Carlos N. Pato - US grants

DESCRIPTION (Adapted from applicant's abstract): We will study a relatively genetically homogeneous population to test the hypotheses that genetic factors are linked to schizophrenia. The study will focus on two populations. The first is from the Azores, a nine island archipelago in the Atlantic ocean that is a Portuguese state. The Azores have a centralized health system. All ten psychiatrists on the islands are collaborating with us on this project. The second population is from continental Portugal. The majority of the Azorean population is derived from this population base. Families with multiple affected members with schizophrenia, will be studied employing both parametric and non-parametric analytic strategies. We projected approximately 100 families segregating for schizophrenia, including over 300 affected family members. A complementary strategy will be used to study candidate loci. We will study a sample of 225 subjects suffering from schizophrenia and their parents (Total n=675) employing the haplotype relative risk and the transmission/disequilibrium test strategies. This strategy insures that we control for all ancestry for each subject, using the uninherited haplotype derived from the two parents. The third sample will include all other Azorean patients with schizophrenia, who agreed to participate in hopefully, achieving close to complete ascertainment of patients with schizophrenia in the Azores. This will be a valuable sample for linkage disequilibrium approaches given the nature of the Azorean population and provide us with a unique epidemiologic frame. These complementary strategies will allow us to cross validate any positive results. The careful diagnostic definition of phenotype will be based on detailed structured clinical data employing the Diagnostic Interview for Genetic Studies (DIGS), which we have translated into Portuguese. Our project is designed to capture a very complete history of the patients illness, as well as to be able to follow most subjects prospectively for a long period of time. This will be extremely valuable for achieving diagnostic certainty and minimizing false positives. An important new addition to this proposal is the Whitehead/MIT Center for Genome Research, that will perform a genome-wide scan and collaborate on all data analysis for the project.

DESCRIPTION (Adapted from the Investigator's Abstract): The investigators will study a relatively genetically homogeneous population to test the hypotheses that genetic factors are linked to bipolar disorder. The study will focus on the population of the Azores, a nine island archipelago in the Atlantic Ocean. The Azores have a centralized health system. All ten psychiatrists on the islands are collaborating with the investigators on this project. The investigators are currently funded to study schizophrenia in this same population and believe that it is critical to study all of the patients suffering with bipolar including over 300 affected family members. The pilot study has already identified 25 families with 84 affected members. A complementary strategy will be used to study candidate loci. They will study a sample of 225 subjects suffering from bipolar disorder and their parents (Total n=675) employing the haplotype relative risk and the transmission/disequilibrium test strategies. This strategy insures that the investigators control for all ancestry for each subject, using the uninherited haplotype derived from the two parents. The third sample will include all other Azorean patients with bipolar disorder in the Azores. This will be a valuable sample for assessing the prevalence of any mutations that are identified in the population. These complementary strategies will allow them to cross validate any positive results. The careful diagnostic definition of phenotype will be based on detailed structured clinical data employing the diagnostic interview for genetic studies (DIGS), which they have translated into Portuguese. The project is designed to capture a very complete history of the patient's illness, as well as to be able to follow most subjects prospectively for a long period of time. This will be extremely valuable for achieving diagnostic certainty, and minimizing false positives. The Whitehead/MIT Center for Genome Research will perform a genome-wide scan and collaborate on all data analysis for the project.

DESCRIPTION (provided by applicant): Genomic Parsing of Bipolar Disorder and Schizophrenia: Studies of Large Cohorts in the U.S. and Across the Globe. The University of Southern California (USC Center for Genomic Psychiatry), the Massachusetts General Hospital (MGH)-Broad Institute (Stanley Center) and a nation-wide network of academic medical centers have created the Genomic Psychiatry Cohort (GPC). This application seeks to expand the resources currently available to the field, through the NIMH Repository, with an additional sample of 10,000 well-characterized patients with schizophrenia and 10,000 controls from the same geographic regions. Further, a genome-wide association study of 5,000 patients and 5,000 controls will be performed to identify genetic risks for schizophrenia. The blood/DNA from the 20,000 subjects will be deposited in the NIMH repository, along with clinical and phenotypic data, and genome wide SNP data from the GWA study. In addition, we plan to genotype the second 10,000 subjects for ancestry informative markers and replication of candidate genes. Our intent is to ascertain and recruit a large clinical cohort of patients with schizophrenia that will be prospectively followed in order to allow ongoing careful assessment of phenotype and the possibility of future nested case-control studies. We will also provide the bioinformatics and molecular infrastructure for rapid replication of specific genetic results and future potential large-scale high-throughput genomic investigations. The University of Southern California (USC) and its partners have created the Genomic Psychiatry Cohort to study very large groups of patients suffering with schizophrenia treated in their health systems. Members of the cohort are long-term patients that have agreed to participate in studies related to understanding the genetic and environmental risks for these disorders. This type of population study is critical to understanding risk, helping develop treatments, and understanding prevention of this major illness.

