The long-term goal of the NIDA Core Center of Excellence in Omics, Systems Genetics, and the Addictome is to empower current and future researchers supported by NIDA and NIAAA to analyze the interwoven roles of genetic, epigenetic and environmental variation on drug abuse risk, relapse, and treatment. We will assemble sophisticated analytic/synthetic omics resources-primarily for rat models-that will give investigators mechanistic and behavioral insights. With a focus on reproducible research, we will centralize and archive data, metadata, and software stacks. This will help users compare across sexes, strains, species, and treatments-facilitating analysis and reanalysis for years. This Center will take a leadership role in the acquisition, curation, distribution, reuse, and analysis of all rat neurogenomic data sets-past, present, and future-related to addiction.

The Past: The Center will assemble, reannotate, and normalize genome and transcriptome data from past research programs. We will perform intensive quality control to update data. Researchers will be able to realize the potential of a decade of addiction-related research for reanalysis and hypothesis testing. The Present: We will strengthen active addiction research programs-particularly those that have genetic, genomic, or molecular components. We will provide hands-on help for computationally intensive workflows. We will teach teams how to analyze and publish core omics data and how to disseminate results and models. We will help build connections and collaborations among groups. The Future: This Center will have a significant impact on the next wave of research by working closely with new grantees and early career scientists, and by training researchers on how to implement new and more quantitative methods in addiction research.

The SAM Research Support Core, led by Dr. Saunak Sen (senresearch.org), has three goals:

1. To support researchers analyzing complex addictome data-essentially to amplify their efforts by embedding their data in the Omics Portal for Addiction Research (OPAR)
2. To integrate a wide range of software for open-access analytics to enable researchers without computational skills to address complex questions using vetted methods and interfaces
3. To develop new methods to dissect genotype-to-phenotype (G2P) relations in model organisms-rats in particular

Current projects under development that will be implemented in OPAR include:

• Smart search capabilities to connect investigator queries with relevant information across rat genetic websites and databases
• Fast linear mixed model computations for QTL analysis with population structure (e.g., Heterogeneous Stock and Hybrid Rat Diversity Panel)
• Matrix linear models for mapping multivariate traits
• Methods/workflow for single cell RNA-Seq data
• Development of data mining methods including unsupervised clustering methods such as Bayesian Mixture Model and Expectation Maximization (GEM) (Yousefi et al. 2014, 2016), K-means, and Density-based Spatial Clustering of Applications with Noise (DBSCAN), supervised classification techniques such as Bayesian ensemble learning (boosting and random forests), and tree-based classifiers, Markov Random Fields (MRFs) (Yousefi et al. 2011, 2013), Change Detection using Optimization Framework (CDOF) (Yousefi et al. 2015), Hidden Markov Models (HMMs), and deep learning.

The long-term goal of the TIM Research Support Core, led by Dr. Laura Saba (http://www.ucdenver.edu/academics/colleges/pharmacy/Research/ResearchLabs/Systems-Genetics-and-Bioinformatics/Pages/default.aspx) is to help addiction researchers uncover the complex interactions and genetic mechanisms that drive addiction disease in order to build better, more personalized therapeutics and diagnostics for predicting disease. To reach this goal we will facilitate increased productivity and effectiveness by:

1. Providing databases in a format that is easily utilized for systems genetics research
2. Centralizing the labor- and computationally-intensive tasks of processing RNA-Seq data
3. Sharing our statistical and computational expertise through improved analysis pipelines and effective visualizations of systems genetics analysis results.

