Schizophrenia (SZ) is a common and debilitating disorder affecting ∼1% of the population worldwide. Despite the availability of criteria for reliable diagnosis, SZ is a clinically heterogeneous disorder. Multiple lines of evidence suggest a strong genetic component, most likely with extensive genetic heterogeneity.
Genome-wide linkage studies by our group on an Ashkenazi Jewish (AJ) sample and others on a Han Chinese sample from Taiwan implicated 10q22-q23 as a SZ susceptibility locus. To further explore our linkage signal, we performed a peakwide association fine mapping using 1414 single nucleotide polymorphisms (SNPs) across ∼12.5 Mb in 10q22-23. We genotyped 1515 AJ individuals, including 285 parent-child trios, 173 unrelated cases and 487 unrelated controls. We analyzed the binary diagnostic phenotype of SZ and 9 heritable quantitative traits (factors) derived from a principal components factor analysis. We found strong evidence of association with the "delusion" factor at three SNPs (rs10883866, rs10748842, and rs6584400) located in a 13 kb interval in intron 1 of Neuregulin 3 (NRG3). Our best p value from family-based association analysis was 7.26x10-7, which could be replicated in 173 unrelated AJ cases (p = 1.55x10-2), with a combined p value of 2.30x10-7. Association tests with additional independent samples provided further suggestive evidence for the importance of NRG3.
Another good biological SZ candidate gene, glutamate receptor, ionotropic, delta 1 (GRID1), is also located within this linkage region. Three independent studies across different populations have shown significant associations between GRID1 and SZ. We made two lines of Grid1 knock-out (KO) mice in order to study the function of this gene and to test its role in SZ. KO mice of early mixed background stages showed reduced body weight and alteration in some behavioral tests (such as pre-pulse inhibition test and open-field activity test) compared to their wild-type littermates. We are in the process of backcrossing and tissue-specific Cre mice crossing in order to eliminate the possible confounding factors. Additionally, we successfully raised 3 antibodies against different parts of GRID1/Grid1, which will be useful for future immunoprecipitation, co-immunoprecipitation and/or immunohistochemistry analyses.
|Advisor:||Valle, David, Huganir, Richard L.|
|School:||The Johns Hopkins University|
|School Location:||United States -- Maryland|
|Source:||DAI-B 71/01, Dissertation Abstracts International|
|Subjects:||Mental health, Genetics|
|Keywords:||Association, GRID1, Linkage, NRG3, Schizophrenia|
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