Identifying genetic risk factors for mental illness and substance abuse

Genetic factors contribute strongly to risk for mental illness, explaining ~50% of risk for major depression, and as much as 90% of risk for schizophrenia and autism spectrum disorders. Identifying the specific genes that are involved in risk holds great promise for the development of new, more effective medicines. Researchers at IGS are involved in multiple projects to identify genetic risk factors for mental illness through whole-genome genotyping and sequencing of large cohorts. The Ament Lab is especially interested in identifying the contributions of rare genetic variation to risk for adult-onset psychiatric disorders. The Seneviratne Lab focuses on genetic variation to risk for alcohol and other drugs of abuse.

Elucidating disease-perturbed networks in the developing and adult brain

Interpreting genomic data in the context of biological networks is another powerful strategy to discover disease mechanisms. We use cutting-edge informatics tools to analyze high-throughput genomic data in order to develop hypotheses about mechanisms of brain diseases. Recently, we have developed methods to reconstruct gene regulatory networks in the human and mouse brain, leveraging sequence motifs, epigenomic and transcriptomic data to predict the tissue-specific binding sites and target genes for hundreds of transcription factors(TFs). We are applying these methods to predict identify master regulator TFs in psychiatric and neurodegenerative diseases. We have validated several of these hypotheses through ChIP-seq and lentiviral overexpression of TFs in animal and cellular models, and using CRISPR/Cas9 genome editing. We are eager to collaborate with experimental groups generating new trancsriptomics and epigenomic datasets. Current projects aim to elucidate gene regulatory networks in psychiatric disorders, Huntington’s disease, hearing loss, and brain development.

Modeling psychiatric disorders with human stem cells.

Pluripotent stem cells (PSCs) and PSC-derived neurons are a promising system in which to characterize phenotypes associated with the genetic variation underlying human disease. The Ament lab is using stem cells to model neurodevelopmental mechanisms by which genetic variants influence psychiatric disorders. We are utilizing genome editing in isogenic stem cell lines as well as a unique resource of patient-derived lines from deeply phenotyped Amish pedigrees with mental illnesses to investigate functional consequences of genetic variants. We are using these cell lines to test two hypotheses emerging from psychiatric genetics and systems biology studies. First, we hypothesize that psychiatric disorders involve neurodevelopmental changes in gene regulation. Second, we hypothesize that psychiatric disorders involve synaptic changes inducing neuronal hyperexcitability. Both mechanisms are predicted to alter the structure and function of the adult brain, perhaps in subtle ways.

Modeling neuropsychiatric disorders with genetically precise animal models

Animal models are essential for characterizing the effects of genes on brain function and behavior. However, early efforts to use animal models to model neurological and psychiatric disorders produced unreliable results, in part because they did not accurately model the disease-causing mutations. The discovery of rare mutations with large effects on risk, together with the development of efficient genome-editing technologies like CRISPR/Cas9 will enable us to develop a new generation of genetically precise mouse models for neuropsychiatric disorders. We are currently characterizing a ‘humanized’ knock-in mouse that carries the precise mutation observed in a large family with bipolar disorder, and we hope to expand our study to additional mutations over the next few years.

Single-cell transcriptomics

High-throughput single-cell transcriptomics has emerged as an exciting new technology to characterize gene expression in thousands of single-cells in parallel. A variation, single-nucleus RNA-seq, extends this technology to tissues that are difficult to dissociate into their component cells, including both fresh and frozen brain tissue. We are applying single-cell and single-nucleus RNA-seq to address a variety of neuroscience research questions that would have been impossible to address just a few years ago. In one study, we are characterizing trajectories from wellness to disease by profiling many thousands of single-cells from the brains of individuals with a neurodegenerative disorder, Huntington’s disease. A second study aims to characterize the effects of early life infection on postnatal brain development.

Hearing Restoration Project

The Hearing Health Foundation (HHF)’s Hearing Restoration Project (HRP) is the first international research consortium focused on investigating hair cell regeneration as a cure for hearing loss and tinnitus. The overarching principle of the HRP consortium is cross-disciplinary collaboration: open sharing of data and ideas. By having almost immediate access to each other’s data, HRP scientists are able to perform follow-up experiments much faster, rather than having to wait years until data is published. The Ament lab is responsible for integrated systems biology analyses that combine genomic data from multiple species to identify genes that may be valuable to target for regenerating cochlea hair cells. For more information, see https://hearinghealthfoundation.org/hearing-restoration-project

Integrative systems biology of Huntington's disease

Huntington's disease is a fatal neurodegnerative disease caused by mutations in the HTT gene. The goal of this project is characterize both gain- and loss-of-function effects of Huntington’s disease mutations, using cutting-edge genomic techniques such as ChIP-seq, genome sequencing of rare somatic mutations, and single-nucleus RNA-seq. The long-term goals of the project are to understand the biological mechanisms, identify biomarkers, and develop novel therapeutic targets. This project is funded by the CHDI Foundation in collaboration with Jeff Carroll's laboratory at Western Washington University.

The Bipolar Sequencing Consortium

The Bipolar Sequencing Consortium is an international consortium using data from whole genome and whole exome sequencing studies to characterize the roles of rare genetic variants in risk for bipolar disorder. Bipolar disorder is a severe psychiatric disorder, characterized by alternation between episodes of elated or agitated mania and depression and affected 1-2% of the population worldwide. Identifying rare mutations with large effects on disease risk would accelerate the discovery of disease mechanisms and could lead to new ways of treating this disorder. This project is supported by a grant from the National Institute of Mental Health, in collaboration with researchers at Johns Hopkins University and researchers from four continents.

Pharmacogenomics of medications tested for substance use disorders

The pharmacogenomics of substance use disorders (SUD) describes the genetics of individual differences in the absorption, distribution, metabolism and/or excretion of a drug as well as individual differences in drug targets, such as the G-protein coupled receptors, transporters, and ligand-gated ion channels that are the primary targets of many drugs of abuse, and “higher order” pharmacogenomics that provide individual differences in post-receptor drug responses. Such post-receptor drug responses are more likely to be common to the actions of abused substances that come from several different chemical classes and act at distinct primary receptor or transporter sites in the brain and other organ systems. We hypothesize that, established medications targeting these receptor systems can be re-purposed to develop more efficacious treatments for substance use disorders by identifying sub-populations of individuals carrying specific genetic variations that may alter their functions. The Seneviratne lab, in collaboration with other clinical researchers, is involved in identifying pharmacogenomic targets and testing them in clinical trials that assign treatments in a random and prospective manner to research volunteers with substance use disorders, based on their carrier status for specific genetic markers. We are also involved in retrospective analysis of clinical samples (research) for identifying novel pharmacogenomic markers for various treatments tested for SUDs, using whole-genome RNA and DNA sequencing techniques.