Current projects under development that will be implemented in OPAR include:

• Brain and liver transcriptome reconstructions from 43 strains of the Hybrid Rat Diversity Panel
• Quantitation and transcriptome reconstruction of over 50 heterogeneous stock rats in 5 different brain regions based on data generated as part of the NIDA Center for GWAS in Outbred Rats (ratgenes.org)
• Development of pipelines for RNA-Seq data processing in mass
• Identification of polyadenylation sites from RNA-Seq read coverage and DNA sequence information
• Evaluating protein-coding potential of novel transcripts based on RNA-Seq and DNA sequence information

Members of the TIM Research Support Core:

• Laura Saba (http://www.ucdenver.edu/academics/colleges/pharmacy/Research/ResearchLabs/Systems-Genetics-and-Bioinformatics/Pages/default.aspx) - Core Lead and Center Co-Director
• Katerina Kechris (http://csph.ucdenver.edu/Sites/Kechris/) - Co-Investigator
• Lauren Vanderlinden - Analyst
• Harry Smith - Analyst
• Spencer Mahaffey - Computer Programmer

This pilot program is designed to entice early career investigators to explore the role of genetics and genomics of addiction by reducing and eliminating some of the barriers to implementation and to promote the development of collaborative, inter-disciplinary teams. Grant application must include one Principal Investigator (early career scientist) and a collaborator from a different laboratory within the same institution or a different institution.

Types of grants that will be supported. The Center will fund two general types of pilot grants: 1) pilot grants to investigate new and cutting-edge technologies to study addiction and 2) pilot grants to expand current behavioral and exposure rat models to a more genetically diverse population (e.g., heterogeneous stock, recombinant inbred panels, the Hybrid Rat Diversity Panel).

The Omics Portal for Addiction Research (OPAR) - under development

RNA-Seq Data Processing (via TIM Core) - under development

Analysis Software and Pipelines - under development

Short Courses. The P30 will offer short courses in at least four areas-twice a year from years 2-5. Topics are: (1) systems genetics and complex trait analysis of addiction; (2) transcriptome analysis and epigenomics (3) advanced methods in causal inference and modeling; and (4) computational infrastructure and web services stacks for computational biology, omics, and addictome research. See News and Calendar for upcoming short courses. If you are interested in hosting a short course at your institute, please contact either Rob Williams (rwilliams at uthsc.edu) or Laura Saba (Laura.Saba at ucdenver.edu).

Training via the web. We hope that the most permanent and lasting form of training that we provide will be part of OPAR. This will include a collection of on-line tutorials from how to maximize your time on the OPAR website to quantitating RNA-Seq data on a desktop computer. We will make this a priority, once we have the OPAR website is fully developed. If you have specific suggestions about training topics, please submit to OPAR

Tutorials. We will also offer short hands-on tutorials as several of the related society meetings, e.g., Complex Trait Consortium, Society for Neuroscience, College on Problems of Drug Dependence, Research Society on Alcoholism, International Drug Abuse Research Society. These short tutorials are a way to introduce the Center and OPAR to a broader community and to stimulate interest in the web service and the topic. See News and Calendar for upcoming events.

Fellows and students. Each of the key personnel in the P30 application work closely with inter-disciplinary graduate students and postdoctoral fellows as part of their academic appointments. Given the structure of this Center, they have the opportunity to work closely with multiple mentors, mentees, and with NIDA grantees. We will continue to make a special effort to cross-train everyone in the essentials of systems genetics, modeling, addiction biology, and genomics. See News for announcements for particular positions and visit the faculty websites of P30 collaborators for additional information.

Rob Williams, University of Tennessee Health Science Center (www.nervenet.org)

Laura Saba, University of Colorado Anschutz Medical Campus (http://www.ucdenver.edu/pharmacy/SystemsGeneticsandBioinformatics)

Saunak Sen, University of Tennessee Health Science Center (www.senresearch.org)

Siamak Yousefi, University of Tennessee Health Science Center (www.syousefy.wixsite.com/yousefilab)

Katerina Kechris, University of Colorado Anschutz Medical Campus (csph.ucdenver.edu/Sites/Kechris/)

Outreach to drug abuse research communities, educational organizations, general public, and policy makers. Our Center will participate in any and all programs brought forward by NIDA staff or by our grantees where we think we can be helpful. Our best use of effort and energy may be to reach out to the research community itself-from the level of undergraduates in physiological psychology courses to young scientists in addiction research interested in adding systems genetics into their areas of competence. For more information about outreach, please contact Center Director, Rob Williams (rwilliams at uthsc.edu).