Developmental aspects of cardiac arrhythmias

2018 ◽  
Author(s):  
Alex V. Postma ◽  
David Sedmera ◽  
Frantisek Vostarek ◽  
Vincent M. Christoffels ◽  
Connie R. Bezzina
Keyword(s):  
Regional Differences ◽  
Causal Relation ◽  
Association Studies ◽  
The Body ◽  
Developmental Changes ◽  
Genome Wide Association Studies ◽  
Electrophysiological Properties ◽  
Functional Aspects ◽  
Genome Wide ◽  
Insight Into

The rhythmic and synchronized contraction of atria and ventricles is essential for efficient pumping of blood throughout the body. This process relies on the proper generation and conduction of the cardiac electrical impulse. Electrophysiological properties differ in various regions of the heart, revealing intrinsic heterogeneities rooted, at least in part, in regional differences in expression of ion channel and gap junction subunit genes. A causal relation between transcription factors and such regionalized gene expression has been established. Abnormal cardiac electrical function and arrhythmias in the postnatal heart may stem from a developmental changes in gene regulation. Genome-wide association studies have provided strong evidence that common genetic variation at developmental gene loci modulates electrocardiographic indices of conduction and repolarization and susceptibility to arrhythmia. Functional aspects are illustrated by description of selected prenatally occurring arrhythmias and their possible mechanisms. We also discuss recent findings and provide background insight into these complex mechanisms.

26-OR: Meta-analyses of Genome-Wide Association Studies for Proinsulin Provide Insight into Glycemic Trait Dysregulation

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 26-OR
Author(s):  
K. ALAINE BROADAWAY ◽  
XIANYONOG YIN ◽  
ALICE WILLIAMSON ◽  
EMMA WILSON ◽  
MAGIC INVESTIGATORS
Keyword(s):  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Meta Analyses ◽  
Insight Into

scholarly journals An approach to gene-based testing accounting for dependence of tests among nearby genes

2021 ◽  
Author(s):  
Ronald J Yurko ◽  
Kathryn Roeder ◽  
Bernie Devlin ◽  
Max G'Sell
Keyword(s):  
Multiple Testing ◽  
Association Studies ◽  
Autism Spectrum ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Strongly Correlated ◽  
Test Statistics ◽  
Test Statistic ◽  
Genome Wide ◽  
Insight Into

In genome-wide association studies (GWAS), it has become commonplace to test millions of SNPs for phenotypic association. Gene-based testing can improve power to detect weak signal by reducing multiple testing and pooling signal strength. While such tests account for linkage disequilibrium (LD) structure of SNP alleles within each gene, current approaches do not capture LD of SNPs falling in different nearby genes, which can induce correlation of gene-based test statistics. We introduce an algorithm to account for this correlation. When a gene's test statistic is independent of others, it is assessed separately; when test statistics for nearby genes are strongly correlated, their SNPs are agglomerated and tested as a locus. To provide insight into SNPs and genes driving association within loci, we develop an interactive visualization tool to explore localized signal. We demonstrate our approach in the context of weakly powered GWAS for autism spectrum disorder, which is contrasted to more highly powered GWAS for schizophrenia and educational attainment. To increase power for these analyses, especially those for autism, we use adaptive p-value thresholding (AdaPT), guided by high-dimensional metadata modeled with gradient boosted trees, highlighting when and how it can be most useful. Notably our workflow is based on summary statistics.

scholarly journals Proportion of idiopathic pulmonary fibrosis risk explained by known genetic loci

2020 ◽  
Author(s):  
Olivia C Leavy ◽  
Shwu-Fan Ma ◽  
Philip L Molyneaux ◽  
Toby M Maher ◽  
Justin M Oldham ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Genetic Architecture ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Risk Variants ◽  
Genome Wide ◽  
The Impact ◽  
Insight Into

Genome-wide association studies have identified 14 genetic loci associated with susceptibility to idiopathic pulmonary fibrosis (IPF), a devastating lung disease with poor prognosis. Of these, the variant with the strongest association, rs35705950, is located in the promoter region of the MUC5B gene and has a risk allele (T) frequency of 30-35% in IPF cases. Here we present estimates of the proportion of disease liability explained by each of the 14 IPF risk variants as well as estimates of the proportion of cases that can be attributed to each variant. We estimate that rs35705950 explains 5.9-9.4% of disease liability, which is much lower than previously reported estimates. Of every 100,000 individuals with the rs35705950_GG genotype we estimate 30 will have IPF, whereas for every 100,000 individuals with the rs35705950_GT genotype 152 will have IPF. Quantifying the impact of genetic risk factors on disease liability improves our understanding of the underlying genetic architecture of IPF and provides insight into the impact of genetic factors in risk prediction modelling.

scholarly journals Genome-Wide Association Study of Body Fat Distribution identifies Novel Adiposity Loci and Sex-Specific Genetic Effects

2017 ◽  
Author(s):  
Mathias Rask-Andersen ◽  
Torgny Karlsson ◽  
Weronica E Ek ◽  
Åsa Johansson
Keyword(s):  
Body Fat ◽  
Genome Wide Association Study ◽  
Metabolic Diseases ◽  
Association Studies ◽  
Fat Distribution ◽  
Body Fat Distribution ◽  
The Body ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

Body mass and body fat composition are of clinical interest due to their links to cardiovascular- and metabolic diseases. Fat stored in the trunk has been suggested as more pathogenic compared to fat stored in other compartments of the body. In this study, we performed genome-wide association studies (GWAS) for the proportion of body fat distributed to the arms, legs and trunk estimated from segmental bio-electrical impedance analysis (sBIA) for 362,499 individuals from the UK Biobank. A total of 97 loci, were identified to be associated with body fat distribution, 40 of which have not previously been associated with an anthropometric trait. A high degree of sex-heterogeneity was observed and associations were primarily observed in females, particularly for distribution of fat to the legs or trunk. Our findings also implicate that body fat distribution in females involves mesenchyme derived tissues and cell types, female endocrine tissues a well as several enzymatically active members of the ADAMTS family of metalloproteinases, which are involved in extracellular matrix maintenance and remodeling.

scholarly journals The UMOD Locus: Insights into the Pathogenesis and Prognosis of Kidney Disease

2017 ◽  
Vol 29 (3) ◽  
pp. 713-726 ◽  
Author(s):  
Olivier Devuyst ◽  
Cristian Pattaro
Keyword(s):  
Kidney Disease ◽  
Kidney Diseases ◽  
Association Studies ◽  
Biochemical Properties ◽  
Genome Wide Association Studies ◽  
Genetic Studies ◽  
Rare Mutations ◽  
Genome Wide ◽  
Genomic Regions ◽  
Insight Into

The identification of genetic factors associated with kidney disease has the potential to provide critical insights into disease mechanisms. Genome-wide association studies have uncovered genomic regions associated with renal function metrics and risk of CKD. UMOD is among the most outstanding loci associated with CKD in the general population, because it has a large effect on eGFR and CKD risk that is consistent across different ethnic groups. The relevance of UMOD for CKD is clear, because the encoded protein, uromodulin (Tamm–Horsfall protein), is exclusively produced by the kidney tubule and has specific biochemical properties that mediate important functions in the kidney and urine. Rare mutations in UMOD are the major cause of autosomal dominant tubulointerstitial kidney disease, a condition that leads to CKD and ESRD. In this brief review, we use the UMOD paradigm to describe how population genetic studies can yield insight into the pathogenesis and prognosis of kidney diseases.

scholarly journals Genome-wide association study of serum liver enzymes implicates diverse metabolic and liver pathology

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Vincent L. Chen ◽  
Xiaomeng Du ◽  
Yanhua Chen ◽  
Annapurna Kuppa ◽  
Samuel K. Handelman ◽  
...  
Keyword(s):  
Liver Enzyme ◽  
Genome Wide Association Study ◽  
Metabolic Diseases ◽  
Liver Enzymes ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Insight Into

AbstractSerum liver enzyme concentrations are the most frequently-used laboratory markers of liver disease, a major cause of mortality. We conduct a meta-analysis of genome-wide association studies of liver enzymes from UK BioBank and BioBank Japan. We identified 160 previously-unreported independent alanine aminotransferase, 190 aspartate aminotransferase, and 199 alkaline phosphatase genome-wide significant associations, with some affecting multiple different enzymes. Associated variants implicate genes that demonstrate diverse liver cell type expression and promote a range of metabolic and liver diseases. These findings provide insight into the pathophysiology of liver and other metabolic diseases that are associated with serum liver enzyme concentrations.

scholarly journals Melanocortin Pathways: Suppressed and Stimulated Melanocortin-4 Receptor (MC4R)

2020 ◽  
pp. S245-S254
Author(s):  
V. HAINER ◽  
I. ALDHOON HAINEROVÁ ◽  
M. KUNEŠOVÁ ◽  
R. TAXOVÁ BRAUNEROVÁ ◽  
H. ZAMRAZILOVÁ ◽  
...  
Keyword(s):  
Association Studies ◽  
Gene Mutations ◽  
The Body ◽  
Genome Wide Association Studies ◽  
New Horizons ◽  
Mc4r Gene ◽  
Melanocortin 4 Receptor ◽  
Cardiovascular Side Effects ◽  
Genome Wide ◽  
Melanocortin Signaling

Leptin-melanocortin pathway plays an essential role in the body weight regulation. Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. The discovery of monogenic obesities with dysfunction of melanocortin-4 receptor (MC4R) greatly contributed to understanding of energy balance regulation. This review presents phenotypical characterization and prevalence of the MC4R gene mutations. Genome-wide association studies revealed that MC4R gene is significantly related not only to monogenic obesities but also to common obesity. An interaction of variants in the MC4R gene with fat mass and obesity associated (FTO) gene significantly increases the risk for obesity, particularly in adolescence. On the other hand, about 15 % of the MC4R gene variants result in a gain of function that protects against obesity and is associated with favorable metabolic profile. Long-term attempts to activate the MC4R have recently been finalized by a discovery of setmelanotide, a novel specific MC4R agonist that is devoid of untoward cardiovascular side-effects. The employment of specific MC4R agonists may open new horizons not only in the treatment of rare monogenic obesities but also in some common obesities where stimulation of MC4R could be achieved.

scholarly journals Investigating the role of insulin in increased adiposity: Bi-directional Mendelian randomization study

2017 ◽  
Author(s):  
RC Richmond ◽  
KH Wade ◽  
L Corbin ◽  
J Bowden ◽  
G Hemani ◽  
...  
Keyword(s):  
Large Scale ◽  
Causal Effect ◽  
Association Studies ◽  
The Body ◽  
Genome Wide Association Studies ◽  
Fasting Insulin ◽  
Insulin Levels ◽  
Genome Wide ◽  
Weighted Median ◽  
High Degree

AbstractInsulin may serve as a key causal agent which regulates fat accumulation in the body. Here we assessed the causal relationship between fasting insulin and adiposity using publicly-available results from two large-scale genome-wide association studies for body mass index and fasting insulin levels in a two-sample, bidirectional Mendelian Randomized approach. This approach is only valid on the condition that the two instruments are independent of one another. In analysis excluding overlapping loci, there was an increase of 0.20 (0.17, 0.23) log pmol/L fasting insulin per SD increase in BMI (P= 2.80 x 10−36), while there was a null effect of fasting insulin on BMI, with a 0.01 (−0.39, 0.38) SD decrease in BMI per log pmol/L increase in fasting insulin (P= 0.98). Furthermore, a high degree of heterogeneity in the causal estimates was obtained from the insulin-related variants, which may be attributed to varying mechanisms of action of the insulin-associated variants. Results were largely consistent when an Egger regression technique and weighted median and mode estimators were applied. Findings suggest that the positive correlation between adiposity and fasting insulin levels are at least in part explained by the causal effect of adiposity on increasing insulin, rather than vice versa.

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