scholarly journals Mutations in RPL3L and MYZAP increase risk of atrial fibrillation

2017 ◽  
Author(s):  
Rosa B. Thorolfsdottir ◽  
Gardar Sveinbjornsson ◽  
Patrick Sulem ◽  
Stefan Jonsson ◽  
Gisli H. Halldorsson ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Association Studies ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Meta Analysis ◽  
Low Frequency ◽  
Exon Skipping ◽  
Missense Variant ◽  
Ribosomal Gene ◽  
Genome Wide Association Studies ◽  
Splice Donor

AbstractWe performed a meta-analysis of genome-wide association studies on atrial fibrillation (AF) among 14,710 cases and 373,897 controls from Iceland and 14,792 cases and 393,863 controls from the UK Biobank, focusing on low frequency coding and splice mutations, with follow-up in samples from Norway and the US. We observed associations with two missense (OR=1.19 for both) and one splice-donor mutation (OR=1.52) in RPL3L, encoding a ribosomal protein primarily expressed in skeletal muscle and heart. Analysis of 167 RNA samples from the right atrium revealed that the splice donor mutation in RPL3L results in exon skipping. AF is the first disease associated with RPL3L and RPL3L is the first ribosomal gene implicated in AF. This finding is consistent with tissue specialization of ribosomal function. We also found an association with a missense variant in MYZAP (OR=1.37), encoding a component of the intercalated discs of cardiomyocytes, the organelle harbouring most of the mutated proteins involved in arrhythmogenic right ventricular cardiomyopathy. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.

scholarly journals Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Sonia Shah ◽  
◽  
Albert Henry ◽  
Carolina Roselli ◽  
Honghuang Lin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Cardiac Development ◽  
Association Studies ◽  
Meta Analysis ◽  
Left Ventricular ◽  
Genome Wide Association ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractHeart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

scholarly journals Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation

2020 ◽  
Vol 13 (5) ◽  
pp. 387-395
Author(s):  
Lu-Chen Weng ◽  
Amelia Weber Hall ◽  
Seung Hoan Choi ◽  
Sean J. Jurgens ◽  
Jeffrey Haessler ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Rare Variants ◽  
Association Studies ◽  
Low Frequency ◽  
P Wave ◽  
Cardiac Conduction ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Wave Duration ◽  
P Wave Duration

Background: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci ( TTN , CAND2 , SCN10A , PITX2 , CAV1 , SYNPO2L , SOX5 , TBX5, MYH6, RPL3L ). The top variants at known sarcomere genes ( TTN, MYH6 ) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A ) were associated with longer PWD but lower AF risk. Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

scholarly journals Missense variant in interleukin-6 signal transducer identified as susceptibility locus for rheumatoid arthritis in Chinese patients

2021 ◽  
Vol 36 (4) ◽  
pp. 603-610
Author(s):  
Khai Pang Leong ◽  
Mei Yun Yong ◽  
Liuh Ling Goh ◽  
Chia Mun Woo ◽  
Chia Wei Lim ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Interleukin 6 ◽  
Association Studies ◽  
Low Frequency ◽  
Missense Variant ◽  
Chinese Patients ◽  
Genome Wide Association Studies ◽  
Signal Transducer ◽  
Resultant Data ◽  
Genetic Burden

Objectives: This study aims to uncover variants of large effect size and allele frequency below 5% by sequencing all extant genes associated with rheumatoid arthritis (RA) in a homogeneous patient cohort. Patients and methods: This retrospective study was conducted between January 2001 and December 2017. We selected Chinese RA patients positive for anti-citrullinated peptide antibody (ACPA). All the 128 known candidate genes identified through genome-wide association studies were sequenced in 48 RA patients (15 males, 33 females; mean age 53.32±8.98 years; range, 32 to 75 years) and 45 controls (11 males, 34 females; mean age 32.18±9.54; range, 21 to 57 years). The exonic regions of these genes were sequenced. The resultant data were analyzed for association using single variant association and pathway-based association enrichment tests. The genetic burden due to low-frequency variants was assessed with the C-alpha test. The candidate variants that showed significant association were validated in a larger cohort of 500 RA cases (71 males, 429 females; mean age 48.6±12.2 years; range, 24 to 92 years) and 500 controls (66 males, 434 females; mean age 32.3±10.1 years; range, 21 to 73 years). Results: Thirty-nine variants in 21 genes were identified using single variant association analysis and C-alpha test, with stepwise filtering. Among these, the missense variant in interleukin-6 signal transducer (IL-6ST) 5:55260065 (p.Cys47Phe) was significantly associated with RA in Chinese patients in Singapore. Conclusion: Our results suggest that a mutation in IL-6ST (5:55260065) confers risk of RA in Chinese patients in Singapore.

scholarly journals Integrated Analyses of Growth Differentiation Factor-15 Concentration and Cardiometabolic Diseases in Humans

2021 ◽  
Author(s):  
Susanna Lemmela ◽  
Eleanor M Wigmore ◽  
Christian Benner ◽  
Aki Havulinna ◽  
Rachel MY Ong ◽  
...  
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Missense Variant ◽  
Cardiometabolic Disease ◽  
Mendelian Randomisation ◽  
Significant Heterogeneity ◽  
Genome Wide Association Studies ◽  
Growth Differentiation Factor 15 ◽  
Cardiometabolic Diseases ◽  
Differentiation Factor

Growth differentiation factor 15 (GDF15) is a stress response cytokine that is elevated in several cardiometabolic diseases and has attracted interest as a potential therapeutic target. To further explore the association of GDF15 with human disease, we conducted a broad study into the phenotypic and genetic correlates of GDF15 concentration in up to 14,099 individuals. Assessment of 772 traits across 6,610 participants in FINRISK identified associations of GDF15 concentration with a range of phenotypes including all-cause mortality, cardiometabolic disease, respiratory diseases and psychiatric disorders as well as inflammatory markers. A meta-analysis of genome-wide association studies (GWAS) of GDF15 concentration across 3 different assay platforms (n=14,099) confirmed significant heterogeneity due to a common missense variant rs1058587 in GDF15, potentially due to epitope-binding artefacts. After conditioning on rs1058587, statistical fine-mapping identified 4 independent putative causal signals at the locus. Mendelian randomisation (MR) analysis did not find evidence of a causal relationship between GDF15 concentration and cardiometabolic traits. Using reverse MR, we identified a potential causal association of body mass index on GDF15 (IVW pFDR=0.0072). Taken together, our data do not support a role for elevated GDF15 concentrations as a causal factor in human cardiometabolic disease but support its role as a biomarker of metabolic stress.

scholarly journals Genome-wide association study provides new insights into the genetic architecture and pathogenesis of heart failure

2019 ◽  
Author(s):  
Sonia Shah ◽  
Albert Henry ◽  
Carolina Roselli ◽  
Honghuang Lin ◽  
Garðar Sveinbjörnsson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Meta Analysis ◽  
Left Ventricular ◽  
Genome Wide Association ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractHeart failure (HF) is a leading cause of morbidity and mortality worldwide1. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained2–4. We report the largest GWAS meta-analysis of HF to-date, comprising 47,309 cases and 930,014 controls. We identify 12 independent variant associations with HF at 11 genomic loci, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function suggesting shared genetic aetiology. Expression quantitative trait analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homeostasis (BAG3), and cellular senescence (CDKN1A). Using Mendelian randomisation analysis we provide new evidence supporting previously equivocal causal roles for several HF risk factors identified in observational studies, and demonstrate CAD-independent effects for atrial fibrillation, body mass index, hypertension and triglycerides. These findings extend our knowledge of the genes and pathways underlying HF and may inform the development of new therapeutic approaches.

scholarly journals Recessive Genome-wide Meta-analysis Illuminates Genetic Architecture of Type 2 Diabetes

2021 ◽  
Author(s):  
Mark J. O’Connor ◽  
Philip Schroeder ◽  
Alicia Huerta-Chagoya ◽  
Paula Cortés-Sánchez ◽  
Silvía Bonàs-Guarch ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Complex Traits ◽  
Association Studies ◽  
Meta Analysis ◽  
Low Frequency ◽  
Additive Models ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide

