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.

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 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.

TLR1 and PRKAA1 Gene Polymorphisms in the Development of Atrophic Gastritis and Gastric Cancer

2018 ◽  
Vol 27 (4) ◽  
pp. 363-369 ◽  
Author(s):  
Gintare Dargiene ◽  
Greta Streleckiene ◽  
Jurgita Skieceviciene ◽  
Marcis Leja ◽  
Alexander Link ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Atrophic Gastritis ◽  
Genetic Polymorphisms ◽  
Association Studies ◽  
Control Group ◽  
Similar Distribution ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
Infection Susceptibility ◽  
H Pylori

Background & Aims: Previous genome-wide association studies showed that genetic polymorphisms in toll-like receptor 1 (TLR1) and protein kinase AMP-activated alpha 1 catalytic subunit (PRKAA1) genes were associated with gastric cancer (GC) or increased Helicobacter pylori (H. pylori) infection susceptibility. The aim of this study was to evaluate the association between TLR1 and PRKAA1 genes polymorphisms and H.pylori infection, atrophic gastritis (AG) or GC in the European population.Methods: Single-nucleotide polymorphisms (SNPs) were analysed in 511 controls, 340 AG patients and 327 GC patients. TLR1 C>T (rs4833095) and PRKAA1 C>T (rs13361707) were genotyped by the real-time polymerase chain reaction. H. pylori status was determined by testing for anti-H. pylori IgG antibodies in the serum.Results: The study included 697 (59.2%) H. pylori positive and 481 (40.8%) H. pylori negative cases. We observed similar distribution of TLR1 and PRKAA1 alleles and genotypes in H. pylori positive and negative cases. TLR1 and PRKAA1 SNPs were not linked with the risk of AG. TC genotype of TLR1 gene was more prevalent in GC patients compared to the control group (29.7% and 22.3% respectively, p=0.002). Carriers of TC genotype had a higher risk of GC (aOR=1.89, 95% CI: 1.26–2.83, p=0.002). A similar association was observed in a dominant inheritance model for TLR1 gene SNP, where comparison of CC+TC vs. TT genotypes showed an increased risk of GC (aOR=1.86, 95% CI: 1.26–2.75, p=0.002). No association between genetic polymorphism in PRKAA1 gene and GC was observed.Conclusions: TLR1 rs4833095 SNP was associated with an increased risk of GC in a European population, while PRKAA1 rs13361707 genetic variant was not linked with GC. Both genetic polymorphisms were not associated with H. pylori infection susceptibility or the risk of AG.

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 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.

Monogenic and oligogenic cardiovascular diseases: genetics of arrhythmias—short QT syndrome

2018 ◽  
Author(s):  
Erol Tülümen ◽  
Martin Borggrefe
Keyword(s):  
Atrial Fibrillation ◽  
Genetic Basis ◽  
Association Studies ◽  
Single Gene ◽  
Candidate Gene Approach ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Short Qt Syndrome ◽  
Dispersion Of Repolarization ◽  
Qt Syndrome

Short QT syndrome (SQTS) is a very rare, sporadic or autosomal dominant inherited channelopathy characterized by abnormally short QT intervals on the electrocardiogram and increased propensity to atrial and ventricular tachyarrhythmias and/or sudden cardiac death. Since its recognition as a distinct clinical entity in 2000, significant progress has been made in defining the clinical, molecular, and genetic basis of SQTS. To date, several causative gain-of-function mutations in potassium channel genes and loss-of-function mutations in calcium channel genes have been identified. The physiological consequence of these mutations is an accelerated repolarization, thus abbreviated action potentials and shortened QT interval with an increased inhomogeneity and dispersion of repolarization. Regarding other rare monogenetic arrhythmias, a genetic basis of atrial fibrillation was considered very unlikely until very recently. However, in the last decade the heritability of atrial fibrillation in the general population has been well described in several epidemiological studies. So far, more than 30 genes have been implicated in atrial fibrillation through candidate gene approach studies, and 14 loci were found to be associated with atrial fibrillation through genome-wide association studies. This genetic heterogeneity and the low prevalence of mutations in any single gene restrict the clinical utility of genetic screening in atrial fibrillation.

scholarly journals Long-range Pitx2c enhancer–promoter interactions prevent predisposition to atrial fibrillation

2019 ◽  
Vol 116 (45) ◽  
pp. 22692-22698 ◽  
Author(s):  
Min Zhang ◽  
Matthew C. Hill ◽  
Zachary A. Kadow ◽  
Ji Ho Suh ◽  
Nathan R. Tucker ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Long Range ◽  
Association Studies ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
Genome Wide Association Studies ◽  
Range Interaction ◽  
Chromosome Conformation ◽  
Risk Variants ◽  
Increased Risk

