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Medical Inflammation Research, Lund University, Lund, Sweden
Linkage analysis of F2 crosses has led to identification of large numbers of quantitative trait loci (QTL) for complex diseases, but identification of the underlying genes has been more difficult. Reasons for this could be complications that arise from separation of interacting or neighboring loci. We made a partial advanced intercross (PAI) to characterize and fine-map linkage to collagen-induced arthritis in two chromosomal regions derived from the DBA/1 strain and crossed into the B10.Q strain: Cia7 on chromosome 7 and a locus on chromosome 15. Only Cia7 was detected by a previous F2 cross. Linkage analysis of the PAI revealed a different linkage pattern than the F2 cross, adding multiple loci and strong linkage to the previously unlinked chromosome 15 region. Subcongenic strains derived from animals in the PAI confirmed the loci and revealed additional subloci. In total, no less than seven new loci were identified. Several loci interacted and three loci were protective, thus partly balancing the effect of the disease-promoting loci. Our results indicate that F2 crosses do not reveal the full complexity of identified QTLs, and that detection is more dependent on the genetic context of a QTL than the potential effect of the underlying gene.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Anna Greta Crafoord, Crafoord, King Gustaf V’s 80-Year Foundation, the Kock and Österlund Foundations, the Swedish Association against Rheumatism, the Swedish Medical Research Council, the Strategic Research Foundation, and the European Union Grants MUGEN LSHG-CT-2005-005203 and NeuroproMi Se-LSHM-CT-2005-018637.
2 Address correspondence and reprint requests to Emma Ahlqvist, Medical Inflammation Research, I11, BMC, Lund University, Lund 22184, Sweden. E-mail address: emma.ahlqvist{at}med.lu.se
3 Current address: Cartela AB, Box 709, 22007 Lund, Sweden.
4 Abbreviations used in this paper: CIA, collagen-induced arthritis; CII, collagen type II; EAE, experimental autoimmune encephalomyelitis; LOD, logarithm of odds; LODint, interactive LOD; LODjnt, joint LOD; PAI, partial advanced intercross; QTL, quantitative trait loci.
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  L Backdahl, J P Guo, M Jagodic, K Becanovic, B Ding, T Olsson, and J C Lorentzen Definition of arthritis candidate risk genes by combining rat linkage-mapping results with human case-control association data Ann Rheum Dis, December 1, 2009; 68(12): 1925 - 1932. [Abstract] [Full Text] [PDF]
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