DCM&B Seminar: Gerald Higgins, MD, PhD, University of Michigan

Title: Psychiatric Pharmacogenomics: Clinical Translation and Novel Variant Discovery Abstract: The benefit of pharmacogenomic testing and decision support has not been well established, although some evidence has emerged to support its utility in psychiatric practice.  Medications prescribed in psychiatry lead to approximately 90,000 visits to emergency departments on an annual basis in the U.S., and psychotropic drugs used in psychiatry, neurology and anesthesiology account for almost a third of the FDA’s precaution labels based on pharmacogenomics.  Not only has the pace of new CNS drug discovery slowed since the turn of the century, but also thousands of published gene association studies in neuropharmacology are primarily based on a few dozen exon variants in a handful of genes.  Recent advances in our understanding of transcriptional regulation in the context of the spatial organization of the human genome, including the role of noncoding regulatory mechanisms and the epigenome, are being used to render challenges in psychiatric pharmacogenomics more tractable.   For example, chromatin conformation capture methods have revealed the four-dimensional (4D) organization of the nucleus, bringing interactions between distant regulatory elements into close proximity in a periodic manner.  We have used computational approaches based on this pharmacoepigenomic paradigm to elucidate mechanisms of CNS drug response and side effects that have previously been unrecognized.  These include discovery of putative pharmacodynamic pathways that underlie lithium response in bipolar disorder, adverse events related to antipsychotic medications, and novel mechanisms of antidepressant response.