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

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.

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

Nature Communications ◽

10.1038/s41467-019-13690-5 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 36

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.

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

10.1101/682013 ◽

2019 ◽

Cited By ~ 1

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.

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Mutations in RPL3L and MYZAP increase risk of atrial fibrillation

10.1101/223578 ◽

2017 ◽

Cited By ~ 1

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.

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Genome-wide association and multi-omic analyses reveal new mechanisms for Heart Failure

10.1101/19006510 ◽

2019 ◽

Author(s):

Marios Arvanitis ◽

Yanxiao Zhang ◽

Wei Wang ◽

Adam Auton ◽

Ali Keramati ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Muscle ◽

Association Studies ◽

Meta Analysis ◽

Regulatory Region ◽

Causal Variant ◽

Left Ventricular ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide

AbstractHeart failure is a major medical and economic burden in the healthcare system affecting over 23 million people worldwide. Although recent pedigree studies estimate heart failure heritability around 26%, genome-wide association studies (GWAS) have had limited success in explaining disease pathogenesis. We conducted the largest meta-analysis of heart failure GWAS to-date and replicated our findings in a comparable sized cohort to identify one known and two novel variants associated with heart failure. Leveraging heart failure sub-phenotyping and fine-mapping, we reveal a putative causal variant found in a cardiac muscle specific regulatory region that binds to the ACTN2 cardiac sarcolemmal gene and affects left ventricular adverse remodeling and clinical heart failure in response to different initial cardiac muscle insults. Via genetic correlation, we show evidence of broadly shared heritability between heart failure and multiple musculoskeletal traits. Our findings extend our understanding of biological mechanisms underlying heart failure.

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Minor allele of GJA1 gene polymorphism is associated with higher heart rate during atrial fibrillation

Scientific Reports ◽

10.1038/s41598-021-82117-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sho Okamura ◽

Yuko Onohara ◽

Hidenori Ochi ◽

Takehito Tokuyama ◽

Naoya Hironobe ◽

...

Keyword(s):

Atrial Fibrillation ◽

Heart Rate ◽

Association Studies ◽

Electrophysiological Study ◽

Left Ventricular ◽

Minor Allele ◽

Left Ventricular Ejection ◽

Genome Wide Association Studies ◽

Ventricular Ejection Fraction ◽

Af Ablation

AbstractAtrial fibrillation (AF) tachycardia causes heart failure and requires more attention. The genetic background of individual heart rate (HR) variations during AF are unclear. We hypothesized that HR-associated single nucleotide polymorphisms (SNPs) reported in Genome-Wide Association Studies (GWAS) are also associated with HR during AF. We enrolled patients with persistent AF (311 for screening and 146 for replication) who underwent AF ablation and were genotyped for the 21 h-associated SNPs reported in GWAS. The patients underwent 24-h Holter monitoring before AF ablation and electrophysiological study after AF ablation during sinus rhythm. Only the GJA1 SNP rs1015451 (T>C) was significantly associated with total HR (TT 110,643 ± 17,542 beats/day, TC 116,350 ± 19,060 beats/day, CC 122,163 ± 25,684 beats/day, P = 8.5 × 10−4). We also confirmed this significant association in the replication set. The intra-atrial conduction was faster in AF patients with the GJA1 minor allele than in those without it. Multivariate analysis revealed the presence of a GJA1 SNP rs1015451 additive model, female gender, lower left ventricular ejection fraction, and higher 1:1 atrioventricular nodal conduction were independently associated with higher HR during AF. The GJA1 SNP might be a new genetic marker for AF tachycardia.

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Tissue-specific multiOMICs analysis of atrial fibrillation

10.1101/2020.04.06.021527 ◽

2020 ◽

Author(s):

Ines Assum ◽

Julia Krause ◽

Markus O. Scheinhardt ◽

Christian Müller ◽

Elke Hammer ◽

...

Keyword(s):

Atrial Fibrillation ◽

Molecular Mechanisms ◽

Association Studies ◽

Molecular Networks ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Tissue Specific ◽

Protein Levels ◽

Atrial Tissue ◽

Regulatory Variants

AbstractGenome-wide association studies (GWAS) for atrial fibrillation (AF) have uncovered numerous disease-associated variants. Their underlying molecular mechanisms, especially consequences for mRNA and protein expression remain largely elusive. Thus, novel multiOMICs approaches are needed for deciphering the underlying molecular networks. Here, we integrated genomics, transcriptomics, and proteomics of human atrial tissue which allowed for identifying widespread effects of genetic variants on both transcript (cis eQTL) and protein (cis pQTL) abundance. We further established a novel targeted trans QTL approach based on polygenic risk scores to identify candidates for AF core genes. Using this approach, we identified two trans eQTLs and four trans pQTLs for AF GWAS hits, and elucidated the role of the transcription factor NKX2-5 as a link between the GWAS SNP rs9481842 and AF. Altogether, we present an integrative multiOMICs method to uncover trans-acting networks in small datasets and provide a rich resource of atrial tissue-specific regulatory variants for transcript and protein levels for cardiovascular disease gene prioritization.

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Insight into the genetic aetiology of retinal detachment by combining small clinical and large population-based datasets

10.1101/581165 ◽

2019 ◽

Author(s):

Thibaud S. Boutin ◽

David G. Charteris ◽

Aman Chandra ◽

Susan Campbell ◽

Caroline Hayward ◽

...

