Biomedical Data Science Seminar Series, BRB Gaulton Auditorium

Title: Multiscale Neurogenomics : Mapping Gene Dosage Disorders Across Phenotypic Layers

This week hosted by the Center for AI and Data Science for Integrated Diagnostics (AI2D) – Theodore Satterthwaite, PhD

Abstract

Gene dosage disorders (GDDs) – including aneuploidies and sub-chromosomal copy number variations (CNVs) – offer powerful objective footholds in the complex biology of neurodevelopmental disorders. Phenotypic characterization of GDDs – especially when comparing different GDDs and considering multiple phenotypic layers in parallel – has the potential to illuminate mechanism of risk for common psychiatric presentations and may also provide a path to advances in precision psychiatry. At the same time, research in GDDs can inform our basic science understanding by serving as a quasi-experimental probe for dissecting the architecture of human brains and behaviors. This talk will unpack these ideas by presenting two complementary streams of research from the NIMH Intramural Program Section on Developmental Neurogenomics. I will first present our findings from deep-phenotypic comparisons of different GDDs using high-dimensional measures of behavior and brain anatomy. This work develops new ways of characterizing the complex psychiatric presentations of GDDs and uses these approaches to delineate shared and divergent clinical features between different GDDs. Complementary comparisons of brain organization in GDDs using multimodal neuroimaging data reveal how dosage alterations of different gene sets can induce highly distinctive fingerprints of brain change, but that amongst this variegation there is a shared axis of human brain vulnerability to rare genetic disorders which aligns with shared brain changes in common behaviorally defined neurodevelopmental disorders. I will then present new work which develops a normative framework for integrating multiscale measures of the human brain in health – spanning in vivo neuroimaging data and postmortem maps of gene expression proxies for cortical layers, cells and subcellular compartments. This normative framework helps to contextualize and fractionate known genetic risks for neurodevelopmental disorders, such that the intrinsic spatial expression patterns of some risk genes can predicts the spatial patterning of altered gene expression and brain anatomy in patients.  By combining these two synergistic lines of research – deep phenotypic studies in patients with GDDs and neuroinformatic annotation of known risk genes – we hope to both prioritize biological pathways that concentrate genetic risk for neuropsychiatric disorders, and better understand the clinical consequences of genetic risk in ways that might improve care.

Bio

Armin Raznahan, is a child and adolescent psychiatrist, and Chief of the Section on Developmental Neurogenomics (SDN). The SDN research program combines neuroimaging, genomic and bioinformatic techniques to better understand the architecture of human brain development in health, and in neurogenetic disorders that increase risk for psychiatric symptoms. Dr. Raznahan completed his undergraduate and graduate training in London, UK (Medicine and pediatrics at King’s College University/ Hospital; psychiatry and the Maudsley Hospital), and then trained as a postdoctoral fellow with Drs. Jay Giedd and Judith Rapoport at the NIMH Intramural Research Program. Dr. Raznahan joined the NIH-Lasker Clinical Research Scholars Program in 2015 and became a tenured Senior Investigator at the NIMH IRP in 2020. Dr. Raznahan is a member of the UK Royal College of Psychiatrists, the UK Royal College of Pediatrics and Child Health, and the American College of Neuropsychopharmacology (ACNP). He currently serves on the Editorial Board of NeuroImage, the ACNP Membership Committee, and the AXYS (Association for X- and Y-Chromosome Variations) Clinical & Research Advisory Committee. Dr. Raznahan has received the NIMH Director’s Award for Outstanding Mentorship, as well as awards from ACNP (Eva King-Killam Award for Translational Research) and the American Psychopathological Association (Robins-Guze Award).