title: Genome-wide and species-wide dissection of the genetics of arthritis severity in heterogeneous stock mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Joslin Diabetes Center and Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Alyssa K
authors.initials: AK
authors.lastname: Johnsen
authors.forename: William
authors.initials: W
authors.lastname: Valdar
authors.forename: Louis
authors.initials: L
authors.lastname: Golden
authors.forename: Adriana
authors.initials: A
authors.lastname: Ortiz-Lopez
authors.forename: Robert
authors.initials: R
authors.lastname: Hitzemann
authors.forename: Jonathan
authors.initials: J
authors.lastname: Flint
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D016678:Genome; D055106:Genome-Wide Association Study; D051379:Mice; D040641:Quantitative Trait Loci; D012720:Severity of Illness Index