Thorac Cardiovasc Surg 2018; 66(S 02): S111-S138
DOI: 10.1055/s-0038-1628326
Oral Presentations
Monday, February 19, 2018
DGPK: Basic Science and Clinical Studies
Georg Thieme Verlag KG Stuttgart · New York

Systems Genetics Approach to Study Congenital Heart Disease in a Fish Model

J. Gierten
1   Department of Pediatric Cardiology, University Hospital Heidelberg, Heidelberg, Germany
,
F. Loosli
4   Karlsruhe Institute of Technology (KIT), Institute of Toxicology and Genetics (ITG), Eggenstein-Leopoldshafen, Germany
,
J. Gehrig
5   ACQUIFER is a division of DITABIS, Digital Biomedical Imaging Systems AG, Pforzheim, Germany
,
C. Pylatiuk
6   Karlsruhe Institute of Technology (KIT), Institute for Applied Computer Science (IAI), Eggenstein-Leopoldshafen, Germany
,
T. Fitzgerald
7   European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
,
E. Birney
7   European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom
,
J. Wittbrodt
2   Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany
,
M. Gorenflo
1   Department of Pediatric Cardiology, University Hospital Heidelberg, Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
22 January 2018 (online)

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Objectives: Congenital heart disease (CHD) is a leading cause of perinatal morbidity and mortality. Epidemiological studies point toward substantial heritability but up to date only a minor fraction of CHD cases could be linked to genetic variants/mutations. The central objective of our research is to study genetic determinants of cardiac traits using medaka (Japanese rice fish) as a vertebrate model and to correlate detected variants with the human orthologous genes. For a proof of concept genome-wide association study (GWAS) we focused on heart rate (HR) and its dependence on temperature.

Methods: A panel of 100 medaka inbred strains with fully sequenced genomes was used as a mapping population (unpublished). We established a high-throughput phenotyping assay using automated microscopy to score HR of medaka embryos under physiological conditions. This assay was applied to profile the panel and to assess broad-sense heritability (H2, in process). To resolve genetic elements associated with extreme phenotypes (slow/fast HR) we leveraged two previously available highly inbred medaka strains (S1, S2) that were subjected to F2 segregation analysis combining phenotyping with whole-genome sequencing (WGS).

Results: WGS of the medaka inbred panel revealed high levels of homozygosity within strains and millions of segregating variants across strains. Phenotyping a subset of the panel revealed substantial differences in heart rates (max. 20%). Phenotyping the entire panel is currently completed to asses H2 and to perform a GWAS using called genetic variants. Piloting a F2 segregation analysis using strains with slow (S1) and fast (S2) HRs revealed an intermediate phenotype in F1-hybrids and a phenotypic distribution in F2 spanning between the two parental phenotypes. To link phenotypic measurements to variants, regulatory regions or genes, WGS is currently performed in the F2 population.

Conclusion: We present a genome-wide approach to dissect genetic determinants of human disease-relevant phenotypes in a medaka genomics resource. Profiling this first vertebrate inbred panel for heart rates revealed substantial phenotypic variation. A segregation analysis demonstrated a mode of complex phenotype inheritance. Strategies to detect and validate novel causative genetic elements are currently being established. We expect that downstream evaluation of new genetic variants will indicate novel loci relevant for heart development, function and disease susceptibility.