Studying child and adolescent onset psychosis in mexico: phenotypic complexity and rare genetic variation

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. The “Genetic Architecture of Early-Onset Psychosis in Mexicans” (EPIMex) study involves deep phenotyping and sequencing of EOP probands and demographically matched youth living in Mexico City. For a subset of probands, both parents and a non-psychotic sibling are recruited to facilitate the search for inherited and de novo mutations associated with EOP. Children and adolescents and their families are primarily being 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 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 association 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. EPIMex is designed 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. We will describe our initial findings from over 700 participants that highlight the phenotypic complexity of EOP probands, document cognitive and psychosocial impairment in this group, examine the impact of social determinates of health on clinical and cognitive presentation, and provide an initial estimate of rare loss of function variants in EOP probands and their family members.