Abstract
Quantitative trait locus (QTL) mapping was employed to investigate the genetic determinants of cholesterol gallstone formation in a large intercross between mouse strains SM/J (resistant) and NZB/B1NJ (susceptible). Animals consumed a gallstonepromoting diet for 18 weeks. QTL analyses were performed using gallstone weight and gallstone absence/presence as phenotypes; various models were explored for genome scans. We detected seven single QTLs: three new, significant QTLs were named Lith17 [chromosome (Chr) 5, peak = 60 cM, LOD = 5.4], Lith18 (Chr 5, 76 cM, LOD = 4.3), and Lith19 (Chr 8, 0 cM, LOD = 5.3); two confirmed QTLs identified previously and were named Lith20 (Chr 9, 44 cM, LOD = 2.7) and Lith21 (Chr 10, 24 cM, LOD = 2.9); one new, suggestive QTL (Chr 17) remains unnamed. Upon searching for epistatic interactions that contributed to gallstone susceptibility, the final suggestive QTL on Chr 7 was determined to interact significantly with Lith18 and, therefore, was named Lith22 (65 cM). A second interaction was identified between Lith19 and a locus on Chr 11; this QTL was named Lith23 (13 cM). mRNA expression analyses and amino acid haplotype analyses likely eliminated Slc10a2 as a candidate gene for Lith19. The QTLs identified herein largely contributed to gallstone formation rather than gallstone severity. Cloning the genes underlying these murine QTLs should facilitate prediction and cloning of the orthologous human genes.
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Acknowledgments
Supported in part by National Institutes of Health grants DK51568 (to B.P.), DK36588, DK52911, and DK34854 (to M.C.C.), HL66611 (the Program for Genomic Applications), CA34196 (core grant to The Jackson Laboratory). M.A.L. was supported by fellowships and awards from the National Health and Medical Research Council of Australia (222913), The American Physiological Society, and the American Liver Foundation. We are indebted to Dr. Karl Broman (Johns Hopkins University) and Dr. Henning Wittenburg (University of Leipzig) for helpful discussions and review of the manuscript, Ms. Jennifer Torrance (TJL) for assistance with graphics, and to Eric Taylor (TJL) for colony management.
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Abbreviations: CI, confidence interval; F1,first filial generation; F2, second filial (intercross) generation; LOD, logarithm of the odds ratio; NZB, NZB/B1NJ; QTL, quantitative trait locus; SM, SM/J.
The nucleotide sequence data for Slc10a2 were submitted to GenBank and were assigned the accession numbers AY529655 (strain SM) and AY529656 (strain NZB).
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Lyons, M.A., Korstanje, R., Li, R. et al. Single and interacting QTLs for cholesterol gallstones revealed in an intercross between mouse strains NZB and SM. Mamm Genome 16, 152–163 (2005). https://doi.org/10.1007/s00335-004-2446-5
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DOI: https://doi.org/10.1007/s00335-004-2446-5