Z Gastroenterol 2004; 42 - AB_2_64
DOI: 10.1055/s-2004-816089

Improved Power and Resolution of QTL Mapping for Cholesterol Gallstone Susceptibility Loci Based on Combined Analysis of Two Independent Crosses

H Wittenburg 1, R Li 2, MA Lyons 2, MC Carey 3, J Mössner 1, GA Churchill 2, B Paigen 2
  • 1Medizinische Klinik und Poliklinik II, Universitätsklinikum Leipzig
  • 2The Jackson Laboratory
  • 3Brigham and Women's Hospital and Harvard Medical School

To date, employing quantitative trait locus (QTL) mapping, we have identified 16 loci that harbor cholesterol gallstone (GS) susceptibility genes (Lith loci) in inbred mice. We previously reported QTL mapping in two separate crosses of gallstone-susceptible PERA/Ei mice with each of the resistant strains I/LnJ and DBA/2J. Here, we re-analyzed the combined data based on a new binary allelic model.

After consumption of a lithogenic diet, F2 offspring of PERA x I/Ln and PERA x DBA/2 crosses were phenotyped for GS weight and a scoring system for cholelithiasis. Progeny were genotyped using PCR amplification of microsatellite markers. For genome-wide QTL re-analysis, strain PERA was recoded „S“ (susceptible) and strains I/Ln and DBA/2 were recoded „R“ (resistant). For region-specific re-analysis of Lith loci shared between crosses, alleles were recoded as „S“ or „R“ based on contribution to the phenotype in this region. The software PSEUDOMARKER was used for multiple interval mapping.

In the PERA x I/Ln cross we detected Lith7, Lith8 and Lith9 (chromosome (Chr) 10, Chr 4, and Chr 17, respectively). The PERA x DBA/2 cross revealed Lith15 and Lith16 (Chr 13 and Chr 8, respectively). Our genome-wide combined analysis identified additional Lith loci for GS weight on Chr 3, Chr 6 (Lith6), Chr 9 (Lith5) and Chr 13 (Lith15), which were not detected for this phenotype in the individual crosses. For the GS score, the combined analysis detected one additional QTL on both Chr 3 and Chr 18 and two additional QTL’s on Chr 8 (Lith16). Combined analysis reduced 95% confidence intervals of Lith loci by 5 to 25 cM. Region-specific analysis indicated the likelihood of three separate Lith loci on Chr 6 (Lith6).

Our combined analysis of two crosses improves the identification of all Lith loci in inbred mice by increasing the power of detecting QTL’s, narrowing previously identified Lith loci and resolving closely linked Lith loci on the same chromosome.

Key words

QTL mapping - cholesterol gallstones - inbred mice