title: High-resolution genetic mapping of complex traits from a combined analysis of F2 and advanced intercross mice.
abstract: Genetic influences on anxiety disorders are well documented; however, the specific genes underlying these disorders remain largely unknown. To identify quantitative trait loci (QTL) for conditioned fear and open field behavior, we used an F2 intercross (n = 490) and a 34th-generation advanced intercross line (AIL) (n = 687) from the LG/J and SM/J inbred mouse strains. The F2 provided strong support for several QTL, but within wide chromosomal regions. The AIL yielded much narrower QTL, but the results were less statistically significant, despite the larger number of mice. Simultaneous analysis of the F2 and AIL provided strong support for QTL and within much narrower regions. We used a linear mixed-model approach, implemented in the program QTLRel, to correct for possible confounding due to familial relatedness. Because we recorded the full pedigree, we were able to empirically compare two ways of accounting for relatedness: using the pedigree to estimate kinship coefficients and using genetic marker estimates of "realized relatedness." QTL mapping using the marker-based estimates yielded more support for QTL, but only when we excluded the chromosome being scanned from the marker-based relatedness estimates. We used a forward model selection procedure to assess evidence for multiple QTL on the same chromosome. Overall, we identified 12 significant loci for behaviors in the open field and 12 significant loci for conditioned fear behaviors. Our approach implements multiple advances to integrated analysis of F2 and AILs that provide both power and precision, while maintaining the advantages of using only two inbred strains to map QTL.
authors.affiliation: Department of Psychology and Program in Neuroscience, Middlebury College, Middlebury, Vermont 05753.
authors.forename: Clarissa C
authors.initials: CC
authors.lastname: Parker
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois 60637.
authors.forename: Peter
authors.initials: P
authors.lastname: Carbonetto
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois 60637.
authors.forename: Greta
authors.initials: G
authors.lastname: Sokoloff
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois 60637.
authors.forename: Yeonhee J
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois 60637.
authors.forename: Mark
authors.initials: M
authors.lastname: Abney
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois 60637 Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, Illinois 60637 aap@uchicago.edu.
authors.forename: Abraham A
authors.initials: AA
authors.lastname: Palmer
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics*; D002874:Chromosome Mapping; D002875:Chromosomes / Q000235:genetics*; D003214:Conditioning, Classical; D005239:Fear; D005260:Female; D006824:Hybridization, Genetic; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
keywords: Advanced Intercross Line; GWAS; MPP; Multiparent Advanced Generation Inter-Cross (MAGIC); Multiparental populations; QTL mapping; advanced intercross line; anxiety; complex traits; conditioned fear; genome-wide association study (GWAS); mixed models; quantitative genetics; single nucleotide polymorphism (SNP)