Research

Project 1: Electronic Health Record Phenotyping and Genomics of Opioid Addiction

Project Overview

In Project 1 we are undertaking an ambitious effort to perform the largest genome wide association study of opioid addiction, to date. With over 100,000 genomes represented and a focus on clinically relevant “real-world” addiction phenotypes extracted from electronic health records, we will be well positioned to identify individual genetic variants that increase likelihood of addiction. We will be working closely with the Synergy Core to develop models of opioid addiction that maximize biologically meaningful discovery. Lastly, we will conduct additional bioinformatic analyses of the variants, genes, and pathways that are identified in the GWAS.

Project Goals

  • To derive EHR-based phenotypes for opioid addiction.
  • To identify genetic variants that increase the likelihood of addiction.
  • To gain biological insight into the genes and pathways implicated in the GWAS.

Key Staff

Lea K. Davis, PhD
MPI for Project 1
Dr. Lea K. Davis, MPI for Project 1 (EHR Phenotyping and Genomics of Opioid Addiction), is an Associate Professor of Genetic Medicine, Psychiatry and Behavioral Sciences, and Biomedical Informatics. Dr. Davis' work employs a population level approach to investigate the genetic basis of a wide range of complex phenotypes including addiction phenotypes. Her lab's research aims to discover how polygenic risk, rare variant risk, and environment interact to result in common complex diseases and conditions. To accomplish this goal, she applies genomic and bioinformatic approaches to biobank data and phenotypes extracted from the electronic health record.
Vanessa Troiani, PhD
MPI for Project 1
Dr. Troiani, MPI for Project 1 (EHR Phenotyping and Genomics of Opioid Addiction), is an Associate Professor of Neuroscience at Geisinger Commonwealth School of Medicine with expertise in behavioral and genetic contributions to atypical motivational circuitry in the brain and how they manifest in different psychiatric disorders, including addiction. Dr. Troiani will lead the identification of opioid addiction cases and exposed controls among whole genome sequenced patients in Geisinger Health System and will extend that work to identification of the same among patients at Vanderbilt University, and the extended PsycheMERGE Network. She will direct the work of Geisinger research scientists and postdoctoral fellows involved in Project 1 to refine EHR phenotypes for optimal case/control selection for subsequent GWAS.
Sandra Sanchez-Roige, PhD
Dr. Sanchez-Roige, MPI for Project 1 (EHR Phenotyping and Genomics of Opioid Addiction), is an Associate Professor of Psychiatry with expertise in behavioral neuroscience and genetics of substance use disorders, comorbid disorders, and related traits. Dr. Sanchez-Roige's laboratory uses genomic, phenomic and bioinformatic techniques to identify opioid addiction cases and exposed controls from real-world hospital cohorts within the PsycheMERGE Network. This work will enable large-scale multivariate genomic studies of opioid addiction and comorbid phenotypes.

Project 2: Gene Regulation in Opioid Dependent Human Brain

Project Overview

The work proposed in Project 2 combines multi-omics resources to examine specific hypotheses regarding the functional brain architecture of Opioid Use Disorder (OUD). Guided by existing theory implicating the prefrontal cortex, nucleus accumbens, and amygdala in the cycle of substance abuse, we propose to generate and combine existing data at multiple Omics levels in each brain region using post-mortem human tissue collected from opioid overdose cases and matched controls. The measurement approaches we use are genome-wide, in each of the 3 brain regions and in each biological domain: SNP, epigenome (DNA methylation and histone acetylation) and transcript (via RNA-Seq) in our combined sample, with planned replication in outside samples.

Project Goals

  • Integrated existing combined cohort data containing gene expression, DNAme and histone acetylation
  • Generate histone acetylation and RNA-seq data for Amygdala samples
  • Integrate Amygdala data with existing histone acetylation, DNAme and RNA-seq from PFC and NAc
  • Perform genome-wide association mapping, including histone modification- (hm), DNA methylation- (DNAm) and gene expression- (e) QTL mapping, to identify genetic variants that account for the regulatory differences observed between cases and controls.

Key Staff

Dr. Olivia Corradin
Dr. Olivia Corradin was appointed as a Whitehead Member and Assistant Professor at MIT in 2021. She began her independent career in 2016 through the Whitehead Institute Fellows program. Prior to that, Olivia completed her PhD at Case Western Reserve University under the mentorship of Dr. Peter Scacheri. In 2018, Olivia received the Avenir award to pursue her lab's studies of the genetics of substance use disorders. The Corradin Lab investigates genetic and epigenetic variation that contribute to diverse human diseases including multiple sclerosis and opioid use disorder.
Dr. Brion Maher
Dr. Brion Maher is a Professor of Mental Health and Psychiatry at Johns Hopkins University whose expertise is in genetic epidemiology and the genetics and epigenetics of substance use and psychiatric disorders. He is also Director of the NIDA Epidemiology Training Program at JHU. Dr. Maher has been Principal Investigator of multiple R01 projects focused on genetic or epigenetic of substance use disorders in human populations, including studies of epigenetic and expression changes associated with opioid use in post-mortem tissue in multiple cohorts.
Dr. Deborah Mash
Dr. Deborah Mash is a Research Professor in the Dr. Kiran C. Patel College of Allopathic Medicine at Nova Southeastern University with expertise in the neuroscience of addiction and the application of anatomic, neurochemical, and genomic methods to postmortem human brains reported in over 390 articles, monographs, and presentations at national meetings. Dr. Mash will be a Co-I on Project 2. She will lead the dissection and preparation of postmortem brain issue for this study (N=100).
Dr. Schahram Akbarian
Dr. Schahram Akbarian is Professor and head of the Division of Psychiatric Epigenomics in the Departments of Psychiatry and Neuroscience at Mount Sinai School of Medicine. He has a long track record working with the human postmortem brain and pioneered some of the first cell-type specific chromatin assays applicable to human postmortem brain. His laboratory studies epigenetic mechanism in preclinical model systems and human brain for more than 20 years. Most recently, his group has developed protocols to map chromosomal loopings and higher order chromatin in human brain tissue, and to compare 3- dimensional genome organization across different cell types and species.