Keyword(s):

Retinal Detachment ◽

Genetic Risk ◽

Association Studies ◽

Population Based ◽

Self Report ◽

Cataract Operation ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Genome Wide ◽

Independent Population

AbstractIdiopathic retinal detachment is a serious common condition, but genetic studies to date have been hampered by the small size of the assembled cohorts. Genetic correlations between retinal detachment and high myopia or cataract operation were high, respectively 0.46 (SE=0.08) and 0.44 (SE=0.07), in the UK Biobank dataset and in line with known epidemiological associations. Meta-analysis of genome-wide association studies using UK Biobank retinal detachment cases (N=3977) and two cohorts, each comprising ∼1000 rhegmatogenous retinal detachment patients, uncovered 11 genome-wide significant association signals, near or withinZC3H11B, BMP3, COL22A1, DLG5, PLCE1, EFEMP2, TYR, FAT3, TRIM29, COL2A1andLOXL1.Replication in the 23andMe dataset, where retinal detachment is self-reported by participants, firmly establishes association at six lociFAT3, COL22A1, TYR, BMP3, ZC3H11BandPLCE1.The former two seem to particularly impact on retinal detachment, the latter three shed light on shared aetiologies with cataract, myopia and glaucoma.Author SummaryRetinal detachments are common conditions that may lead to permanent severe sight reduction or blindness; they are a major cause of emergency eye surgery. The most common type of retinal detachment follows a break in the retina and is thought to be in part genetically determined but little is known about the contributing individual genetic risk variants. The condition prevalence increases with age and with common eye conditions such as myopia, cataract or glaucoma. We showed that the retinal detachment cases derived from self-report or hospitalisation records in the large UK Biobank dataset show very similar characteristics to samples of carefully clinically evaluated retinal detachment with break cases and therefore could be used to perform genetic analysis of the condition. Association studies require large sample of cases and by pooling Biobank and clinical cases, this study identifies 11 novel significant associations, six of which were further replicated in an independent population-based dataset (23andMe). Two of the replicated findings seem to specifically underline retinal detachment risk while three others highlight shared genetic risk with myopia, cataract and/or glaucoma, paving the way to better understanding of these conditions and of their overlap.

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Polygenic Risk Scores Shed Light on the Relationship between Schizophrenia and Cognitive Functioning: Review and Meta-Analysis

Journal of Clinical Medicine ◽

10.3390/jcm9020341 ◽

2020 ◽

Vol 9 (2) ◽

pp. 341 ◽

Cited By ~ 4

Author(s):

Jasmina Mallet ◽

Yann Le Strat ◽

Caroline Dubertret ◽

Philip Gorwood

Keyword(s):

Association Studies ◽

Meta Analysis ◽

Treatment Strategies ◽

Population Based ◽

Current Treatment ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Efficient Treatment ◽

Polygenic Risk ◽

Complex Human Traits

Schizophrenia is a multifactorial disease associated with widespread cognitive impairment. Although cognitive deficits are one of the factors most strongly associated with functional impairment in schizophrenia (SZ), current treatment strategies hardly tackle these impairments. To develop more efficient treatment strategies in patients, a better understanding of their pathogenesis is needed. Recent progress in genetics, driven by large genome-wide association studies (GWAS) and the use of polygenic risk scores (PRS), has provided new insights about the genetic architecture of complex human traits, including cognition and SZ. Here, we review the recent findings examining the genetic links between SZ and cognitive functions in population-based samples as well as in participants with SZ. The performed meta-analysis showed a negative correlation between the polygenetic risk score of schizophrenia and global cognition (p < 0.001) when the samples rely on general and healthy participants, while no significant correlation was detected when the three studies devoted to schizophrenia patients were meta-analysed (p > 0.05). Our review and meta-analysis therefore argues against universal pleiotropy for schizophrenia alleles and cognition, since cognition in SZ patients would be underpinned by the same genetic factors than in the general population, and substantially independent of common variant liability to the disorder.

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Prioritizing rs7294 as a mirSNP contributing to warfarin dosing variability

Pharmacogenomics ◽

10.2217/pgs-2019-0137 ◽

2020 ◽

Vol 21 (4) ◽

pp. 257-267

Author(s):

Linda Koshy ◽

S Harikrishnan ◽

PR Sudhakaran

Keyword(s):

Linkage Disequilibrium ◽

Association Studies ◽

Meta Analysis ◽

Warfarin Dose ◽

In Silico Analysis ◽

Population Based ◽

Genome Wide Association Studies ◽

Warfarin Dosing ◽

Dosing Accuracy ◽

Dose Variability

Aim: The role of mirSNPs in the 3′UTR of VKORC1, CYP2C9 and CYP4F2 genes that could influence warfarin dose variability via a discrete miRNA-mediated mechanism remains unexplained. Methods: Genotypic data in the 1000 Genomes dataset were analyzed for pair-wise linkage disequilibrium and allelic enrichment. Results: MirSNP rs7294 in the 3′UTR of VKORC1 gene displayed varying strengths of linkage disequilibrium with rs9923231 and rs9934438 across populations, albeit consistently associated with higher warfarin dose requirements based on genome-wide association studies, meta-analysis and population-based association studies. In silico analysis predicted altered hybrid stability for the hsa-miR-133a-3p conserved binding site, providing evidence for miRNA-mediated gene regulation. Conclusion: The results support the inclusion of rs7294 as a functional variable for population-specific dosing algorithms to improve dosing accuracy.

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