Large-scale molecular genetic studies
The aim of this subproject (SP) is to identify rare, high penetrance genetic variants which contribute to the development of schizophrenia (SCZ), bipolar disorder (BD), and unipolar affective disorder (MD).
The basis of SP3 is the exome-wide sequencing of large, multigenerational families (accessed via SP2), in which at least three individuals are affected by SCZ, BD, or MD. In these families, it is likely that genetic variants with particularly strong effects make a substantial contribution to the development of psychiatric symptoms. The analysis of the genetic data is performed in close collaboration with the other SPs, in particular SP1.
All co-segregating genetic variants identified in these families - or genes that are implicated thereby - are then further investigated by the various Consortium projects using a multidimensional approach. In close collaboration with SP1, SP6, SP8, and others, a newly identified potential candidate gene will be investigated more closely in terms of its potential contribution to disease development, and prioritized for follow-up studies.
To identify further mutations in these candidate genes, DNA from thousands of further patients and control subjects is being investigated (in cooperation with SP2). Mutation specific knock-out mouse models are being generated and subjected to detailed phenotype characterization (in cooperation with SP7). Furthermore, induced pluripotent stem cells from mutation carriers are being reprogrammed into nerve cells and functionally analyzed (in cooperation with SP9). Together with the imaging data of SP4 the generated genetic data form the basis for the development of neurodynamic models in SP10. In addition, the exome sequencing data will be integrated in the modeling of disease pathways (SP1).