Identification of female-specific QTLs affecting an emotionality-related behavior in rats (original) (raw)
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Biological Psychiatry, 2008
Background-Human anxiety disorders are complex diseases with largely unknown etiology. We have taken a cross-species approach to identify genes that regulate anxiety-like behavior with inbred mouse strains that differ in their innate anxiety levels as a model. We previously identified 17 genes with expression levels that correlate with anxiety behavior across the studied strains. In the present study, we tested their 13 known human homologues as candidate genes for human anxiety disorders with a genetic association study.
A Quantitative Trait Locus Influencing Anxiety in the Laboratory Rat
Genome Research, 2002
A critical test for a gene that influences susceptibility to fear in animals is that it should have a consistent pattern of effects across a broad range of conditioned and unconditioned models of anxiety. Despite many years of research, definitive evidence that genetic effects operate in this way is lacking. The limited behavioral test regimes so far used in genetic mapping experiments and the lack of suitable multivariate methodologies have made it impossible to determine whether the quantitative trait loci (QTL) detected to date specifically influence fear-related traits. Here we report the first multivariate analysis to explore the genetic architecture of rodent behavior in a battery of animal models of anxiety. We have mapped QTLs in an F2 intercross of two rat strains, the Roman high and low avoidance rats, that have been selectively bred for differential response to fear. Multivariate analyses show that one locus, on rat chromosome 5, influences behavior in different models of anxiety. The QTL influences two-way active avoidance, conditioned fear, elevated plus maze, and open field activity but not acoustic startle response or defecation in a novel environment. The direction of effects of the QTL alleles and a coincidence between the behavioral profiles of anxiolytic drug and genetic action are consistent with the QTL containing at least one gene with a pleiotropic action on fear responses. As the neural basis of fear is conserved across species, we suggest that the QTL may have relevance to trait anxiety in humans. 6 Corresponding author. E-MAIL jf@molbiol.ox.ac.uk; FAX (44) 1861 287501. Article and publication are at
Genetics and Molecular Biology, 2008
The Floripa H and L rat lines, selected for high and low locomotion in the central aversive area of an open field, a widely used emotionality test, were proposed as a model for studying the genetic basis of anxiety. The present study aimed to verify if the QTL Ofil1, mapped to rat chromosome 4 and previously identified as being related to emotionality in another population of rats, contributes to the behavioral variability observed in the Floripa rat lines. To this purpose, rats of five generations of selective breeding were genotyped for two polymorphic markers, D4RAT59 and D4MGH27, flanking Ofil1. Changes in genotype and allele frequencies throughout generations were evaluated in both H and L lines, in order to assess if the bidirectional selection based on behavioral scores induced divergent changes in the genotype of this genome region. There were significant changes in genotype frequencies for both molecular markers, however, only the genotype variations of the D4RAT59 marker were significantly correlated with the variations in the selected phenotype. This result suggests that the region of the genome near D4RAT59 contains one or more genes contributing to the interindividual variation in central locomotion in the open field test.
The American Journal of Human Genetics, 2006
We conducted a 10-centimorgan linkage autosomal genome scan in a set of 19 extended American pedigrees (219 subjects) ascertained through probands with panic disorder. Several anxiety disorders-including social phobia, agoraphobia, and simple phobia-in addition to panic disorder segregate in these families. In previous studies of this sample, linkage analyses were based separately on each of the individual categorical affection diagnoses. Given the substantial comorbidity between anxiety disorders and their probable shared genetic liability, it is clear that this method discards a considerable amount of information. In this article, we propose a new approach that considers panic disorder, simple phobia, social phobia, and agoraphobia as expressions of the same multivariate, putatively genetically influenced trait. We applied the most powerful multipoint Haseman-Elston method, using the grade of membership score generated from a fuzzy clustering of these phenotypes as the dependent variable in Haseman-Elston regression. One region on chromosome 4q31-q34, at marker D4S413 (with multipoint and single-point nominal P values ! .00001), showed strong evidence of linkage (genomewide significance at ). The same P ! .05 region is known to be the site of a neuropeptide Y receptor gene, NPY1R (4q31-q32), that was recently connected to anxiolytic-like effects in rats. Several other regions on four chromosomes 3) met criteria for suggestive linkage (multipoint nominal P values ! .01). Family-by-family analysis did not show any strong evidence of heterogeneity. Our findings support the notion that the major anxiety disorders, including phobias and panic disorder, are complex traits that share at least one susceptibility locus. This method could be applied to other complex traits for which shared genetic-liability factors are thought to be important, such as substance dependencies.