? DESCRIPTION (provided by applicant): The goal of this collaborative project among investigators led by Drs. Michael Boehnke at the University of Michigan, Steven McCarroll of Harvard University and the Broad Institute, and Carlos Pato at the University of Southern California, is to use high-throughput DNA sequencing to identify genes and pathways that contribute to the risk for schizophrenia and bipolar disorder, and to construct a data resource for future genetic studies of these and other psychiatric disorders. This proposal builds on active collaborations among our groups on these important disorders and more generally on our experience in building genome variation resources, such as the 1000 Genomes Project, that are used throughout human genetics. Our research team combines strengths in high-throughput genetics and genomics, development and application of innovative computational and statistical analyses that maximize the benefits of new technologies, and leadership of large scientific consortia. In four Specific Aims, we propose whole genome sequencing (at ~30x coverage) and statistical analysis of 10,000 well-phenotyped and re-contactable individuals from the Genomic Psychiatry Cohort (GPC), equally divided among schizophrenia cases, bipolar cases, and psychiatrically normal controls, and comprised of equal numbers of European-Ancestry (EA), African-Ancestry (AA), and Latino individuals. We will carry out association analysis comparing schizophrenia cases to controls, bipolar cases to controls, and the combined cases to controls in the resulting sequence data, and by collaboration and meta-analysis with other investigators with relevant sequence data that become available. We will also use these sequence data as part of a reference panel to impute into tens of thousands of other genomes in the broader Psychiatric GWAS Consortium (PGC) data to allow association analysis based on substantially larger numbers of individuals. Finally, we will share data and methods to support similar studies of other psychiatric phenotypes and more broadly across the scientific community. The successful completion of these aims will provide new insights into molecular etiology that could catalyze breakthroughs in the prevention, treatment, and diagnosis of schizophrenia and bipolar disorder.

ABSTRACT This endowment award will establish a new and sustainable Translational Program of Health Disparities Research Training (TRANSPORT). TRANSPORT will provide a foundation for growing and developing a diverse biomedical research workforce that will position Downstate as a national leader in translational disparities and population health research. Our efforts will focus on recruiting and training underrepresented minority (URM) junior faculty, postdoctoral candidates and undergraduate students who come from Brooklyn and other communities that are vulnerable to health disparities. We propose the following five objectives in TRANSPORT: 1. Establish a new Translational Program Of Health Disparities Research Training (TRANSPORT) that will support a range of research training initiatives from undergraduate pipeline programs, faculty development, and recruitment under BHDC. 2. Enroll 3 junior faculty candidates per year of endowment income, into a 2-year development program of TRANSPORT, leveraging the experience and success of PRIDE. 3. Enroll URM post-doctoral fellows who are identified as exceptional candidates and who are most likely to benefit from academic experience when matched with the most successful faculty investigators at Downstate. The endowment will support 2 fellows directly, full time for two years each, but other mechanisms will be used to support up to 6 fellows annually. 4. Expand partnerships with local colleges such as Medgar Evers College, where over 90% of students are URMs, to recruit 5 students in year 1, increasing by an additional 5 students each year, reaching 25 students/year in year 5 forward. These students will be enrolled into the Summer Program in Translational and Community Engaged Research (SPRINTER). SPRINTER will provide research opportunities in all 5 Colleges/Schools for undergraduate students and will greatly enhance pipelines into our schools, and ultimately into health disparities research. 5. Establish the Presidents Multi-disciplinary Investigator Seminar (PREMIS) series and an annual TRANSPORT interdisciplinary health disparities research symposium. These initiatives will greatly increase health disparities awareness and expand the range of research options offered by each of the colleges/Schools. This will enhance the academic environment and lead to opportunities for transdisciplinary collaborations in health disparities research. IMPACT: TRANSPORT will provide a rigorous research training infrastructure that will produce a critical mass of trained health disparities investigators and career advancement opportunities, which will ultimately contribute to the elimination of health disparities in Brooklyn and beyond.

Project Summary 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, we will create 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. PUMAS will be well powered to discover new genes for schizophrenia and bipolar; it will dramatically increase the diversity of genetic discovery efforts, an important step towards reducing health disparities; and it will expand the scope of psychiatric genomics by generating low-pass whole genome sequencing for 120,000 samples (which we will analyze together with 22,500 samples already sequenced by our team). Through these efforts we 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; and 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. Our 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.