Genome-wide association studies found that increased risk for atrial fibrillation (AF), the most common human heart arrhythmia, is associated with noncoding sequence variants located in proximity to PITX2. Cardiomyocyte-specific epigenomic and comparative genomics uncovered 2 AF-associated enhancers neighboring PITX2 with varying conservation in mice. Chromosome conformation capture experiments in mice revealed that the Pitx2c promoter directly contacted the AF-associated enhancer regions. CRISPR/Cas9-mediated deletion of a 20-kb topologically engaged enhancer led to reduced Pitx2c transcription and AF predisposition. Allele-specific chromatin immunoprecipitation sequencing on hybrid heterozygous enhancer knockout mice revealed that long-range interaction of an AF-associated region with the Pitx2c promoter was required for maintenance of the Pitx2c promoter chromatin state. Long-range looping was mediated by CCCTC-binding factor (CTCF), since genetic disruption of the intronic CTCF-binding site caused reduced Pitx2c expression, AF predisposition, and diminished active chromatin marks on Pitx2. AF risk variants located at 4q25 reside in genomic regions possessing long-range transcriptional regulatory functions directed at PITX2.

scholarly journals Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways

2020 ◽  
pp. jmedgenet-2020-107095
Author(s):  
William Schierding ◽  
Julia A Horsfield ◽  
Justin M O'Sullivan
Keyword(s):  
Association Studies ◽  
Genome Wide Association Studies ◽  
Cohesin Complex ◽  
Loss Of Function ◽  
Regulatory Variants ◽  
Genome Wide ◽  
Genes Encoding ◽  
Full Complement ◽  
Transcriptional Changes ◽  
Robust Regulation

Background: The cohesin complex plays an essential role in genome organisation and cell division. A full complement of the cohesin complex and its regulators is important for normal development, since heterozygous mutations in genes encoding these components can be sufficient to produce a disease phenotype. The implication that genes encoding the cohesin subunits or cohesin regulators must be tightly controlled and resistant to variability in expression has not yet been formally tested.Methods: Here, we identify spatial-regulatory connections with potential to regulate expression of cohesin loci (Mitotic: SMC1A, SMC3, STAG1, STAG2, RAD21/RAD21-AS; Meiotic: SMC1B, STAG3, REC8, RAD21L1), cohesin-ring support genes (NIPBL, MAU2, WAPL, PDS5A, PDS5B) and CTCF, including linking their expression to that of other genes. We searched the genome-wide association studies (GWAS) catalogue for SNPs mapped or attributed to cohesin genes by GWAS (GWAS-attributed) and the GTEx catalogue for SNPs mapped to cohesin genes by cis-regulatory variants in one or more of 44 tissues across the human body (expression quantitative trail locus-attributed).Results: Connections that centre on the cohesin ring subunits provide evidence of coordinated regulation that has little tolerance for perturbation. We used the CoDeS3D SNP-gene attribution methodology to identify transcriptional changes across a set of genes coregulated with the cohesin loci that include biological pathways such as extracellular matrix production and proteasome-mediated protein degradation. Remarkably, many of the genes that are coregulated with cohesin loci are themselves intolerant to loss-of-function.Conclusions: The results highlight the importance of robust regulation of cohesin genes and implicate novel pathways that may be important in the human cohesinopathy disorders.

scholarly journals Genetically Based Atrial Fibrillation: Current Considerations for Diagnosis and Management

2022 ◽  
Author(s):  
Anthony V. Pensa ◽  
Jayson R. Baman ◽  
Megan J. Puckelwartz ◽  
Jane Wilcox
Keyword(s):  
Atrial Fibrillation ◽  
Genetic Testing ◽  
Genetic Variants ◽  
Early Onset ◽  
Association Studies ◽  
Single Gene ◽  
Risk Identification ◽  
Genome Wide Association Studies ◽  
Clinical Genetic ◽  
Common Genetic Variants

Atrial fibrillation (AF) is the most common atrial arrhythmia and is subcategorized into numerous clinical phenotypes. Given its heterogeneity, investigations into the genetic mechanisms underlying AF have been pursued in recent decades, with predominant analyses focusing on early onset or lone AF. Linkage analyses, genome wide association studies (GWAS), and single gene analyses have led to the identification of rare and common genetic variants associated with AF risk. Significant overlap with genetic variants implicated in dilated cardiomyopathy syndromes, including truncating variants of the sarcomere protein titin, have been identified through these analyses, in addition to other genes associated with cardiac structure and function. Despite this, widespread utilization of genetic testing in AF remains hindered by the unclear impact of genetic risk identification on clinical outcomes and the high prevalence of variants of unknown significance (VUS). However, genetic testing is a reasonable option for patients with early onset AF and in those with significant family history of arrhythmia. While many knowledge gaps remain, emerging data support genotyping to inform selection of AF therapeutics. In this review we highlight the current understanding of the complex genetic basis of AF and explore the overlap of AF with inherited cardiomyopathy syndromes. We propose a set of criteria for clinical genetic testing in AF patients and outline future steps for the integration of genetics into AF care.

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