This proposal responds to Request for Applications RFA-MH-08-131, which seeks Collaborative R01 applications that propose to enrich pre-existing resources for schizophrenia in the NIMH Human Genetics Initiative and to apply genomic methods to further our understanding of the molecular etiology of the disorder. The overarching aims of this proposal are to quickly and cost-effectively ascertain a large sample of trio families affected by schizophrenia, and to discover causal variants for the disorder in the first family-based genome-wide association study (GWAS) of the illness. In our recently completed NIMH-funded Genetic Linkage Study of Schizophrenia (R01MH059624;PI: Ming T. Tsuang), we established a large and efficient ascertainment network and infrastructure in Taiwan, which will again be utilized and expanded in the proposed study. Through additional ascertainment within this framework, we will collect an aggregate sample of 5,000 trios with adequate power for detecting in a GWAS those variants that make even small contributions to the risk for the disorder. We will meet the overarching goals of this project by accomplishing several Specific Aims, as follows: 1) Supplement our previously collected sample of 1,200 Han Chinese schizophrenia-affected nuclear families from Taiwan by rapidly screening and collecting an additional 3,800 trios from ten ascertainment sites in Taiwan;2) Assess the association of schizophrenia with a genome-wide panel of single-nucleotide polymorphisms and their constituent haplotypes;3) Perform a genome-wide survey for copy-number variations related to schizophrenia;4) Test for gene-gene interactions (epistasis);5) Test for gene-environment interactions, such as the well-established effect of season of birth;6) Analyze quantitative schizophrenia phenotypes, such as symptom scores and age at onset;and 7) Enhance the NIMH Genetics Initiative collections by sending all clinical data, biomaterials, and genotypes to the appropriate repositories. The project would achieve the goals of the RFA by enriching the existing resources of the NIMH Human Genetics Initiative and by applying the latest genomic research methods to further our understanding of the molecular etiology of the disorder. Also, by capitalizing on an existing clinical infrastructure and an efficient screening and assessment protocol, we will obtain a well-powered sample in a very rapid and cost-effective manner.
This work will provide critical insights into the biological basis of schizophrenia, will identify factors that may be useful for profiling risk for the disorder, and may provide a basis for identifying subjects for early intervention and prevention protocols as well as the development of novel therapeutics.
|Wang, S-H; Hsiao, P-C; Yeh, L-L et al. (2018) Polygenic risk for schizophrenia and neurocognitive performance in patients with schizophrenia. Genes Brain Behav 17:49-55|
|Lin, Wan-Yu; Chen, Wei J; Liu, Chih-Min et al. (2017) Adaptive combination of Bayes factors as a powerful method for the joint analysis of rare and common variants. Sci Rep 7:13858|
|Lek, Monkol; Karczewski, Konrad J; Minikel, Eric V et al. (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285-91|
|Auther, A M; Cadenhead, K S; Carrión, R E et al. (2015) Alcohol confounds relationship between cannabis misuse and psychosis conversion in a high-risk sample. Acta Psychiatr Scand 132:60-8|
|Breen, M S; Maihofer, A X; Glatt, S J et al. (2015) Gene networks specific for innate immunity define post-traumatic stress disorder. Mol Psychiatry 20:1538-45|
|Rees, E; Kirov, G; Walters, J T et al. (2015) Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia. Transl Psychiatry 5:e607|
|McLoughlin, Gráinne; Makeig, Scott; Tsuang, Ming T (2014) In search of biomarkers in psychiatry: EEG-based measures of brain function. Am J Med Genet B Neuropsychiatr Genet 165B:111-21|
|Soontornniyomkij, Benchawanna; Everall, Ian P; Chana, Gursharan et al. (2011) Tyrosine kinase B protein expression is reduced in the cerebellum of patients with bipolar disorder. J Affect Disord 133:646-54|