Multi-pronged genetic studies of schizophrenia in an inbred population

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DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a common, lifelong, disabling disorder. Its treatment remains unsatisfactory across the world. Thus, research into its causation and pathogenesis is needed urgently. Based on the substantial heritability (~70%), gene mapping efforts are in progress. Credible risk variants have been found, but the identified factors explain only a small proportion of the estimated heritability. Even the limited information has highlighted novel pathways for SZ genesis, so additional gene mapping studies are warranted. Such efforts will require many thousands of participants in outbred populations. Our plan with an inbred population promises novel insights with more modest effort. We will build on a collaborative R21 project between investigators at the University of Pittsburgh (PITT) and Mansoura University (MU, Egypt). In the Nile delta region, we have found increased consanguinity among patients with SZ compared with unaffected controls. The results are consistent with recessive genetic risk factors for SZ. We will employ a powerful tool called homozygosity by descent (HBD) analysis that has been successfully used to map several hundred recessive Mendelian diseases and genetically more complex disorders like autism and intellectual disability. Our preliminary studies suggest similar success for SZ. Our proposal is novel also because most SZ gene mapping studies have been conducted among Caucasian ancestry participants. Investigations of other ethnic groups, particularly those with unusual patterns of inheritance may yield useful, complementary insights. Through the NIMH genetics repository, we will share samples and data with members of the scientific community, further increasing the impact of our work. There is increasing interest in harnessing genomics research, as well as recognition of the