scholarly journals Loss-of-Function Variants in the SYNPO2L Gene Are Associated With Atrial Fibrillation

2021 ◽  
Vol 8 ◽  
Author(s):  
Alexander Guldmann Clausen ◽  
Oliver Bundgaard Vad ◽  
Julie Husted Andersen ◽  
Morten Salling Olesen
Keyword(s):  
Atrial Fibrillation ◽  
Cardiac Myocyte ◽  
Association Studies ◽  
Structural Development ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genome Wide ◽  
Increased Risk ◽  
Rare Genetic Variants ◽  
And Function

Multiple genome-wide association studies (GWAS) have identified numerous loci associated with atrial fibrillation (AF). However, the genes driving these associations and how they contribute to the AF pathogenesis remains poorly understood. To identify genes likely to be driving the observed association, we searched the FinnGen study consisting of 12,859 AF cases and 73,341 controls for rare genetic variants predicted to cause loss-of-function. A specific splice site variant was found in the SYNPO2L gene, located in an AF associated locus on chromosome 10. This variant was associated with an increased risk of AF with a relatively high odds ratio of 3.5 (p = 9.9 × 10−8). SYNPO2L is an important gene involved in the structural development and function of the cardiac myocyte and our findings thus support the recent suggestions that AF can present as atrial cardiomyopathy.

scholarly journals Genetics of Atrial Fibrillation in 2020

2020 ◽  
Vol 127 (1) ◽  
pp. 21-33 ◽  
Author(s):  
Carolina Roselli ◽  
Michiel Rienstra ◽  
Patrick T. Ellinor
Keyword(s):  
Atrial Fibrillation ◽  
Complex Disease ◽  
Association Studies ◽  
Heart Rhythm ◽  
Genome Wide Association Studies ◽  
Future Directions ◽  
Genetics Research ◽  
Genome Wide ◽  
Increased Risk ◽  
Rhythm Disorder

Atrial fibrillation is a common heart rhythm disorder that leads to an increased risk for stroke and heart failure. Atrial fibrillation is a complex disease with both environmental and genetic risk factors that contribute to the arrhythmia. Over the last decade, rapid progress has been made in identifying the genetic basis for this common condition. In this review, we provide an overview of the primary types of genetic analyses performed for atrial fibrillation, including linkage studies, genome-wide association studies, and studies of rare coding variation. With these results in mind, we aim to highlighting the existing knowledge gaps and future directions for atrial fibrillation genetics research.

scholarly journals Genetic Analysis of Osteoblast Activity Identifies Zbtb40 as a Regulator of Osteoblast Activity and Bone Mass

2019 ◽  
Author(s):  
Madison L. Doolittle ◽  
Gina M Calabrese ◽  
Larry D. Mesner ◽  
Dana A. Godfrey ◽  
Robert D. Maynard ◽  
...  
Keyword(s):  
Bone Formation ◽  
Genetic Basis ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Mineral Density ◽  
Osteoblast Activity ◽  
Genome Wide ◽  
Increased Risk

ABSTRACTOsteoporosis is a genetic disease characterized by progressive reductions in bone mineral density (BMD) leading to an increased risk of fracture. Over the last decade, genome-wide association studies (GWASs) have identified over 1000 associations for BMD. However, as a phenotype BMD is challenging as bone is a multicellular tissue affected by both local and systemic physiology. Here, we focused on a single component of BMD, osteoblast-mediated bone formation in mice, and identified associations influencing osteoblast activity on mouse Chromosomes (Chrs) 1, 4, and 17. The locus on Chr. 4 was in an intergenic region between Wnt4 and Zbtb40, homologous to a locus for BMD in humans. We tested both Wnt4 and Zbtb40 for a role in osteoblast activity and BMD. Knockdown of Zbtb40, but not Wnt4, in osteoblasts drastically reduced mineralization. Additionally, loss-of-function mouse models for both genes exhibited reduced BMD. Our results highlight that investigating the genetic basis of in vitro osteoblast mineralization can be used to identify genes impacting bone formation and BMD.

scholarly journals Atrial fibrillation—a complex polygenetic disease

2020 ◽  
Author(s):  
Julie H. Andersen ◽  
Laura Andreasen ◽  
Morten S. Olesen
Keyword(s):  
Atrial Fibrillation ◽  
Rare Variants ◽  
Association Studies ◽  
Epidemiological Studies ◽  
Research Field ◽  
Genome Wide Association Studies ◽  
Functional Studies ◽  
Genome Wide ◽  
Transcription Factor Genes ◽  
Rare Genetic Variants

