Mammalian Genome

, Volume 27, Issue 5–6, pp 179–190 | Cite as

Mouse genome-wide association study identifies polymorphisms on chromosomes 4, 11, and 15 for age-related cardiac fibrosis

  • Qiaoli Li
  • Annerose Berndt
  • Beth A. Sundberg
  • Kathleen A. Silva
  • Victoria E. Kennedy
  • Clinton L. Cario
  • Matthew A. Richardson
  • Thomas H. Chase
  • Paul N. Schofield
  • Jouni Uitto
  • John P. Sundberg


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.


Quantitative Trait Locus Inbred Strain Cardiac Fibrosis Inbred Mouse Strain Ventricular Free Wall 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors thank Jesse Hammer and Josiah Raddar for technical assistance. Research reported in this publication was supported by the Ellison Medical Foundation, Parker B. Francis Foundation, and the National Institutes of Health (R01AR055225 and K01AR064766). Mouse colonies were supported by the National Institutes of Health under Award Number AG025707 for the Jackson Aging Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Jackson Laboratory Shared Scientific Services were supported in part by a Basic Cancer Center Core Grant from the National Cancer Institute (CA34196).

Supplementary material

335_2016_9634_MOESM1_ESM.doc (234 kb)
Supplementary material 1 (DOC 234 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Qiaoli Li
    • 1
  • Annerose Berndt
    • 2
    • 3
  • Beth A. Sundberg
    • 4
  • Kathleen A. Silva
    • 4
  • Victoria E. Kennedy
    • 4
  • Clinton L. Cario
    • 2
  • Matthew A. Richardson
    • 2
  • Thomas H. Chase
    • 4
  • Paul N. Schofield
    • 4
    • 5
  • Jouni Uitto
    • 1
  • John P. Sundberg
    • 4
  1. 1.Department of Dermatology and Cutaneous BiologySidney Kimmel Medical College at Thomas Jefferson UniversityPhiladelphiaUSA
  2. 2.Department of MedicineUniversity of PittsburghPittsburghUSA
  3. 3.University of Pittsburgh Medical CenterPittsburghUSA
  4. 4.The Jackson LaboratoryBar HarborUSA
  5. 5.Department of Physiology, Development and Neuroscience, University of CambridgeCambridgeUK

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