title: Mouse genome-wide association study identifies polymorphisms on chromosomes 4, 11, and 15 for age-related cardiac fibrosis.
abstract: Dystrophic cardiac calcinosis (DCC), also called epicardial and myocardial fibrosis and mineralization, has been detected in mice of a number of laboratory inbred strains, most commonly C3H/HeJ and DBA/2J. In previous mouse breeding studies between these DCC susceptible and the DCC-resistant strain C57BL/6J, 4 genetic loci harboring genes involved in DCC inheritance were identified and subsequently termed Dyscalc loci 1 through 4. Here, we report susceptibility to cardiac fibrosis, a sub-phenotype of DCC, at 12 and 20 months of age and close to natural death in a survey of 28 inbred mouse strains. Eight strains showed cardiac fibrosis with highest frequency and severity in the moribund mice. Using genotype and phenotype information of the 28 investigated strains, we performed genome-wide association studies (GWAS) and identified the most significant associations on chromosome (Chr) 15 at 72 million base pairs (Mb) (P < 10(-13)) and Chr 4 at 122 Mb (P < 10(-11)) and 134 Mb (P < 10(-7)). At the Chr 15 locus, Col22a1 and Kcnk9 were identified. Both have been reported to be morphologically and functionally important in the heart muscle. The strongest Chr 4 associations were located approximately 6 Mb away from the Dyscalc 2 quantitative trait locus peak within the boundaries of the Extl1 gene and in close proximity to the Trim63 and Cap1 genes. In addition, a single-nucleotide polymorphism association was found on chromosome 11. This study provides evidence for more than the previously reported 4 genetic loci determining cardiac fibrosis and DCC. The study also highlights the power of GWAS in the mouse for dissecting complex genetic traits.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, 233 South 10th Street BLSB Building, Suite 431, Philadelphia, PA, 19107, USA. Qiaoli.Li@Jefferson.edu.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA.|University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
authors.forename: Annerose
authors.initials: A
authors.lastname: Berndt
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Sundberg
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Silva
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Kennedy
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
authors.forename: Clinton L
authors.initials: CL
authors.lastname: Cario
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Richardson
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Chase
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, 04609, USA.|Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Schofield
authors.affiliation: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, 233 South 10th Street BLSB Building, Suite 431, Philadelphia, PA, 19107, USA.
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Sundberg
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002114:Calcinosis / Q000235:genetics / Q000503:physiopathology; D002874:Chromosome Mapping / Q000379:methods; D002875:Chromosomes / Q000235:genetics; D003433:Crosses, Genetic; D005355:Fibrosis / Q000235:genetics* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics