IP: Prof. Dr. S.A. Kushner, MD, PhD

Resumen del proyecto: A profound problem in studying the neurobiology of psychiatric disorders
has always been the wide phenomenological heterogeneity. In fact, there is emerging consensus that the diagnosis of a psychotic disorder reflects a multitude of different syndromes at the biological level. Such limitations have likely been the principle cause of the historical difficulties in establishing causative biological factors, exemplified by recent genomewide association studies. Therefore, our study attempts to circumvent the difficulties inherent in studying genetically unrelated patients by using a family-based design, which has yielded some notable successes. Further, recent advances in genetic technology, such as whole-genome exon sequencing, have encouraged the possibility for higher specificity using a family-based gene finding approach, particularly for complex psychiatric diseases. Towards this goal, we have initiated the GEZIN study to identify families with a high incidence of psychosis and a transmission pattern that is strongly suggestive of identifiable high-penetrance genetic mutations.
One of the main objectives of the GEZIN study is to identify the causativegenomic locus for the psychotic syndrome in families recruited based upon a Mendelian pattern of disease expression. Thusfar, we have already found more than 20 families that are unique in having a high incidence of psychosis, given that the incidence in the general population is only 3%. This increases the likelihood that a high-penetrance genetic mutation is responsible and identifiable in these families. In particular, the feasibility of next generation sequencing methods guided by classical linkage analysis has provided a powerful framework by which family-based genetic investigations have been increasingly successful. Therefore, it would be of great value to our project to be able to compare potential pathogenic variants with other European DNA samples of relevant patients to filter out those that are more frequent in the population.

Entidad financiadora: Erasmus University Medical Center Rotterdam, The Netherlands