Depression Grand Challenge

Genetic discovery for schizophrenia and bipolar disorder lags behind that in other areas of medicine, where the identification of mutations responsible for familial forms of major disorders has yielded extraordinary biological insights. However, recent successes in gene identification from both rare and common variant analyses indicate what the field needs to do to catch up: expand the size, diversity and scope of genetic studies. Indeed, NIMH recognized this need, issuing PAR-20-027, “Genetic Architecture of Mental Disorders in Ancestrally Diverse Populations.” In response to this call, researchers created the Populations Underrepresented in Mental illness Association Studies (PUMAS) Project, an international collaboration of investigators from the US, South America and Africa with the strongest track record of large-scale psychiatric genetic research in Latino and African populations, along with several of the field’s leaders in genetic data generation and analysis. Nelson B. Freimer, MD, Depression Grand Challenge director, is PI of this project.

PUMAS is well-powered to discover new genes for schizophrenia and bipolar; it dramatically increases the diversity of genetic discovery efforts, an important step towards reducing health disparities; and it expands the scope of psychiatric genomics by generating low-pass whole genome sequencing for 120,000 samples (which researchers will analyze together with 22,500 samples already sequenced by the research team). Through these efforts, PUMAS researchers will also discover similarities and differences in genetic architecture of schizophrenia and bipolar across diverse ancestries and environments.

The aims of the PUMAS project are to:

1. Build the PUMAS sample bank of schizophrenia cases, bipolar cases and controls from Africa and from admixed populations in the Americas, achieving a total sample of 183,500 (88,600 cases and 94,900 matched population controls) by recruiting 17,000 new cases and 16,500 controls.
2. Generate low-pass whole genome sequencing (WGS) data and variant calls on 40,000 cases of schizophrenia, 40,000 cases of bipolar disorder and 40,000 matched controls from African, Native American and admixed ancestries b) perform extensive sample and variant quality control.
3. a) Systematically analyze the combined dataset to power discovery of the genetic basis of schizophrenia and bipolar across diverse ancestries and down the allele frequency spectrum.
   
   b) Through portals and browsers, share the data and results of the genetic studies with the world. The PUMAS 120,000 sample WGS dataset, together with data for 22,500 previously sequenced admixed (AA+EA) samples, provides sufficient statistical power for genetic discovery for SZ, BP, and combined across diverse ancestries. The study will identify new genes and loci, increase the precision of fine-mapping of known loci, and form the foundational knowledge base for polygenic risk scores (PRS) of global value.

NIH project number: 1U01MH125042-01