BackgroundAnimal models for neurodevelopmental disorders (NDD) generally rely on a single genetic mutation on a fixed genetic background. Recent human genetic studies however indicate that a clinical diagnosis with ASDAutism Spectrum Disorder (ASD) is almost always associated with multiple genetic fore- and background changes. The translational value of animal model studies would be greatly enhanced if genetic insults could be studied in a more quantitative framework across genetic backgrounds.MethodsWe used the Collaborative Cross (CC), a novel mouse genetic reference population, to investigate the quantitative genetic architecture of mouse behavioral phenotypes commonly used in animal models for NDD.ResultsClassical tests of social recognition and grooming phenotypes appeared insufficient for quantitative studies due to genetic dilution and limited heritability. In contrast, digging, locomotor activity, and stereotyped exploratory patterns were characterized by continuous distribution across our CC sample and also mapped to quantitative trait loci containing genes associated with corresponding phenotypes in human populations.ConclusionsThese findings show that the CC can move animal model studies beyond comparative single gene-single background designs, and point out which type of behavioral phenotypes are most suitable to quantify the effect of developmental etiologies across multiple genetic backgrounds.Electronic supplementary materialThe online version of this article (10.1186/s13229-018-0252-2) contains supplementary material, which is available to authorized users.
BackgroundMouse models offer an essential tool to unravel the impact of genetic mutations on autism-related phenotypes. The behavioral impact of some important candidate gene models for autism spectrum disorder (ASD) has not yet been studied, and existing characterizations mostly describe behavioral phenotypes at adult ages, disregarding the developmental nature of the disorder. In this context, the behavioral influence of CNTN4, one of the strongest suggested ASD candidate genes, is unknown. Here, we used our recently established developmental test battery to characterize the consequences of disruption of contactin 4 (Cntn4) on neurological, sensory, cognitive, and behavioral phenotypes across different developmental stages.MethodsC57BL/6J mice with heterozygous and homozygous disruption of Cntn4 were studied through an extensive, partially longitudinal, test battery at various developmental stages, including various paradigms testing social and restricted repetitive behaviors.ResultsDevelopmental neurological and cognitive screenings revealed no significant differences between genotypes, and ASD-related behavioral domains were also unchanged in Cntn4-deficient versus wild-type mice. The impact of Cntn4-deficiency was found to be limited to increased startle responsiveness following auditory stimuli of different high amplitudes in heterozygous and homozygous Cntn4-deficient mice and enhanced acquisition in a spatial learning task in homozygous mice.ConclusionsDisruption of Cntn4 in the C57BL/6J background does not affect specific autism-related phenotypes in developing or adult mice but causes subtle non-disorder specific changes in sensory behavioral responses and cognitive performance.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-016-9140-2) contains supplementary material, which is available to authorized users.
Background: Common psychiatric disorders are characterized by complex disease architectures with many small genetic effects that contribute and complicate biological understanding of their etiology. There is therefore a pressing need for in vitro experimental systems that allow for interrogation of polygenic psychiatric disease risk to study the underlying biological mechanisms. Methods: We have developed an analytical framework that integrates genome-wide disease risk from GWAS with longitudinal in vitro gene expression profiles of human neuronal differentiation. Results: We demonstrate that the cumulative impact of risk loci of specific psychiatric disorders is significantly associated with genes that are differentially expressed and upregulated during differentiation. We find the strongest evidence for schizophrenia, a finding that we replicate in an independent dataset. A longitudinal gene cluster involved in synaptic function primarily drives the association with SCZ risk. Conclusions: These findings reveal that in vitro human neuronal differentiation can be used to translate the polygenic architecture of schizophrenia to biologically relevant pathways that can be modeled in an experimental system. Overall, this work emphasizes the use of longitudinal in vitro transcriptomic signatures as a cellular readout and the application to the genetics of complex traits.
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