Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Genetic loci associated with heart rate variability and their effects on cardiac disease risk
Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands..
Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands.;Univ Adelaide, Sch Med, Dept Epidemiol, Adelaide, SA 5005, Australia.;Bahir Dar Univ, Coll Med & Hlth Sci, Bahir Dar 6000, Ethiopia..
Show others and affiliations
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. Vol. 8, article id 15805
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-329672DOI: 10.1038/ncomms15805ISI: 000403216600001PubMedID: 28613276OAI: oai:DiVA.org:uu-329672DiVA, id: diva2:1142582
Available from: 2017-09-19 Created: 2017-09-19 Last updated: 2019-03-11Bibliographically approved
In thesis
1. Translating Cardiac and Cardiometabolic GWAS Using Zebrafish
Open this publication in new window or tab >>Translating Cardiac and Cardiometabolic GWAS Using Zebrafish
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
GWAS, Zebrafish
National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-378941 (URN)978-91-513-0590-5 (ISBN)
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

Open Access in DiVA

fulltext(592 kB)75 downloads
File information
File name FULLTEXT01.pdfFile size 592 kBChecksum SHA-512
208a2d4941b2131c272476cbd82f7d220efa81609288851e0fe04820ae9baafa08fe43d23a4ea6371a8ef73a35d07f94eadb17d42c421352754b3d9cfb5ceefe
Type fulltextMimetype application/pdf
Erratum(141 kB)8 downloads
File information
File name ERRATA01.pdfFile size 141 kBChecksum SHA-512
05823467b51b93e8232d257702eabe8352828795464e6619f8aa2548fba34537887533a851df382e43f58e2e66793bb9ad34e711b19c1256416a7c6fdb4637cb
Type errataMimetype application/pdf

Other links

Publisher's full textPubMedErratum

Search in DiVA

By author/editor
von der Heyde, BenediktAxelsson, TomasGiedraitis, VilmantasSyvänen, Ann-ChristineIngelsson, Erikden Hoed, Marcel
By organisation
Molecular epidemiologyScience for Life Laboratory, SciLifeLabMolecular MedicineGeriatrics
In the same journal
Nature Communications
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 75 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 421 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf