PROJECT SUMMARY/ABSTRACT Despite recent progress, clinical heterogeneity has likely hindered efforts to clearly delineate the genetic architecture of psychotic disorders like schizophrenia and bipolar disorder. However, this heterogeneity also presents an opportunity for studying individuals with extreme phenotypes, virulent forms of the illness with putatively more homogeneous etiologies. Early onset psychosis (EOP, onset prior to 18 years) represents such an extreme phenotype, with dramatically higher rates of rare deleterious mutations in EOP than adult-onset psychosis. Consequently, studying EOP cohorts provides a unique opportunity to discover rare genetic loci influencing illness risk. We will deep phenotype and sequence 1900 EOP probands and 1900 non-psychotic, demographically matched youth. For 400 probands, both parents and a non-psychotic sibling will be recruited to facilitate the search for inherited and de novo mutations associated with EOP (n=1200 family members). Children and adolescents and their families will be recruited from a single, large public pediatric psychiatric hospital in Mexico City. To date, most psychiatric genetic studies focus on European-ancestry (EA) cohorts, while excluding of other ancestry groups. Yet, no single population is sufficient to fully illuminate the genetic architecture of complex traits like psychosis, and the EA focus could exacerbate health care disparities. Latinos make up ~8% of the world population (~18% of the US population) but appear in less than 1% of published genome-wide studies. Complicating matters, Latinos are genetically heterogeneous, with substantial differences between Central and South American and Caribbean populations, reflecting continental-level ancestral group admixture and the substructure of local Indigenous American populations. As 62% of the Latinos in the US are of Mexican origin findings from the Mexican population are directly relevant for most individuals in the nation’s largest racial/ethnic minority. During our initial 1-year project, we recruited 1000 participants from the same psychiatric hospital and using identical procedures, thus demonstrating the feasibility of the current study. Combining these 1000 individuals with the additional 5000 participants we now propose to acquire, we aim to: 1) characterize EOP probands and siblings in terms of cognitive and psychosocial functioning, frequency of adverse life events, social determinants, and cannabis use; 2) document the prevalence of rare loss of function mutations and CNVs previously associated with schizophrenia or autism spectrum disorder in EOP participants relative to their unaffected family members and demographic and population controls; and 3) utilize ancestry analysis to identify chromosomal regions and runs of homozygosity shared in common by multiple unrelated EOP cases but not by unaffected individuals. David Glahn (BCH), Laura Almasy (CHOP), Humberto Nicolini (Instituto Nacional de Medicina Genómica) and Carlos Bustamante (Stanford) lead this project.

PROJECT NARRATIVE Children and adolescents with early onset psychosis (EOP) have a dramatically increased prevalence of rare genetic mutations compared to adult-onset cases. We will acquire the largest EOP sample to date to search for inherited and de novo protein altering mutations predisposing this debilitating illness.