Nancy J. Cox - US grants

Abstract: We propose in this application to use truly unique resources available to the Vanderbilt University research community to identify and characterize genetic risk factors for neuropsychiatric disorders. Our overarching hypothesis is that co-morbid phenotypes that cut across neuropsychiatric disorders can be used to identify more homogeneous genetic risk factors that will also be cross-cutting for neuropsychiatric diseases. To address this hypothesis, we will harness the long-standing strengths in neuroscience at Vanderbilt including extensive expertise in conducting in vivo and in vitro experimental validation studies, the strong team of investigators with long-standing research programs in key co-morbid phenotypes and neuropsychiatric disease, and our track record in developing and applying novel integrative approaches for genome investigation. The clinical data warehouse at Vanderbilt is called the Synthetic Derivative (SD), and contains continuously updated electronic health records (EHR) on more than 2,500,000 individuals. DNA samples are available on more than 217,000 of the individuals in the SD through BioVU, the biobank at Vanderbilt University. Individuals with more longitudinal data some going back as long as 20-30 years have been prioritized for genome investigation, and genome interrogation (GWAS or whole genome sequencing) will be available on > 120,000 of these subjects in 2018. The SD provides unprecedented power for characterizing cross-cutting comorbidities for neuropsychiatric disorders, and the large number of BioVU samples with genome interrogation coupled with the novel analytic approaches we have devised to optimize genome investigations in BioVU create a dynamic engine for discovery research. Our specific aims are to: 1) Use EHR data on more than 2,500,000 individuals to investigate the relationship between neuropsychiatric disorders and comorbid phenotypes shared among multiple of these disorders; 2) Use the novel PrediXcan approach to identify genes for which genetically predicted expression is significantly associated with neuropsychiatric disease, neuropsychiatric disease plus comorbidity, or comorbidity for more than 120,000 samples in BioVU; and 3) Prioritize genes for validation using improved network and pathway analyses, and then experimentally validate genes implicated in neuropsychiatric and comorbid phenotypes.

Abstract The large number of disease susceptibility loci identified from genome-wide association studies (GWAS) is enabling polygenic risk scores (PRS) to deliver on their promise to improve health outcomes and to transform the practice of personalized medicine. The reduced quality of PRS for common diseases and related quantitative traits for populations of recent African, Asian, and Native American ancestries relative to those for populations of recent European ancestries, however, threatens to create a new class of disparities in the delivery of healthcare based on PRS. The number of individuals of non-European ancestry with genome interrogation are growing much more rapidly now than 5 years ago; nevertheless, the number of individuals of recent European ancestries with genome interrogation grows still more rapidly and it is likely to be many years before sample sizes for genome interrogation in even major continental groups are close to proportional to relative population sizes. Thus, it is critical to optimize PRS performance for diverse populations in as many ways as we can. Given the substantial and growing fraction of the US population with genomes admixed from different continental ancestries, we believe that high quality PRS for much of the US population is unlikely to be achieved without properly accounting for local ancestries. Similarly, focused strategies to identify high-impact but population-specific variants could improve the quality of PRS in populations with such alleles. DNA variants from regions with a signature of natural selection often demonstrate such properties, and have been shown to be enriched among top associations for a number of hematological and immune/inflammatory traits that are important biomarkers for key chronic diseases. We propose to focus our PRS studies on hematological and immune/inflammatory traits and their associated chronic diseases and to extend methods for the development of PRS to accommodate estimates of local ancestry, high impact population-specific variants and multiple endophenotypes. Thus, our Specific Aims are: 1) Assemble and harmonize data sets needed to accomplish the goals of the project, including hematological traits (red blood cell, white blood cell, platelet), and immune/inflammatory traits (CRP, fibrinogen, D-dimer) from: Jackson Heart Study, Women?s Health Initiative, BioVU, and GeneSTAR. 2) Extend PRS methods to: a) explicitly model local ancestry; b) accommodate large-effect but population-specific risk alleles (such as those from regions with a signature of natural selection); and c) enable joint modeling of multiple endophenotypes; and 3) Develop and apply novel PRS and overall disease prediction models to: a) estimate risk of common diseases and related biomarkers affected by hematological, thrombotic and immune/inflammatory biology; and b) enable calculation of PRS-adjusted clinical laboratory values to reduce structural health disparities.

