title: Three-locus and four-locus QTL interactions influence mouse insulin-like growth factor-I.
abstract: A previous analysis of serum insulin-like growth factor I (IGF-I) levels in a mouse population (n = 961) derived from a cross of (BALB/cJ x C57BL/6J) F1 females and (C3H/HeJ x DBA/2J) F1 males documented quantitative trait loci (QTL) on chromosomes 1, 10, and 17. We employed a newly developed, random walk-based method to search for three- and four-way allelic combinations that might influence IGF-I levels through nonadditive (conditional or epistatic) interactions among 185 genotyped biallelic loci and with significance defined by experiment-wide permutation (P < 0.05). We documented a three-locus combination in which an epistatic interaction between QTL on paternal-derived chromosomes 5 and 18 had an opposite effect on the phenotype based on the allele inherited at a third locus on maternal-derived chromosome 17. The search also revealed three four-locus combinations that influence IGF-I levels through nonadditive genetic interactions. In two cases, the four-allele combinations were associated with animals having high levels of IGF-I, and, in the third case, a four-allele combination was associated with animals having low IGF-I levels. The multiple-locus genome scan algorithm revealed new IGF-I QTL on chromosomes 2, 4, 5, 7, 8, and 12 that had not been detected in the single-locus genome search and showed that levels of this hormone can be regulated by complex, nonadditive interactions among multiple loci. The analysis method can detect multilocus interactions in a genome scan experiment and may provide new ways to explore the genetic architecture of complex physiological phenotypes.
authors.affiliation: Department of Mathematics, University of Michigan, Ann Arbor, Michigan 48109-0618, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Hanlon
authors.forename: William Andrew
authors.initials: WA
authors.lastname: Lorenz
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Shao
authors.forename: James M
authors.initials: JM
authors.lastname: Harper
authors.forename: Andrzej T
authors.initials: AT
authors.lastname: Galecki
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
authors.forename: David T
authors.initials: DT
authors.lastname: Burke
mesh_terms: D000465:Algorithms; D000818:Animals; D016386:Chromosome Walking; D003433:Crosses, Genetic; D004843:Epistasis, Genetic; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008957:Models, Genetic; D010641:Phenotype; D040641:Quantitative Trait Loci
chemical_list: D007334:Insulin-Like Growth Factor I