Sex- and lineage-specific inheritance of depression-like behavior in the rat

Abstract

The Wistar-Kyoto (WKY) rat exhibits physiological and behavioral similarities to endophenotypes of human depression. In the forced swim test (FST), a well-characterized antidepressant-reversible test for behavioral despair in rodents, WKYs express characteristics of behavioral despair; increased immobility, and decreased climbing. To map genetic loci linked to behavior in the FST, we conducted a quantitative trait loci (QTL) analysis of the segregating F2 generation of a WKY x Fisher 344 (F344) reciprocal intercross. Using linear-model-based genome scans to include covariate (sex or lineage)-by-QTL interaction effects, four significant QTL influencing climbing behavior were identified. In addition, we identified three, seven, and two suggestive QTL for climbing, immobility, and swimming, respectively. One of these loci was pleiotropic, affecting both immobility and climbing. As found in human linkage studies, several of these QTL showed sex- and/or lineage-dependent effects. A simultaneous search strategy identified three epistatic locus pairs for climbing. Multiple regression analysis was employed to characterize the joint contributions of these QTL and to clarify the sex- and lineage-dependent effects. As expected for complex traits, FST behavior is influenced by multiple QTL of small effect, each contributing 5%-10%, accounting for a total 10%-30% of the phenotypic variance. A number of loci mapped in this study share overlapping candidate regions with previously identified emotionality QTL in mice as well as with susceptibility loci recognized by linkage or genome scan analyses for major depression or bipolar disorder in humans. The presence of these loci across species suggests that these QTL may represent universal genetic factors contributing to mood disorders.

Pleiotropic Patterns of Quantitative Trait Loci for 70 Murine Skeletal Traits

“…A significant sexby-QTL interaction at the 5% level indicates that the QTL effects are sex specific. Functionally, our test is the same as the one performed by Solberg et al (2004), but using a leastsquares fit rather than maximum likelihood. This test for sex specificity is considered protected from multiple comparisons because the location was previously identified on the basis of its pooled-sex effect.…”

Diabetic modifier QTLs identified in F2 intercrosses between Akita and A/J mice

“…We applied trait-specific significance threshold values obtained by permutation tests for multiple testing, with LOD scores of 2.8 and 4.3 set as limits for suggestive and significant levels, respectively (Lander and Kruglyak 1995). We performed the covariate-dependent single-locus genome scan using the ''scanone'' function of R/qtl software (http://www.biostat.jhsph.edu/$kbroman/qtl/) as described previously (Solberg et al 2004). …”

Genetic loci affecting bone structure and strength in inbred COP and DA rats

“…Sex specificity of each QTL was evaluated following the method described by Solberg et al [6]. This method involves calculating the likelihood of the genotype and phenotype data under two models.…”