American Journal of Medical Genetics, 2001
Family and twin studies have indicated that genes in¯uence susceptibility to panic and phobic anxiety disorders, but the location of the genes involved remains unknown. Animal models can simplify gene-mapping efforts by overcoming problems that complicate human pedigree studies including genetic heterogeneity and high phenocopy rates. Homology between rodent and human genomes can be exploited to map human genes underlying complex traits. We used regions identi®ed by quantitative trait locus (QTL)-mapping of anxiety phenotypes in mice to guide a linkage analysis of a large multiplex pedigree (99 members, 75 genotyped) segregating panic disorder/agoraphobia. Two phenotypes were studied: panic disorder/agoraphobia and a phenotype (``D-type'') designed to capture earlyonset susceptibility to anxiety disorders. A total of 99 markers across 11 chromosomal regions were typed. Parametric lod score analysis provided suggestive evidence of linkage (lod 2.38) to a locus on chromosome 10q under a dominant model with reduced penetrance for the anxiety-proneness (D-type) phenotype. Nonparametric (NPL) analysis provided evidence of linkage for panic disorder/agoraphobia to a locus on chromosome 12q13 (NPL 4.96, P 0.006). Modest evidence of linkage by NPL analysis was also found for the D-type phenotype to a region of chromosome 1q (peak NPL 2.05, P 0.035). While these linkage results are merely suggestive, this study illustrates the potential advantages of using mouse genemapping results and exploring alternative phenotype de®nitions in linkage studies of anxiety disorder. ß
A genetic and multifactorial analysis of anxiety-related behaviours in Lewis and SHR intercrosses
Behavioural Brain Research, 1998
Lewis (LEW) and spontaneously hypertensive rats (SHR) have been shown to differ in a series of fear-related behaviours measured in different anxiety/emotionality tests. In the present study, we have investigated some of the genetic mechanisms underlying these differences. To this end, male and female rats from the two inbred strains were crossed to produce two parental (LEW and SHR), two F1 (LEW or SHR mother), and two F2 (LEW or SHR grandmother) groups. All rats were tested in the elevated plus-maze and in the open field, besides being characterised for systolic blood pressure (BP). LEW rats approached the open arms of the plus-maze and the central area of the open field less than SHRs. The two strains also differed in their BP (SHR\ LEW). LEW/SHR differences were found to be due to direct effects of the genes, rather than to indirect maternal and grand-maternal effects. Central locomotion in the open field was shown to be the most heritable of all the traits considered herein. A factor analysis on the segregating F2 population produced three independent factors. The first one was associated to measures of anxiety from the elevated plus-maze, and the second to measures of locomotion in novel environments. Factor scores revealed that the parental strains differ in relation to the first but not to the second factor. This study demonstrates the usefulness of coupling genetic and multifactorial methods to investigate behavioural traits and it confirms LEW and SHR strains as an interesting genetic tool for the study of anxiety.
Biological Psychiatry, 2011
Background-Anxiety disorders are common psychiatric conditions that are highly comorbid with each other and related phenotypes such as depression, likely due to a shared genetic basis. Fear-related behaviors in mice have long been investigated as potential models of anxiety disorders, making integration of information from both murine and human genetic data a powerful strategy for identifying potential susceptibility genes for these conditions. Methods-We combined genome-wide association analysis of fear-related behaviours with strain distribution pattern analysis in heterogeneous stock mice to identify a preliminary list of 52 novel candidate genes. We ranked these according to three complementary sources of prior anxiety-related genetic data: (1) extant linkage and knock-out studies in mice, (2) a meta-analysis of human linkage scans, and (3) a preliminary human genomewide association study. We genotyped tagging SNPs covering the nine top-ranked regions in a two-stage association study of 1316 subjects from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders chosen for high or low genetic loading for anxiety-spectrum phenotypes (anxiety disorders, neuroticism, and major depression).
Testing Human Anxiety Associations of Genes Previously Implicated by Mouse Anxiety Models
Anxiety disorders are common and can be debilitating, with effective treatments remaining hampered by an incomplete understanding of the underlying genetic etiology. Improvements have been made in understanding the genetic influences on mouse behavioral models of anxiety, yet it is unclear the extent to which genes identified in these experimental systems contribute to genetic variation in human anxiety phenotypes. Leveraging new and existing large-scale human genome-wide association studies, we tested whether sets of genes previously identified in mouse anxiety-like behavior studies contribute to a range of human anxiety disorders. When tested as individual genes, thirteen mouse-identified genes were associated with human anxiety phenotypes, suggesting an overlap of individual genes contributing to both mouse models of anxiety-like behaviors and human anxiety traits. When genes were tested as sets, we did identify fourteen significant associations between mouse gene sets and human ...
Genetic Markers of Predisposition to Increased Anxiety
Bulletin of Experimental Biology and Medicine, 2008
Associations of functional polymorphism in genes of dopamine receptor DRD2, dopamine transporter DAT, and dopamine degrading enzyme COMT with variations in anxiety sensitivity threshold were studied. On the basis of genetic and psychological analysis, an attempt was undertaken to evaluate the relationship of DRD2, DAT and COMT genotypes with values obtained using different anxiety scales. It was found that carriers of VA1+9+ genotype exhibit increased anxiety and significantly differed from individuals with other genotypes. The results were illustrated with model of dopamine diffusion in the extracellular space of the striatum in carriers of different genotypes.