TY - JOUR
T1 - QTL fine mapping by measuring and testing for Hardy-Weinberg and linkage disequilibrium at a series of linked marker loci extreme samples of populations
AU - Deng, Hong Wen
AU - Chen, Wei Min
AU - Recker, Robert R.
N1 - Funding Information:
This study was partially supported by National Institutes of Health grant AR45349, both a program grant and a faculty-development grant from the Health Future Foundation of Creighton University, and a graduate-student tuition waiver (to W.-M.C.) from the Department of Biomedical Sciences of Creighton University. We thank Jian Li, for helpful discussions at the initial stage of this work. We are grateful to the two reviewers, for their helpful comments that improved the manuscript.
PY - 2000
Y1 - 2000
N2 - It has recently been demonstrated that fine-scale mapping of a susceptibility locus for a complex disease can be accomplished on the basis of deviations from Hardy-Weinberg (HW) equilibrium at closely linked marker loci among affected individuals. We extend this theory to fine-scale localization of a quantitative-trait locus (QTL) from extreme individuals in populations, by means of HW and linkage-disequilibrium (LD) analyses. QTL mapping and/or linkage analyses can establish a large genomic region (~30 cM) that contains a QTL. The QTL can be fine mapped by examination of the degree of deviation from HW and LD at a series of closely linked marker loci. The tests can be performed for samples of individuals belonging to either high or low percentiles of the phenotype distribution or for combined samples of these extreme individuals. The statistical properties (the power and the size) of the tests of this fine-mapping approach are investigated and are compared extensively, under various genetic models and parameters for the QTL and marker loci. On the basis of the results, a two-stage procedure that uses extreme samples and different tests (for HW and LD) is suggested for QTL fine mapping. This two-step procedure is economic and powerful and can accurately narrow a genomic region containing a QTL from ~30-1 cM, a range that renders physical mapping feasible for identification of the QTL. In addition, the relationship between parameterizations of complex diseases, by means of penetrance, and those of complex quantitative traits, by means of genotypic values, is outlined. This means that many statistical genetic methods developed for searching for susceptibility loci of complex diseases can be directly adopted and/or extended to QTL mapping for quantitative traits.
AB - It has recently been demonstrated that fine-scale mapping of a susceptibility locus for a complex disease can be accomplished on the basis of deviations from Hardy-Weinberg (HW) equilibrium at closely linked marker loci among affected individuals. We extend this theory to fine-scale localization of a quantitative-trait locus (QTL) from extreme individuals in populations, by means of HW and linkage-disequilibrium (LD) analyses. QTL mapping and/or linkage analyses can establish a large genomic region (~30 cM) that contains a QTL. The QTL can be fine mapped by examination of the degree of deviation from HW and LD at a series of closely linked marker loci. The tests can be performed for samples of individuals belonging to either high or low percentiles of the phenotype distribution or for combined samples of these extreme individuals. The statistical properties (the power and the size) of the tests of this fine-mapping approach are investigated and are compared extensively, under various genetic models and parameters for the QTL and marker loci. On the basis of the results, a two-stage procedure that uses extreme samples and different tests (for HW and LD) is suggested for QTL fine mapping. This two-step procedure is economic and powerful and can accurately narrow a genomic region containing a QTL from ~30-1 cM, a range that renders physical mapping feasible for identification of the QTL. In addition, the relationship between parameterizations of complex diseases, by means of penetrance, and those of complex quantitative traits, by means of genotypic values, is outlined. This means that many statistical genetic methods developed for searching for susceptibility loci of complex diseases can be directly adopted and/or extended to QTL mapping for quantitative traits.
UR - http://www.scopus.com/inward/record.url?scp=0033942599&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033942599&partnerID=8YFLogxK
U2 - 10.1086/302804
DO - 10.1086/302804
M3 - Article
C2 - 10712216
AN - SCOPUS:0033942599
VL - 66
SP - 1027
EP - 1045
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 3
ER -