Quantitative trait and transcriptome analysis of genetic complexity underpinning cardiac interatrial septation in mice using an advanced intercross line

Mahdi Moradi Marjaneh; Edwin P Kirk; Ralph Patrick; Dimuthu Alankarage; David T Humphreys; Gonzalo Del Monte-Nieto; Paola Cornejo-Paramo; Vaibhao Janbandhu; Tram B Doan; Sally L Dunwoodie; Emily S Wong; Chris Moran; Ian C A Martin; Peter C Thomson; Richard P Harvey

doi:10.7554/eLife.83606

Quantitative trait and transcriptome analysis of genetic complexity underpinning cardiac interatrial septation in mice using an advanced intercross line

Elife. 2023 Jun 5:12:e83606. doi: 10.7554/eLife.83606.

Authors

Mahdi Moradi Marjaneh^#^{1

2

3}, Edwin P Kirk^#^{1

4

5}, Ralph Patrick^#¹, Dimuthu Alankarage¹, David T Humphreys^{1

2}, Gonzalo Del Monte-Nieto^{1

2}, Paola Cornejo-Paramo¹, Vaibhao Janbandhu^{1

2}, Tram B Doan¹, Sally L Dunwoodie^{1

2}, Emily S Wong^{1

6}, Chris Moran⁷, Ian C A Martin⁷, Peter C Thomson⁷, Richard P Harvey^{1

2

6}

Affiliations

¹ Victor Chang Cardiac Research Institute, Sydney, Australia.
² School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia.
³ Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, United Kingdom.
⁴ Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, Australia.
⁵ Randwick Genomics Laboratory, NSW Health Pathology, Sydney, Australia.
⁶ School of Biotechnology and Biomolecular Sciences, Faculty of Science, UNSW Sydney, Sydney, Australia.
⁷ Sydney School of Veterinary Science, University of Sydney, Sydney, Australia.

^# Contributed equally.

Abstract

Unlike single-gene mutations leading to Mendelian conditions, common human diseases are likely to be emergent phenomena arising from multilayer, multiscale, and highly interconnected interactions. Atrial and ventricular septal defects are the most common forms of cardiac congenital anomalies in humans. Atrial septal defects (ASD) show an open communication between the left and right atria postnatally, potentially resulting in serious hemodynamic consequences if untreated. A milder form of atrial septal defect, patent foramen ovale (PFO), exists in about one-quarter of the human population, strongly associated with ischaemic stroke and migraine. The anatomic liabilities and genetic and molecular basis of atrial septal defects remain unclear. Here, we advance our previous analysis of atrial septal variation through quantitative trait locus (QTL) mapping of an advanced intercross line (AIL) established between the inbred QSi5 and 129T2/SvEms mouse strains, that show extremes of septal phenotypes. Analysis resolved 37 unique septal QTL with high overlap between QTL for distinct septal traits and PFO as a binary trait. Whole genome sequencing of parental strains and filtering identified predicted functional variants, including in known human congenital heart disease genes. Transcriptome analysis of developing septa revealed downregulation of networks involving ribosome, nucleosome, mitochondrial, and extracellular matrix biosynthesis in the 129T2/SvEms strain, potentially reflecting an essential role for growth and cellular maturation in septal development. Analysis of variant architecture across different gene features, including enhancers and promoters, provided evidence for the involvement of non-coding as well as protein-coding variants. Our study provides the first high-resolution picture of genetic complexity and network liability underlying common congenital heart disease, with relevance to human ASD and PFO.

Keywords: cardiac congenital defects; developmental biology; genetics; genomics; mouse; quantitative trait loci.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Brain Ischemia*
Foramen Ovale, Patent* / genetics
Gene Expression Profiling
Heart Defects, Congenital*
Humans
Mice
Phenotype
Stroke*

Grants and funding

R01 HL068885/HL/NHLBI NIH HHS/United States