AbstractAtrial fibrillation (AF) is the most common type of arrhythmia. Epidemiological studies have documented a substantial genetic component. More than 160 genes have been associated with AF during the last decades. Some of these were discovered by classical linkage studies while the majority relies on functional studies or genome-wide association studies. In this review, we will evaluate the genetic basis of AF and the role of both common and rare genetic variants in AF. Rare variants in multiple ion-channel genes as well as gap junction and transcription factor genes have been associated with AF. More recently, a growing body of evidence has implicated structural genes with AF. An increased burden of atrial fibrosis in AF patients compared with non-AF patients has also been reported. These findings challenge our traditional understanding of AF being an electrical disease. We will focus on several quantitative landmark papers, which are transforming our understanding of AF by implicating atrial cardiomyopathies in the pathogenesis. This new AF research field may enable better diagnostics and treatment in the future.

scholarly journals Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation

2020 ◽  
Vol 9 (2) ◽  
pp. 372 ◽  
Author(s):  
Oliver Bundgaard Vad ◽  
Christian Paludan-Müller ◽  
Gustav Ahlberg ◽  
Silje Madeleine Kalstø ◽  
Jonas Ghouse ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Genetic Correlation ◽  
Early Onset ◽  
Association Studies ◽  
Cytoskeletal Proteins ◽  
Control Group ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Increased Risk ◽  
Genes Encoding

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with an increased risk of heart failure, stroke, dementia, and death. Recently, titin-truncating variants (TTNtv), which are predominantly associated with dilated cardiomyopathy (DCM), were associated with early-onset AF. Furthermore, genome-wide association studies (GWAS) associated AF with other structural genes. In this study, we investigated whether early-onset AF was associated with loss-of-function variants in DCM-associated genes encoding cytoskeletal proteins. Using targeted sequencing, we examined a cohort of 527 Scandinavian individuals with early-onset AF and a control group of individuals free of AF (n = 383). The patients had onset of AF before 50 years of age, normal echocardiogram, and no other cardiovascular disease at onset of AF. We identified six individuals with rare loss-of-function variants in three different genes (dystrophin (DMD), actin-associated LIM protein (PDLIM3), and fukutin (FKTN)), of which two variants were novel. Loss-of-function variants in cytoskeletal genes were significantly associated with early-onset AF when patients were compared with controls (p = 0.044). Using publicly available GWAS data, we performed genetic correlation analyses between AF and 13 other traits, e.g., showing genetic correlation between AF and non-ischemic cardiomyopathy (p = 0.0003). Our data suggest that rare loss-of-function variants in cytoskeletal genes previously associated with DCM may have a role in early-onset AF, perhaps through the development of an atrial cardiomyopathy.

scholarly journals Understanding PITX2-Dependent Atrial Fibrillation Mechanisms through Computational Models

2021 ◽  
Vol 22 (14) ◽  
pp. 7681
Author(s):  
Jieyun Bai ◽  
Yaosheng Lu ◽  
Yijie Zhu ◽  
Huijin Wang ◽  
Dechun Yin ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Computational Models ◽  
Association Studies ◽  
Basic Research ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Patient Health ◽  
Quantitative Understanding ◽  
Whole Heart ◽  
And Function

Atrial fibrillation (AF) is a common arrhythmia. Better prevention and treatment of AF are needed to reduce AF-associated morbidity and mortality. Several major mechanisms cause AF in patients, including genetic predispositions to AF development. Genome-wide association studies have identified a number of genetic variants in association with AF populations, with the strongest hits clustering on chromosome 4q25, close to the gene for the homeobox transcription PITX2. Because of the inherent complexity of the human heart, experimental and basic research is insufficient for understanding the functional impacts of PITX2 variants on AF. Linking PITX2 properties to ion channels, cells, tissues, atriums and the whole heart, computational models provide a supplementary tool for achieving a quantitative understanding of the functional role of PITX2 in remodelling atrial structure and function to predispose to AF. It is hoped that computational approaches incorporating all we know about PITX2-related structural and electrical remodelling would provide better understanding into its proarrhythmic effects leading to development of improved anti-AF therapies. In the present review, we discuss advances in atrial modelling and focus on the mechanistic links between PITX2 and AF. Challenges in applying models for improving patient health are described, as well as a summary of future perspectives.

P1231Loss of function in cytoskeletal genes associates with early onset atrial fibrillation

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
O Vad ◽  
G Ahlberg ◽  
L Refsgaard ◽  
J H Svendsen ◽  
A Tveit ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Early Onset ◽  
Association Studies ◽  
Dystrophin Gene ◽  
Cytoskeletal Proteins ◽  
Control Group ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Structural Genes ◽  
Increased Risk

Abstract Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia. It carries an increased risk of serious complications and an increased mortality. Genome Wide Association Studies have demonstrated that variants in several structural genes are associated with AF, and recently two landmark papers have implicated loss of function (LoF) variants in titin (TTN), a gene associated with dilated cardiomyopathy (DCM), in patients with early onset AF. An atrial cardiomyopathy syndrome has been proposed as a mechanism in the development of AF. Purpose We hypothesized that genes encoding structural proteins that were associated with DCM, could also be involved in atrial cardiomyopathy and contribute to AF. Materials and methods We performed targeted deep sequencing of structural genes associated with DCM. The genes were grouped by cellular function, and the burden of LoF variants was examined in a cohort of 540 early onset AF patients and compared to a control group (n=383). The patients were below age 49 with normal echo, and no other cardiovascular disease at onset of AF. Patient inclusion in the cohort is still ongoing, and we are working on obtaining a CRISPR/CAS9 modified zebra fish model with LoF variants in cytoskeletal proteins. Results We identified a total of 6 carriers of LoF variants in 3 genes thought to encode cytoskeletal proteins (DMD, PDLIM3 and FKTN). The burden of variants in cytoskeletal genes was significantly increased in patients with early onset AF compared with controls (p=0.0385). Four carriers had LoF variants in the dystrophin gene (DMD), while there was 1 carrier of LoF variants in PDLIM3 and FKTN respectively. All carriers with LoF variants in DMD developed persistent AF before age 30. Conclusion Our data suggest that rare mutations in cytoskeletal genes previously associated with DCM, may also play a role in the development of early onset AF. The data supports that AF is a part of an atrial cardiomyopathy syndrome. Acknowledgement/Funding Novo Nordisk Fonden Pre-Graduate Scholarships

scholarly journals GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lucas D. Ward ◽  
Ho-Chou Tu ◽  
Chelsea B. Quenneville ◽  
Shira Tsour ◽  
Alexander O. Flynn-Carroll ◽  
...  
Keyword(s):  
Bile Duct ◽  
Extrahepatic Bile Duct ◽  
Association Studies ◽  
Missense Variant ◽  
Deficiency Anemia ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Extrahepatic Bile Duct Cancer ◽  
Hepatocellular Damage ◽  
Increased Risk

AbstractUnderstanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.

scholarly journals The Genetic Basis of Hypertriglyceridemia

2021 ◽  
Vol 23 (8) ◽  
Author(s):  
Germán D. Carrasquilla ◽  
Malene Revsbech Christiansen ◽  
Tuomas O. Kilpeläinen
Keyword(s):  
Genetic Basis ◽  
Association Studies ◽  
Cumulative Effect ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Risk Variants ◽  
Genome Wide ◽  
Severe Hypertriglyceridemia ◽  
Increased Risk ◽  
Polygenic Scores

Abstract Purpose of Review Hypertriglyceridemia is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. Severe hypertriglyceridemia may sometimes be a monogenic condition. However, in the vast majority of patients, hypertriglyceridemia is due to the cumulative effect of multiple genetic risk variants along with lifestyle factors, medications, and disease conditions that elevate triglyceride levels. In this review, we will summarize recent progress in the understanding of the genetic basis of hypertriglyceridemia. Recent Findings More than 300 genetic loci have been identified for association with triglyceride levels in large genome-wide association studies. Studies combining the loci into polygenic scores have demonstrated that some hypertriglyceridemia phenotypes previously attributed to monogenic inheritance have a polygenic basis. The new genetic discoveries have opened avenues for the development of more effective triglyceride-lowering treatments and raised interest towards genetic screening and tailored treatments against hypertriglyceridemia. Summary The discovery of multiple genetic loci associated with elevated triglyceride levels has led to improved understanding of the genetic basis of hypertriglyceridemia and opened new translational opportunities.

scholarly journals Genetics and Epigenetics of Atrial Fibrillation

2020 ◽  
Vol 21 (16) ◽  
pp. 5717 ◽  
Author(s):  
Estefanía Lozano-Velasco ◽  
Diego Franco ◽  
Amelia Aranega ◽  
Houria Daimi
Keyword(s):  
Atrial Fibrillation ◽  
Regulatory Networks ◽  
Association Studies ◽  
Functional Characterization ◽  
The Elderly ◽  
Supraventricular Arrhythmia ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Transcriptional Regulatory ◽  
Transcriptional Regulatory Mechanisms

Atrial fibrillation (AF) is known to be the most common supraventricular arrhythmia affecting up to 1% of the general population. Its prevalence exponentially increases with age and could reach up to 8% in the elderly population. The management of AF is a complex issue that is addressed by extensive ongoing basic and clinical research. AF centers around different types of disturbances, including ion channel dysfunction, Ca2+-handling abnormalities, and structural remodeling. Genome-wide association studies (GWAS) have uncovered over 100 genetic loci associated with AF. Most of these loci point to ion channels, distinct cardiac-enriched transcription factors, as well as to other regulatory genes. Recently, the discovery of post-transcriptional regulatory mechanisms, involving non-coding RNAs (especially microRNAs), DNA methylation, and histone modification, has allowed to decipher how a normal heart develops and which modifications are involved in reshaping the processes leading to arrhythmias. This review aims to provide a current state of the field regarding the identification and functional characterization of AF-related epigenetic regulatory networks

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