Project 3

Project Overview

The goal of Project 3 (Multi-species Approach to Opioid Addiction) is to integrate human and non-human genetic and genomic datasets to identify key molecular pathways relevant o opioid addiction (OA). Integration of human and non-human data has been highlighted in numerous recent meetings as one of the most significant and enduring challenges in the field of addiction genetics. This project will use human data in Projects 1 and 2 as well as other available human datasets in conjunction with data from mice and rats.

Project Goals

  • Methods will be developed to integrate data by summarizing data at the level of genes, thus taking advantage of genes ortholog as the primary means for cross-species integration
  • Dr. Chesler will continue to develop and use GeneWeaver to identify candidate genes and pathways
  • Dr. Palmer will adapt NetColoc and Polygenic Transcriptomic Risk Scores for use with heterogeneous rat GWAS of oxycodone and heroin self-administration

Key Staff

The Multiple Principal Investigators (MPIs) of Project 3 (Drs. Elissa Chesler and Abraham Palmer) are currently Principal Investigators of a National Institute on Drug Abuse-funded Centers that use mice (Chesler) and rats (Palmer), www.ratgenes.org, to study the genetic basis of addiction-related traits.
Dr. Elissa Chesler
Dr. Elissa Chesler's research emphasizes the integration of genetic, genomic and phenomic resources to improve the ways in which behavioral traits in mice are associated with complex underlying genetics and genomics. She integrates genetic and genomic findings in model organisms including the laboratory mouse with data on human behavioral disorders using novel computational tools and approaches developed in her laboratory.
Dr. Abraham Palmer

Dr. Abraham Palmer earned his undergraduate degree in Biology at the University of Chicago (1992). He then earned a Ph.D. in Biomedical Science at the University of California San Diego (1999), where he studied the interaction of genes and behavior in rats. Dr. Palmer then did a postdoctoral fellowship in behavioral genetics at Oregon Health Sciences University, followed by a second postdoctoral fellowship in genetics and genomics at Columbia University, where he was subsequently promoted to Research Scientist (2004). In 2005 Dr. Palmer returned to the University of Chicago as an Assistant Professor of Human Genetics with a joint appointment in Psychiatry. He was promoted to Associate Professor in 2012 and to Full Professor in 2015. In 2016, Dr. Palmer moved to UCSD where is now Professor and Vice Chair for Basic Science in the Department of Psychiatry.

Dr. Palmer's research uses humans, rats, mice and zebrafish to discover genes that influence variability in behavioral phenotypes (www.palmerlab.org). His use of animal models is intended to elucidate the mechanisms by which specific genes influence behavior at the molecular, cellular and neuroanatomical levels. Dr. Palmer has published over 221 papers and book chapters. He has received grants from the National Institutes for Drug Abuse (NIDA), Mental Health (NIMH), Alcohol Abuse and Alcoholism (NIAAA), General Medical Sciences (NIGMS), the National Science Foundation (NSF) the Tobacco-Related Disease Research Program (TRDRP) and from private foundations including the Schweppe Foundation and the Brain & Behavior Research Foundation. He is currently the PI of a NIDA-funded P50 National Center of Excellence (www.ratgenes.org) as well as several R01s and U01 grants. He is a fellow of the American Association for the Advancement of Science (AAAS) and has received various awards and recognitions, including the 2020 IBANGS Senior Investigator Award and the 2022 UC San Diego Health Sciences Faculty Excellence in Mentoring Award.

Synergy Core

Project Overview

The Synergy Core (SC) supports the overall mission of IOmics-OA by coordinating a unified and rigorous approach to data analysis across the center. The SC facilitates integration across IOmics-OA projects and with OA-related efforts in the larger research community to effect scientific synergy. Research output from IOmics-OA will be distributed by the SC via mapOA, a web-based data portal providing easy exploration and acquisition of robustly QC'ed and harmonized results from all projects and ingested publicly available data. The efforts of the SC will ensure that the research community receives maximum benefit from the center.

Project Goals

  • Align IOmics-OA analyses with milestones set by the Center Steering Committee and coordinate development of analytic techniques, pipelines, standards, procedures, and documentation
  • Ingest, standardize, and analyze external OA datasets and conduct integrative analyses across IOmics-OA and external data
  • Develop mapOA, a user-friendly web-based resource for sharing of integrated OA omics within ICAN and with the broader research community

Key Staff

Eric Otto Johnson, PhD
IOmics-OA PI
Dr. Johnson is a Distinguished Fellow at RTI International with more than 25 years of experience studying genetics and epidemiology of addiction and HIV. He serves as the IOmics-OA PI, Administrative Core PD, Synergy Core Co-PD, and a Co-I on Project 1.
Nathan Gaddis, PhD
Synergy Core PI
Dr. Gaddis is a bioinformaticist and molecular biologist whose background includes extensive experience in development of data portals for biological studies and bioinformatics and computational biology analyses, including large-scale meta-analyses for the NIDA Genetics Consortium GWAS of Opioid Addiction. He serves as the Co-PD for the IOmics-OA Synergy Core.
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