Drs. Johnsen and Valdar contributed equally to this work.
Genome-wide and species-wide dissection of the genetics of arthritis severity in heterogeneous stock mice
Article first published online: 31 AUG 2011
Copyright © 2011 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 63, Issue 9, pages 2630–2640, September 2011
How to Cite
Johnsen, A. K., Valdar, W., Golden, L., Ortiz-Lopez, A., Hitzemann, R., Flint, J., Mathis, D. and Benoist, C. (2011), Genome-wide and species-wide dissection of the genetics of arthritis severity in heterogeneous stock mice. Arthritis & Rheumatism, 63: 2630–2640. doi: 10.1002/art.30425
- Issue published online: 31 AUG 2011
- Article first published online: 31 AUG 2011
- Accepted manuscript online: 10 MAY 2011 03:00PM EST
- Manuscript Accepted: 21 APR 2011
- Manuscript Received: 26 JAN 2011
- NIH (National Institute of Allergy and Infectious Diseases). Grant Number: K08-AI0-72044-01A1
- National Institute of Arthritis and Musculoskeletal and Skin Diseases. Grant Number: R01-AR-055271
- Arthritis National Research Foundation scholarship
Susceptibility to inflammatory arthritis is determined by a complex set of environmental and genetic factors, but only a portion of the genetic effect can be explained. Conventional genome-wide screens of arthritis models using crosses between inbred mice have been hampered by the low resolution of results and by the restricted range of natural genetic variation sampled. The aim of this study was to address these limitations by performing a genome-wide screen for determinants of arthritis severity using a genetically heterogeneous cohort of mice.
Heterogeneous stock (HS) mice derive from 8 founder inbred strains by serial intercrossing (n > 60), resulting in fine-grained genetic variation. With a cohort of 570 HS mice, we performed a genome-wide screen for determinants of arthritis severity in the K/BxN serum–transfer model.
We mapped regions on chromosomes 1, 2, 4, 6, 7, and 15 that contain quantitative trait loci influencing arthritis severity at a resolution of a few megabases. In several instances, these regions proved to contain 2 quantitative trait loci: the region on chromosome 2 included the C5 fraction of complement known to be required for K/BxN serum–transfer arthritis but also contained a second adjacent quantitative trait locus, for which an intriguing candidate is Ptgs1 (Cox1). Interesting candidates on chromosome 4 included the Padi family, encoding the peptidyl arginine deiminases responsible for citrulline protein modification; suggestively, Padi2 and Padi4 RNA expression was correlated with arthritis severity in HS mice.
These results provide a broad overview of the genetic variation that controls the severity of K/BxN serum–transfer arthritis and suggest intriguing candidate genes for further study.