scholarly journals A rare missense mutation inMYH6confers high risk of coarctation of the aorta

2017 ◽  
Author(s):  
Thorsteinn Bjornsson ◽  
Rosa B. Thorolfsdottir ◽  
Gardar Sveinbjornsson ◽  
Patrick Sulem ◽  
Gudmundur L. Norddahl ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Genome Wide Association Study ◽  
Cardiac Development ◽  
Heart Defects ◽  
Coarctation Of The Aorta ◽  
Population Level ◽  
Genome Wide ◽  
Cardiac Syndrome ◽  
A Genome ◽  
And Function

Coarctation of the aorta (CoA) accounts for 4-8% of congenital heart defects (CHDs) and carries substantial morbidity despite treatment1. We performed a genome-wide association study (GWAS) of CoA among 120 Icelandic cases and 355,166 controls and found association with a rare (frequency = 0.34%) missense mutation p.Arg721Trp inMYH6(odds ratio (OR) = 44.2,P= 5.0x10-22), encoding an essential sarcomere protein. Approximately 20% of CoA cases in Iceland carry p.Arg721Trp. This is the first mutation associated with non-familial or sporadic CoA at a population level. P.Arg721Trp also associates with risk of bicuspid aortic valve (BAV) and other CHDs and has been reported to have a broad effect on cardiac electrical function and to associate strongly with sick sinus syndrome (SSS) and atrial fibrillation (AF)2. These findings suggest that p.Arg721Trp inMYH6causes a cardiac syndrome with highly variable expressivity, and emphasize the major importance of sarcomere integrity for cardiac development and function.

scholarly journals Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24

2019 ◽  
Vol 28 (11) ◽  
pp. 1919-1929 ◽  
Author(s):  
Carola Hedberg-Oldfors ◽  
Alexandra Abramsson ◽  
Daniel P S Osborn ◽  
Olof Danielsson ◽  
Afsoon Fazlinezhad ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Development ◽  
Heart Defects ◽  
Cardiovascular Disorder ◽  
Cardiac Transplant ◽  
Genome Wide ◽  
Homozygous Mutations ◽  
Additional Support ◽  
And Function ◽  
Muscle Biopsies

Abstract Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, yet the genetic cause of up to 50% of cases remains unknown. Here, we show that mutations in KLHL24 cause HCM in humans. Using genome-wide linkage analysis and exome sequencing, we identified homozygous mutations in KLHL24 in two consanguineous families with HCM. Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure. KLHL24 is a member of the Kelch-like protein family, which acts as substrate-specific adaptors to Cullin E3 ubiquitin ligases. Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments. Knock-down of the zebrafish homologue klhl24a results in heart defects similar to that described for other HCM-linked genes providing additional support for KLHL24 as a HCM-associated gene. Our findings reveal a crucial role for KLHL24 in cardiac development and function.

scholarly journals Tau in the Pathophysiology of Parkinson’s Disease

2021 ◽  
Author(s):  
Lina Pan ◽  
Lanxia Meng ◽  
Mingyang He ◽  
Zhentao Zhang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genome Wide Association Study ◽  
Lewy Bodies ◽  
Current Evidence ◽  
Gene Encoding ◽  
Passive Element ◽  
Genome Wide ◽  
A Genome ◽  
And Function

AbstractThe pathological hallmarks of Parkinson's disease (PD) are the progressive loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies (LBs) in remaining neurons. LBs primarily consist of aggregated α-Synuclein (α-Syn). However, accumulating evidence suggests that Tau, which is associated with tauopathies such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and argyrophilic grain disease, is also involved in the pathophysiology of PD. A genome-wide association study (GWAS) identified MAPT, the gene encoding the Tau protein, as a risk gene for PD. Autopsy of PD patients also revealed the colocalization of Tau and α-Syn in LBs. Experimental evidence has shown that Tau interacts with α-Syn and influences the pathology of α-Syn in PD. In this review, we discuss the structure and function of Tau and provide a summary of the current evidence supporting Tau’s involvement as either an active or passive element in the pathophysiology of PD, which may provide novel targets for the early diagnosis and treatment of PD.

scholarly journals Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch Microbiome Project

2020 ◽  
Author(s):  
E.A. Lopera-Maya ◽  
A. Kurilshikov ◽  
A. van der Graaf ◽  
S. Hu ◽  
S. Andreu-Sánchez ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Genome Wide Association Study ◽  
Strongly Correlated ◽  
Microbial Composition ◽  
Host Genetics ◽  
Secretor Status ◽  
Genome Wide ◽  
A Genome ◽  
And Function ◽  
Larger Sample

AbstractHost genetics are known to influence the gut microbiome, yet their role remains poorly understood. To robustly characterize these effects, we performed a genome-wide association study of 207 taxa and 205 pathways representing microbial composition and function within the Dutch Microbiome Project, a population cohort of 7,738 individuals from the northern Netherlands. Two robust, study-wide significant (p<1.89×10−10) signals near the LCT and ABO genes were found to affect multiple microbial taxa and pathways, and were replicated in two independent cohorts. The LCT locus associations were modulated by lactose intake, while those at ABO reflected participant secretor status determined by FUT2 genotype. Eighteen other loci showed suggestive evidence (p<5×10−8) of association with microbial taxa and pathways. At a more lenient threshold, the number of loci identified strongly correlated with trait heritability, suggesting that much larger sample sizes are needed to elucidate the remaining effects of host genetics on the gut microbiome.

scholarly journals Genome-wide association study of 1 million people identifies 111 loci for atrial fibrillation

2018 ◽  
Author(s):  
Jonas B. Nielsen ◽  
Rosa B. Thorolfsdottir ◽  
Lars G. Fritsche ◽  
Wei Zhou ◽  
Morten W. Skov ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Striated Muscle ◽  
Heart Defects ◽  
Genome Wide Association ◽  
Deleterious Mutations ◽  
Risk Variants ◽  
Genome Wide ◽  
A Genome

SummaryTo understand the genetic variation underlying atrial fibrillation (AF), the most common cardiac arrhythmia, we performed a genome-wide association study (GWAS) of > 1 million people, including 60,620 AF cases and 970,216 controls. We identified 163 independent risk variants at 111 loci and prioritized 165 candidate genes likely to be involved in AF. Many of the identified risk variants fall near genes where more deleterious mutations have been reported to cause serious heart defects in humans or mice (MYH6, NKX2-5, PITX2, TBC1D32, TBX5),1,2 or near genes important for striated muscle function and integrity (e.g. MYH7, PKP2, SSPN, SGCA). Experiments in rabbits with heart failure and left atrial dilation identified a heterogeneous distributed molecular switch from MYH6 to MYH7 in the left atrium, which resulted in contractile and functional heterogeneity and may predispose to initiation and maintenance of atrial arrhythmia.

scholarly journals MULTITRAIT ANALYSIS EXPANDS GENETIC RISK FACTORS IN CARDIOEMBOLIC STROKE

2021 ◽  
Author(s):  
Jara Carcel-Marquez ◽  
Elena Muino ◽  
Cristina Gallego-Fabrega ◽  
Natalia Cullell ◽  
Miquel Lledos ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Genome Wide Association Study ◽  
Cardiac Development ◽  
Cardioembolic Stroke ◽  
P Value ◽  
Genome Wide ◽  
Independent Analysis ◽  
A Genome ◽  
Electrical Impulses ◽  
Multitrait Analysis

Background and Purpose: The genetic architecture of cardioembolic stroke (CES) is still poorly understood. Atrial fibrillation (AF) is the main cause of CES, with which it shares heritability. We aimed to discover novel loci associated with CES by performing a Multitrait Analysis of the GWAS (MTAG) with atrial fibrillation genetic data. Methods: For the MTAG analysis we used the MEGASTROKE cohort, which comprises European patients with CES and controls (n=362,661) and an AF cohort composed of 1,030,836 subjects. Regional genetic pleiotropy of the significant results was explored using an alternative Bayesian approach with GWAS-pairwise method. A replication was performed in an independent European cohort comprising 9,105 subjects using a Genome Wide Association Study (GWAS). Results: MTAG-CES analysis revealed 40 novel and significant loci (p-value<5x10-8) associated with CES, four of which had not previously been associated with AF. A significant replication was assessed for eight novel loci: CAV1, IGF1R, KIAA1755, NEURL1, PRRX1, SYNE2, TEX41 and WIPF1, showing a p-value<0.05 in the CES vs controls independent analysis. KIAA1755, a locus not previously described associated with AF. Interestingly, 51 AF risk loci were not associated with CES according to GWAS-pairwise analysis. Gene Ontology (GO) analysis revealed that these exclusive AF genes from the 51 loci participate in processes related mainly to cardiac development, whereas genes associated with AF and CES participate mainly in muscle contraction and the conduction of electrical impulses. Conclusions: We found eight new loci associated with CES. In addition, this study provides novel insights into the pathogenesis of CES, highlighting multiple candidate genes for future functional experiments.

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