The Genetics Core will utilize the large and rigorously characterized clinical sample collected by the Johns Hopkins Epidemiology/Genetics program under the direction of Dr. Ann Pulver to determine the role of candidate genes identified in Projects 1-3 in the genesis of human phenotypes. This sample includes 683 Ashkenazi Jewish (AJ) schizophrenia (SZ) or schizoaffective (SZA) probands; 1090 AJ screened controls; 388 outbred (OB) SZ/SZA; 85 OB bipolar I (BP1) probands; and 122 OB probands with related neuropsychiatric phenotypes. Between half to two thirds of each group is as parent-child trios except for the OB BP1 and OB other groups which are as singletons. We will perform and/or provide the samples for sequencing, genotyping and genetic analysis of the candidate genes identified in Projects 1-3. Specifically, we will: 1) Prioritize the candidates on the strength of the biological evidence together with mapping information based on published work and work from our own group; 2) In at least 48 probands for the appropriate disorder, we will sequence all exons and flanking intronic sequence plus the proximal promoter region (-500 bp) and any candidate regulatory regions identified on the basis of sequence conservation; 3) Identified sequence variants (SV) will be prioritized and then genotyped in the appropriate (depending on diagnosis and population group) patient collection using TaqMan genotyping; 4) Analyze the frequency and distribution of the SV in our cases and controls and genotype those that appear to be of interest in our trio sample and perform TDT analysis; and 5) Work with the group identifying the candidate gene to perform functional assays of SV shown to be significantly associated with the clinical phenotype.