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Translating Cardiac and Cardiometabolic GWAS Using Zebrafish
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Genome-wide association studies (GWAS) have identified thousands of loci associated with cardiac and cardiometabolic traits. However, the trait-associated variants usually do not clearly point to causal gene(s), mechanism(s) or tissue(s). Model systems that allow for a comprehensive and quick candidate gene screening are necessary, ideally in vivo. The overall objective of my thesis is to establish large-scale, imaged-based screens in zebrafish embryos and larvae to examine candidate genes for their effects on heart rate and rhythm, as well as on early-onset atherosclerosis and dyslipidemia.

In Study 1, I prioritized 18 candidate genes in eight loci identified in a meta-analysis of GWAS for heart rate variability. Some of these genes were already known to be involved in cardiac pacemaking, whereas others require functional characterization.

In Study 2, I established an experimental pipeline to examine genetic effects on cardiac rate and rhythm and used it to characterize orthologues of six human candidate genes for heart rate and rhythm. I confirmed known effects of rgs6 and hcn4, and established a role for KIAA1755 in HRV.

In Study 3, I contributed to large-scale experiments to establish the zebrafish as a model system for early-onset atherosclerosis and dyslipidemia. Overfeeding and cholesterol-supplementation of the diet were shown to propel independent pro-atherogenic effects. Atherosclerotic burden was alleviated using commonly prescribed drugs in humans. Lastly, the effects of proof-of-concept genes known to be involved in lipid metabolism were examined and showed higher LDLc (apoea) and early-onset atherosclerosis (apobb1).

In Study 4, I characterized genes in GWAS-identified loci for triglyceride levels for a role in lipid metabolism and early-stage atherosclerosis. I identified three previously unanticipated genes that influence triglyceride levels in zebrafish larvae. Several additional genes influence other cardiometabolic risk factors. Interestingly, two genes showed trends towards lower triglycerides levels (dock7 and lpar2a), with directionally opposite effects on vascular inflammation. This emphasizes that candidate genes need to be examined comprehensively to guide further mechanistic studies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. , p. 56
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1547
Keywords [en]
GWAS, Zebrafish
National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-378941ISBN: 978-91-513-0590-5 (print)OAI: oai:DiVA.org:uu-378941DiVA, id: diva2:1295143
Public defence
2019-04-26, Humanistiska Teatern, Engelska Parken, Thunbergsv. 3H, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2019-04-02 Created: 2019-03-11 Last updated: 2019-05-07
List of papers
1. Genetic loci associated with heart rate variability and their effects on cardiac disease risk
Open this publication in new window or tab >>Genetic loci associated with heart rate variability and their effects on cardiac disease risk
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15805Article in journal (Refereed) Published
Abstract [en]

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 < r(g) < -0.55) and blood pressure (-0.35 < r(g) < -0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-329672 (URN)10.1038/ncomms15805 (DOI)000403216600001 ()28613276 (PubMedID)
Available from: 2017-09-19 Created: 2017-09-19 Last updated: 2019-03-11Bibliographically approved
2. Translating GWAS-identified loci for cardiac rhythm and rate using an in vivo, image-based, large-scale genetic screen in zebrafish
Open this publication in new window or tab >>Translating GWAS-identified loci for cardiac rhythm and rate using an in vivo, image-based, large-scale genetic screen in zebrafish
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(English)In: Article in journal (Refereed) Submitted
Abstract [en]

A meta-analysis of genome-wide association studies (GWAS) identified eight loci that are associated with heart rate variability (HRV) in data from 53,174 individuals. However, functional follow-up experiments - aiming to identify and characterize causal genes in these loci - have not yet been performed. We developed an image- and CRISPR-Cas9-based pipeline to systematically characterize candidate genes for HRV in live zebrafish embryos and larvae. Nine zebrafish orthologues of six human candidate genes were targeted simultaneously in fertilized eggs from fish that transgenically express GFP on smooth muscle cells (Tg(acta2:GFP)), to visualize the beating heart using a fluorescence microscope. An automated analysis of repeated 30s recordings of 381 live zebrafish atria at 2 and 5 days post-fertilization highlighted genes that influence HRV (hcn4 and kiaa1755); heart rate (rgs6 and hcn4) and the risk of sinoatrial pauses and arrests (hcn4). Hence, our screen confirmed the role of established genes for heart rate (rgs6 and hcn4), and highlighted a novel gene implicated in HRV (kiaa1755).

Keywords
GWAS, Zebrafish
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-378938 (URN)
Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11
3. Zebrafish larvae as a model system for systematic characterization of drugs and genes in dyslipidemia and atherosclerosis
Open this publication in new window or tab >>Zebrafish larvae as a model system for systematic characterization of drugs and genes in dyslipidemia and atherosclerosis
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(English)In: Article in journal (Refereed) Submitted
Abstract [en]

Background: Hundreds of loci have been robustly associated with circulating lipids, atherosclerosis and coronary artery disease; but for most loci the causal genes and mechanisms remain uncharacterized.

Methods: We developed a semi-automated experimental pipeline for systematic, quantitative, large-scale characterization of mechanisms, drugs and genes associated with dyslipidemia and atherosclerosis in a zebrafish model system. We validated our pipeline using a dietary (n>2000), drug treatment (n>1000), and genetic intervention (n=384).

Results: Our results show that five days of overfeeding and cholesterol supplementation had independent pro-atherogenic effects, which could be diminished by concomitant treatment with atorvastatin and ezetimibe. CRISPR-Cas9-induced mutations in orthologues of proof-of-concept genes resulted in higher LDL cholesterol levels (apoea), and more early stage atherosclerosis (apobb.1).

Conclusions: In summary, our pipeline facilitates systematic, in vivo characterization of drugs and candidate genes to increase our understanding of disease etiology, and can likely help identify novel targets for therapeutic intervention.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-378939 (URN)
Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-11-24
4. Characterising candidate genes for cardiometabolic risk factors in GWAS-identified loci for triglyceride levels using a high-throughput zebrafish screen
Open this publication in new window or tab >>Characterising candidate genes for cardiometabolic risk factors in GWAS-identified loci for triglyceride levels using a high-throughput zebrafish screen
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-378940 (URN)
Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11

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