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(Circulation Research. 2006;98:651.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Quantitative Trait Loci Modifying Cardiac Atrial Septal Morphology and Risk of Patent Foramen Ovale in the Mouse

Edwin P. Kirk, Changbaig Hyun, Peter C. Thomson, Donna Lai, M. Leticia Castro, Christine Biben, Michael F. Buckley, Ian C.A. Martin, Chris Moran, Richard P. Harvey

From the Victor Chang Cardiac Research Institute (E.P.K., C.H., D.L., M.L.C., C.B., R.P.H.), St. Vincent’s Hospital, Darlinghurst; Sydney Children’s Hospital (E.P.K.), Randwick; School of Women’s and Children’s Health (E.P.K.), Faculty of Medicine, University of New South Wales, Kensington; Centre for Advanced Technologies in Animal Genetics and Reproduction (P.C.T., I.C.A.M., C.M.), University of Sydney; Molecular and Cytogenetics Unit (M.F.B.), Prince of Wales Hospital, Randwick; and Faculties of Life Science and Medicine (R.P.H.), University of New South Wales, Kensington. Present address for C.H.: Section of Small Animal Internal Medicine, Department of Veterinary Medicine, Kangwon National University, Chuncheon, Korea.

Correspondence to Richard P. Harvey, Victor Chang Cardiac Research Institute, 384 Victoria St, Darlinghurst, NSW 2010, Australia. E-mail r.harvey{at}victorchang.unsw.edu.au

Atrial septal defect (ASD) is a common congenital heart disease (CHD) occurring in 5 to 7 per 10 000 live births. Mutations in 5 human genes (NKX2.5, TBX5, GATA4, MYHC, ACTC) are known to cause dominant ASD, but these account for a minority of cases. Human and mouse data suggest that ASD exists in an anatomical continuum with milder septal variants patent foramen ovale (PFO) and atrial septal aneurysm, strongly associated with ischemic stroke and migraine. We have previously shown in inbred mice that the incidence of PFO strongly correlates with length of the interatrial septum primum, defining a quantitative trait underlying PFO risk. To better understand genetic causation of atrial septal abnormalities, we mapped quantitative trait loci (QTL) influencing septal morphology using mouse strains (QSi5 and 129T2/SvEms) maximally informative for PFO incidence and 3 quantitative septal anatomical traits including septum primum length. [QSi5x129T2/SvEms]F2 intercross animals (n=1437) were phenotyped and a whole genome scan performed at an average 17-cM interval. Statistical methodology scoring PFO as a binary phenotype was developed as a confirmatory mapping technique. We mapped 7 significant and 6 suggestive QTL modifying quantitative phenotypes, with 4 supported by binary analysis. Quantitative traits, although strongly associated with PFO (P<0.001), correlated poorly with each other and in all but 1 case QTL for different traits were nonoverlapping. Thus, multiple anatomical processes under separate genetic control contribute to risk of PFO. Our findings demonstrate the feasibility of modeling the genetic basis of common CHD using animal genetic and genomic technologies.

Key Words: atrial septal defect • patent foramen ovale • NKX2.5 • quantitative trait locus