Dissecting the genetic causes of schizophrenia
Schizophrenia (SCZ) is one of the most devastating diseases of the central nervous system and affects about 1% of the population. Despite these enormous effects, little is known about the molecular mechanisms of disease development. Since SCZ has a high heritability and thousands of genetic variants (SNPs) are statistically linked to SCZ, genetics offers promising ways to decipher the disease mechanisms. The aim of this project is to translate genetic associations into a better understanding of molecular disease mechanisms. The hypothesis is that the SCZ phenotype is due to the interplay of many SNPs that interfere with the function of numerous gene regulatory elements (GREs) which are active in neural cell populations.
The work plan includes
1.) The prediction of the functional contribution of SCZ-associated SNPs by combining epigenomic datasets with integrative computational analysis of gene regulatory networks.
2.) The experimental testing of the molecular function of SCZ associated SNPs in neural cell types. For this purpose, a human, pluripotent stem cell differentiation system is utilized to generate various neural cell populations and developmental stages. Epigenomic profiling technology combined with highly parallel reporter assays and CRISPR-based genome engineering will then allow the identification of molecularly functional SNPs in GRE, as well as their molecular effect on individual neural cell types.
3.) The characterization of the physiological effects of combinations of SCZ-associated SNPs. To implement this goal, induced pluripotent stem cells of schizophrenia patients are differentiated into neural cell types in vitro and their physiological properties are compared with normal controls.
Donaghey, J., Thakurela, S., Charlton, J., Chen, J.S., Smith, Z.D., Gu, H., Pop, R., Clement, K., Stamenova, E.K., Karnik, R., Kelley, D.R., Gifford, C.A., Cacchiarelli, D., Rinn, J.L., Gnirke, A., Ziller, M.J., Meissner, A., 2018. Genetic determinants and epigenetic effects of pioneer-factor occupancy. Nat. Genet. 50, 250–258. doi.org/10.1038/s41588-017-0034-3
Hoffmann, A., Sportelli, V., Ziller, M., Spengler, D., 2018. From the Psychiatrist’s Couch to Induced Pluripotent Stem Cells: Bipolar Disease in a Dish. Int J Mol Sci 19. doi.org/10.3390/ijms19030770
Hoffmann, A., Sportelli, V., Ziller, M., Spengler, D., 2017. Epigenomics of Major Depressive Disorders and Schizophrenia: Early Life Decides. Int J Mol Sci 18. doi.org/10.3390/ijms18081711
Hoffmann, A., Ziller, M., Spengler, D., 2016. The Future is The Past: Methylation QTLs in Schizophrenia. Genes (Basel) 7. doi.org/10.3390/genes7120104
Ziller, M.J., Ortega, J.A., Quinlan, K.A., Santos, D.P., Gu, H., Martin, E.J., Galonska, C., Pop, R., Maidl, S., Di Pardo, A., Huang, M., Meltzer, H.Y., Gnirke, A., Heckman, C.J., Meissner, A., Kiskinis, E., 2018. Dissecting the Functional Consequences of De Novo DNA Methylation Dynamics in Human Motor Neuron Differentiation and Physiology. Cell Stem Cell. doi.org/10.1016/j.stem.2018.02.012