Genome-Wide Analysis of Polygenic Cardiac Traits in Medaka Inbred Strains

Objectives: Congenital heart disease (CHD) is hypothesized to have a polygenic origin in the significant proportion of cases which remain mostly unexplained. This study aimed to investigate the polygenic nature of cardiac traits using a new vertebrate genomics resource in the medaka (Oryzias latipes) fish model organism.

Methods: Physiological trait variation was analyzed to uncover genetic elements that may underlie susceptibility to cardiac disease. Genotype–phenotype correlations were conducted in a newly established medaka inbred panel consisting of 111 inbred strains derived from a natural population, as well as in previously available (classical) inbred strains. A high-throughput assay for heart rate (HR) determination in medaka embryos was used to explore phenotypic variability. A controlled temperature gradient was employed to study genotype × environment interaction. Experimental crosses and whole-genome sequencing (WGS) generated an F2 mapping population.

Result: HR measurements at 21°C, 28°C, and 35°C revealed substantial inter-strain differences in mean and variance of HR across the panel and among additionally employed classical inbred strains. Two strains were used to generate an F2 mapping population: S1 (slow HR) and Mop (fast HR). HR distributions in the F0-F1-F2 pedigree were consistent with polygenic inheritance. Calling single nucleotide polymorphisms from WGS data of 1192 individually phenotyped F2 embryos established a marker system. Linkage mapping based on recombination blocks identified quantitative trait loci (QTLs) replicated at three different temperatures and different QTLs for HR responses to temperature changes. Furthermore, a high embryonic HR in the Mop strain was associated with a hypoplastic ventricle and accordingly impaired cardiac function. This early phenotype translated into a cardiomyopathy-like phenotype in adult Mop fish linked to reduced fitness-related parameters.

Conclusion: Here we introduce a novel approach complementary to human studies to investigate polygenic cardiac phenotypes leveraging an inbred vertebrate panel in medaka. WGS of an intercross F2 population derived from two phenotypically contrasting inbred strains enabled us to map several QTLs. These loci harbor new candidate genes relevant to HR and potentially also to developmental, structural, and functional phenotypes. Further work is necessary for fine mapping and validation of novel candidates.

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