Most genome-wide association studies (GWAS) of complex traits are performed using models with additive allelic effects. Hundreds of loci associated with type 2 diabetes have been identified using this approach. Additive models, however, can miss loci with recessive effects, thereby leaving potentially important genes undiscovered. We conducted the largest GWAS meta-analysis using a recessive model for type 2 diabetes. Our discovery sample included 33,139 cases and 279,507 controls from seven European-ancestry cohorts including the UK Biobank. We identified 51 loci associated with type 2 diabetes, including five variants undetected by prior additive analyses. Two of the five had minor allele frequency less than 5% and were each associated with more than doubled risk in homozygous carriers. Using two additional cohorts, FinnGen and a Danish cohort, we replicated three of the variants, including one of the low-frequency variants, rs115018790, which had an odds ratio in homozygous carriers of 2.56 (95% CI 2.05-3.19, <i>P</i>=1´10<sup>-16</sup>) and a stronger effect in men than in women (interaction <i>P</i>=7´10<sup>-7</sup>). The signal was associated with multiple diabetes-related traits, with homozygous carriers showing a 10% decrease in LDL and a 20% increase in triglycerides, and colocalization analysis linked this signal to reduced expression of the nearby <i>PELO</i> gene. These results demonstrate that recessive models, when compared to GWAS using the additive approach, can identify novel loci, including large-effect variants with pathophysiological consequences relevant to type 2 diabetes.

Candidate Genes for Nonsyndromic Cleft Palate Detected by Exome Sequencing

2017 ◽  
Vol 96 (11) ◽  
pp. 1314-1321 ◽  
Author(s):  
A.K. Hoebel ◽  
D. Drichel ◽  
M. van de Vorst ◽  
A.C. Böhmer ◽  
S. Sivalingam ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
Rare Variants ◽  
Association Studies ◽  
Low Frequency ◽  
Missense Variant ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Novel Variant

Nonsyndromic cleft palate only (nsCPO) is a facial malformation that has a livebirth prevalence of 1 in 2,500. Research suggests that the etiology of nsCPO is multifactorial, with a clear genetic component. To date, genome-wide association studies have identified only 1 conclusive common variant for nsCPO, that is, a missense variant in the gene grainyhead-like-3 ( GRHL3). Thus, the underlying genetic causes of nsCPO remain largely unknown. The present study aimed at identifying rare variants that might contribute to nsCPO risk, via whole-exome sequencing (WES), in multiply affected Central European nsCPO pedigrees. WES was performed in 2 affected first-degree relatives from each family. Variants shared between both individuals were analyzed for their potential deleterious nature and a low frequency in the general population. Genes carrying promising variants were annotated for 1) reported associations with facial development, 2) multiple occurrence of variants, and 3) expression in mouse embryonic palatal shelves. This strategy resulted in the identification of a set of 26 candidate genes that were resequenced in 132 independent nsCPO cases and 623 independent controls of 2 different ethnicities, using molecular inversion probes. No rare loss-of-function mutation was identified in either WES or resequencing step. However, we identified 2 or more missense variants predicted to be deleterious in each of 3 genes ( ACACB, PTPRS, MIB1) in individuals from independent families. In addition, the analyses identified a novel variant in GRHL3 in 1 patient and a variant in CREBBP in 2 siblings. Both genes underlie different syndromic forms of CPO. A plausible hypothesis is that the apparently nonsyndromic clefts in these 3 patients might represent hypomorphic forms of the respective syndromes. In summary, the present study identified rare variants that might contribute to nsCPO risk and suggests candidate genes for further investigation.

scholarly journals Multicohort Metabolomics Analysis Discloses 9‐Decenoylcarnitine to Be Associated With Incident Atrial Fibrillation

2021 ◽  
Author(s):  
Lars Lind ◽  
Samira Salihovic ◽  
Johan Sundström ◽  
Corey D. Broeckling ◽  
Patrik K. Magnusson ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Meta Analysis ◽  
Population Based ◽  
Left Ventricular ◽  
Genome Wide Association Studies ◽  
Independent Population ◽  
Incident Cases ◽  
Metabolomics Analysis

Background The molecular mechanisms involved in atrial fibrillation are not well known. We used plasma metabolomics to investigate if we could identify novel biomarkers and pathophysiological pathways of incident atrial fibrillation. Methods and Results We identified 200 endogenous metabolites in plasma/serum by nontargeted ultra‐performance liquid chromatography coupled to time‐of‐flight mass spectrometry in 3 independent population‐based samples (TwinGene, n=1935, mean age 68, 43% females; PIVUS [Prospective Investigation of the Vasculature in Uppsala Seniors], n=897, mean age 70, 51% females; and ULSAM [Uppsala Longitudinal Study of Adult Men], n=1118, mean age 71, all males), with available data on incident atrial fibrillation during 10 to 12 years of follow‐up. A meta‐analysis of ULSAM and PIVUS was used as a discovery sample and TwinGene was used for validation. In PIVUS, we also investigated associations between metabolites of interest and echocardiographic indices of myocardial geometry and function. Genome‐wide association studies were performed in all 3 cohorts for metabolites of interest. In the meta‐analysis of PIVUS and ULSAM with 430 incident cases, 4 metabolites were associated with incident atrial fibrillation at a false discovery rate <5%. Of those, only 9‐decenoylcarnitine was associated with incident atrial fibrillation and replicated in the TwinGene sample (288 cases) following adjustment for traditional risk factors (hazard ratio, 1.24 per unit; 95% CI, 1.06–1.45, P =0.0061). A meta‐analysis of all 3 cohorts disclosed another 4 significant metabolites. In PIVUS, 9‐decenoylcarnitine was related to left atrium size and left ventricular mass. A Mendelian randomization analysis did not suggest a causal role of 9‐decenoylcarnitine in atrial fibrillation. Conclusions A nontargeted metabolomics analysis disclosed 1 novel replicated biomarker for atrial fibrillation, 9‐Decenoylcarnitine, but this acetylcarnitine is likely not causally related to atrial fibrillation.

scholarly journals Recessive Genome-wide Meta-analysis Illuminates Genetic Architecture of Type 2 Diabetes

2021 ◽  
Author(s):  
Mark J. O’Connor ◽  
Philip Schroeder ◽  
Alicia Huerta-Chagoya ◽  
Paula Cortés-Sánchez ◽  
Silvía Bonàs-Guarch ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Complex Traits ◽  
Association Studies ◽  
Meta Analysis ◽  
Low Frequency ◽  
Additive Models ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide

Most genome-wide association studies (GWAS) of complex traits are performed using models with additive allelic effects. Hundreds of loci associated with type 2 diabetes have been identified using this approach. Additive models, however, can miss loci with recessive effects, thereby leaving potentially important genes undiscovered. We conducted the largest GWAS meta-analysis using a recessive model for type 2 diabetes. Our discovery sample included 33,139 cases and 279,507 controls from seven European-ancestry cohorts including the UK Biobank. We identified 51 loci associated with type 2 diabetes, including five variants undetected by prior additive analyses. Two of the five had minor allele frequency less than 5% and were each associated with more than doubled risk in homozygous carriers. Using two additional cohorts, FinnGen and a Danish cohort, we replicated three of the variants, including one of the low-frequency variants, rs115018790, which had an odds ratio in homozygous carriers of 2.56 (95% CI 2.05-3.19, <i>P</i>=1´10<sup>-16</sup>) and a stronger effect in men than in women (interaction <i>P</i>=7´10<sup>-7</sup>). The signal was associated with multiple diabetes-related traits, with homozygous carriers showing a 10% decrease in LDL and a 20% increase in triglycerides, and colocalization analysis linked this signal to reduced expression of the nearby <i>PELO</i> gene. These results demonstrate that recessive models, when compared to GWAS using the additive approach, can identify novel loci, including large-effect variants with pathophysiological consequences relevant to type 2 diabetes.

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