Genetic Architecture of Early-Onset Psychosis in Mexicans

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PROJECT SUMMARY/ABSTRACT Psychotic disorders, like schizophrenia and bipolar disorder, are poorly understood illnesses associated with increased mortality and lifelong psychosocial impairment. Unfortunately, current treatments are only partially effective and many individuals with psychosis remain disabled despite our best efforts. Identifying genes that contribute to risk for psychotic disorders should lead to the development of novel diagnostic and therapeutic strategies. It is likely that the clinical heterogeneity of psychosis has limited gene discovery. 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) represents such an extreme phenotype. Consequently, studying EOP cohorts provides a unique opportunity to discover rare genetic loci influencing illness risk. We will acquire the largest EOP sample to date and characterize these individuals in terms of diagnostic presentation, early life adversity (ELA), cognitive ability and burden of rare genetic mutations. Specifically, we will deep phenotype, genotype and exome sequencing 2000 EOP probands and 2000 non-psychotic, demographically matched youth. In addition, nuclear families (unaffected sibling and both parents) for 250 EOP probands (n=750 family members) will allow us to search for inherited and de novo mutations associated with the illness. Children and adolescents and their families will be recruited from a single, large public pediatric psychiatric hospital in Mexico City. To date, the vast majority of psychiatric genetic studies have focused on European-ancestry cohorts alone, which limits our ability to fully characterize the genetic architecture of these complex illnesses and potentially adds to health care disparities. To help reduce this disparity and facilitate discovery, we will conduct our study in a Latino community, the single largest ethnic minority in the US. To determine if rare mutations associated with psychosis liability are linked to haplotypes originating from founders in one of the ancestries, the 2000 demographically matched controls will be supplemented with 5250 archival samples with psychiatric phenotypes who will serve as “population” controls (total n=10000). We aim to: 1) characterize EOP probands and siblings in terms of cognitive and psychosocial functioning and frequency of ELAs to demonstrate that our underserved population is comparable to prior cohorts; 2) document the prevalence of 25 rare but recurrent 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) examine the prevalence of gene-disruptive and putatively protein-damaging rare variants in affected participants relative to unaffected family members and controls. David Glahn and Chris Walsh (BCH), Laura Almasy (CHOP) and Humberto Nicolini (Instituto Nacional de Medicina Genómica) are co-principal investigators. Carlos Bustamante (Stanford) leads a subcontract to conduct admixture analyses. Our multinational team developed this application in response to PAR-20-026.