ◽  
Author(s):  
R. Masella ◽  
C. Santangelo ◽  
M. D’Archivio ◽  
G. LiVolti ◽  
C. Giovannini ◽  
...  

2019 ◽  
Author(s):  
João Pedro de Magalhães ◽  
Jingwei Wang

AbstractAssociating genetic variants with phenotypes is not only important to understand the underlying biology but also to identify potential drug targets for treating diseases. It is widely accepted that for most complex traits many associations remain to be discovered, the so-called “missing heritability.” Yet missing heritability can be estimated, it is a known unknown, and we argue is only a fraction of the unknowns in genetics. The majority of possible genetic variants in the genome space are either too rare to be detected or even entirely absent from populations, and therefore do not contribute to estimates of phenotypic or genetic variability. We call these unknown unknowns in genetics the “fog of genetics.” Using data from the 1000 Genomes Project we then show that larger genes with greater genetic diversity are more likely to be associated with human traits, demonstrating that genetic associations are biased towards particular types of genes and that the genetic information we are lacking about traits and diseases is potentially immense. Our results and model have multiple implications for how genetic variability is perceived to influence complex traits, provide insights on molecular mechanisms of disease and for drug discovery efforts based on genetic information.


Science ◽  
2020 ◽  
Vol 369 (6509) ◽  
pp. 1318-1330 ◽  
Author(s):  

The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the version 8 data, examining 15,201 RNA-sequencing samples from 49 tissues of 838 postmortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue specificity of genetic effects and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.


2019 ◽  
Vol 20 (18) ◽  
pp. 4372 ◽  
Author(s):  
Rafael Pulido ◽  
Roland Lang

Dual specificity phosphatases (DUSPs) constitute a heterogeneous group of enzymes, relevant in human disease, which belong to the class I Cys-based group of protein tyrosine phosphatase (PTP) gene superfamily [...]


Reproduction ◽  
2011 ◽  
Vol 142 (2) ◽  
pp. 221-234 ◽  
Author(s):  
Rabindranath De La Fuente ◽  
Claudia Baumann ◽  
Maria M Viveiros

Functional differentiation of chromatin structure is essential for the control of gene expression, nuclear architecture, and chromosome stability. Compelling evidence indicates that alterations in chromatin remodeling proteins play an important role in the pathogenesis of human disease. Among these, α-thalassemia mental retardation X-linked protein (ATRX) has recently emerged as a critical factor involved in heterochromatin formation at mammalian centromeres and telomeres as well as facultative heterochromatin on the murine inactive X chromosome. Mutations in human ATRX result in an X-linked neurodevelopmental condition with various degrees of gonadal dysgenesis (ATRX syndrome). Patients with ATRX syndrome may exhibit skewed X chromosome inactivation (XCI) patterns, and ATRX-deficient mice exhibit abnormal imprinted XCI in the trophoblast cell line. Non-random or skewed XCI can potentially affect both the onset and severity of X-linked disease. Notably, failure to establish epigenetic modifications associated with the inactive X chromosome (Xi) results in several conditions that exhibit genomic and chromosome instability such as fragile X syndrome as well as cancer development. Insight into the molecular mechanisms of ATRX function and its interacting partners in different tissues will no doubt contribute to our understanding of the pathogenesis of ATRX syndrome as well as the epigenetic origins of aneuploidy. In turn, this knowledge will be essential for the identification of novel drug targets and diagnostic tools for cancer progression as well as the therapeutic management of global epigenetic changes commonly associated with malignant neoplastic transformation.


2015 ◽  
Vol 143 (2) ◽  
pp. 242-255 ◽  
Author(s):  
Akshata Moghe ◽  
Smita Ghare ◽  
Bryan Lamoreau ◽  
Mohammad Mohammad ◽  
Shirish Barve ◽  
...  

Biomolecules ◽  
2018 ◽  
Vol 8 (1) ◽  
pp. 1 ◽  
Author(s):  
Steven Stacker ◽  
Marc Achen

Blood vessels and lymphatic vessels are located in many tissues and organs throughout the body, and play important roles in a wide variety of prevalent diseases in humans. Vascular endothelial growth factor-D (VEGF-D) is a secreted protein that can promote the remodeling of blood vessels and lymphatics in development and disease. Recent fundamental and translational studies have provided insight into the molecular mechanisms by which VEGF-D exerts its effects in human disease. Hence this protein is now of interest as a therapeutic and/or diagnostic target, or as a potential therapeutic agent, in a diversity of indications in cardiovascular medicine, cancer and the devastating pulmonary condition lymphangioleiomyomatosis. This has led to clinical trial programs to assess the effect of targeting VEGF-D signaling pathways, or delivering VEGF-D, in angina, cancer and ocular indications. This review summarizes our understanding of VEGF-D signaling in human disease, which is largely based on animal disease models and clinicopathological studies, and provides information about the outcomes of recent clinical trials testing agonists or antagonists of VEGF-D signaling.


Sign in / Sign up

Export Citation Format

Share Document