Psychiatry remains the only medical specialty with diagnosis based solely on reported symptoms. For progress in personalized medicine, diagnosis must be reliable, sensitive, and specific. Consensus exists the current diagnostic system (DSM), although useful for clinical description, lacks these requirements. Genetics offers potential in psychiatric nosology and in the development of novel prevention strategies and treatments. Numerous variants associated with psychiatric disorders have been discovered recently. These variants if common have low effects sizes and lack disease specificity; if rare, they typically involve genes with broad functions and neuropsychiatric phenotypes (e.g., intellectual disability). Historically in medicine, Mendelian variants have been the first step in understanding the genetic bases of diseases. No single Mendelian variant has been discovered for any psychiatric disease. Across the world (e.g., Saudi Human Genome Program), the most successful approach for mutation discovery used whole exome or whole genome sequencing (WES, WGS) along with homozygosity mapping of consanguineous multiplex pedigrees. US population isolates do not have the requisite coefficient of inbreeding to apply these methods successfully. However, there is a high prevalence of marriages between first cousins in several countries: the highest occurs in Pakistan (>60%). This proposal exploits a newly developed international collaboration (PK, USA): molecular biologists with a track record of successful gene discovery in consanguineous pedigrees; neuropsychiatrists; clinical neuroscientists; bioinformaticians; and neuroimagers. The goals are twofold: 1) To find and characterize Mendelian genes associated with a mental illness; 2) To increase awareness and treatment of mental disorders and to grow Pakistan’s existing research infrastructure including a Pakistani Human Genome Program focusing on the study of mental disorders. Were no Mendelian genes found where they are most expected, this result would provide practical evidence of absence, highly significant in and of itself. If found and because single pedigrees are likely to have only one rare variant, the mutation would essentially define a homogeneous disorder that can be studied with methods such as neuroimaging, molecular/cellular biology, and cognitive neuroscience. Aim one involves the recruitment and characterization of multigenerational, multiplex, consanguineous families afflicted with psychosis. WES will be followed by informatic analyses including only variants that are rare; nonsynonymous; protein altering or likely pathogenic; and showing Mendelian in-heritance (homozygous in affected; heterozygous in obligate carriers). Aim 2 involves increasing within Pakistan the participation of women in STEM; training the next generation of geneticists; educating about mental diseases; collaborating and impacting clinical psychiatry; and decreasing stigma. These goals will deliver significance for p...