Project Summary The Vanderbilt Training Program in Genetic Variation and Human Phenotypes provides support for primary pre-doctoral research in the field of human genetics. While this program has enjoyed broad success throughout its tenure, with students in the program exhibiting good productivity (mean, median publications for students funded on the training grant ? 4.7,4), there is a new and palpable excitement in the field of human genetics today that can only bode well for the future success of the program. Much of that excitement has grown from the unprecedented availability of data: larger numbers of samples are available for studies in human genetics and this as been coupled with breakthroughs in technology allowing us to interrogate much of the common variation in the genome (MAF ? minor allele frequency ? greater than 0.001) for less than $75.00 / sample, and to conduct whole genome sequencing of subjects for less than $1200 / sample, with costs for both genotyping and sequencing technologies continuing to drop. There is a wide array of other ?omics technologies that are allowing us to better understand the function of genome variation as well. Vanderbilt University has hardly been immune to the excitement. With the establishment in 2015 of the Vanderbilt Genetics Institute, Vanderbilt has committed substantial new resources (more than $12 million) for establishing a new university-wide institute, recruitment of additional faculty in genetics and genomics, and additional investment in genome interrogation of subjects in BioVU, the biobank at Vanderbilt University. By mid-2017, BioVU will include more than 230,000 subjects with DNA and more than half of those samples (120,000- 140,000) will have at least dense genome-wide genotype data available, and thousands more will be whole genome-sequenced. Our graduate students are well-rounded biologists, with most matriculating through the Interdisciplinary Graduate Program (IGP) at Vanderbilt and the rest from the Quantitative & Chemical Biology Program (QCBP). They conduct research in an amazing variety of topics interfacing with human genetics, largely focused on generating and/or analyzing state-of-the-art genetic and genomic (and other ?omic) data, including data from the utterly unique BioVU resource. Their education is clearly empowering them, as the students themselves are major drivers of collaborative research within Vanderbilt, and they rightly feel that they are not just benefitting from the excitement in the field of human genetics today, but also contributing to it.  

PROJECT SUMMARY This application seeks to renew the Vanderbilt Genomic Medicine (VGM) training program at Vanderbilt University Medical Center (VUMC). VGM fellows are trained in data science, bioinformatics, laboratory science, and genomic discovery; the program also instructs fellows on the practice of genomic medicine. VGM builds on decades-long strengths in critical enabling resources and infrastructure within VUMC including: 1) BioVU, the largest biobank linking DNA samples to electronic medical records (EMRs) at a single academic institution (now >244,000 subjects), 2) Participation in three NHGRI-funded networks: the Electronic Medical Records and Genomics (eMERGE) network and eMERGE coordinating center, the Implementing Genomics in Practice (IGNITE) Network, and the Undiagnosed Disease Network (UDN), 3) The Pharmacogenomic Resource for Enhanced Decisions In Care and Treatment (PREDICT) project which embeds pharmacogenomic testing within electronic health records (EHRs) to guide drug and dosage choices 4) a Precision Oncology program that applies tumor genome sequencing to identify actionable mutations in cancers and to personalized target therapy, and 6) the largest Department of Biomedical Informatics in the country, with strong research, education, and support programs in clinical information technology. The program has 35 highly collaborative and well-funded faculty preceptors who team up to provide both basic and clinical research opportunities to Ph.D.-level and M.D.-level postdoctoral fellows. Trainees will participate in rotations, seminars, journal clubs, and retreats and interact with other clinical and research fellows and faculty. Under Vanderbilt?s Biomedical Research Education and Training (BRET) Office, the program will provide Responsible Conduct in Research (RCR) training, high-standard Individual Development Plans (IDP), and Career Development programs with the goal of developing fellows to be next-generation leaders in genomic medicine. A Scientific Advisory Committee and an External Advisory Committee provide valuable advice on VGM program development and enhancement. The program actively seeks candidates from diverse populations and professional and research backgrounds. Our fundamental model is to enhance multidisciplinary training through a curriculum tailored for each trainee based on prior experience, coupled to paired mentoring to provide both clinical and methodological expertise.