In this project we will map Quantitative Trait Loci (QTLs) affecting schizophrenia-related traits in mice. Much progress has been made in studying the genetic basis for components of schizophrenia in humans. However, much more statistical power can be achieved for gene mapping through specialized breeding designs and information obtained through genetic transformation in mice than in humans. Several schizophrenia-related traits discovered in humans, such as thalamic volume, volume of the thalamus' mediodorsal nucleus, whole cortex grey matter volume, hippocampal volume, and spatial working and episodic memory, have homologues in mice. We propose to measure broad-sense heritability (Specific Aim 1) and genetic correlations (Specific Aim 2) and to map QTLs (Specific Aim 3) for these schizophrenia-related traits in recombinant inbred (RI) mouse strains, including BXD, AXB(BXA), and LGXSM. After QTL regions are identified, we will select specific QTLs for fine-mapping based on the magnitude and pattern of their effects and validation across populations. We will fine-map QTLs to a 1.0 cM interval (Specific Aim 4) using Recombinant Inbred Intercrosses (RIX), Recombinant Inbred Strain Tests (RIST), and Congenic strain tests as appropriate. Positional candidate genes will be identified in the restricted genomic interval using bioinformatic methods and then tested for sequence and expression polymorphism between the parental strains to identify molecular polymorphisms potentially responsible for the QTL effect (Specific Aim 5). Positional candidate genes displaying such molecular polymorphisms will then be knocked-out, the associated phenotypes scored. Knock-out strains will also be used in a quantitative complementation test to confirm that the selected gene is responsible for the QTL effect. In future, mouse QTL positions uncovered in Specific Aim 4 will be transferred to their syntenic human chromosome positions and then tested in human populations for potential effects on schizophrenia and its component traits.
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