Section on Developmental Neurogenomics

Armin Raznahan, MD PhD, Chief

The Section on Developmental Neurogenomics (SDN) is dedicated to better understanding the biology of pediatric-onset neuropsychiatric disorders in ways that might ultimately help to improve disease prediction, detection and treatment. We work towards this goal through the interwoven three research themes detailed below. All three themes integrate complementary research approaches (clinical work, computational biology and wet-lab) and data modalities (behavioral, neuroimaging and molecular data) to cycle between connected questions in basic and clinical neuroscience.

Theme 1. Studying rare gene dosage disorders (GDDs) that increase risk for mental health difficulties. We see rare GDDs as important medical conditions in their own right, and powerful opportunities to model mechanisms of genetic risk in psychiatry.  We are particularly interested in dosage alterations of the X- and Y-chromosome  (see our clinical study in Sex Chromosome Aneuploidies), but we also incorporate data from many other GDDs. We study GDDs through a “comparative deep-phenotyping” approach which emphasizes the value of having a common set of high-dimensional measures in different genetic cohorts – spanning clinical, neuroimaging and cellular phenotypes. We use these rich data to resolve the architecture of phenotypic variation within and between different GDDs. This research approach improves understanding of each individual GDD studied, and also uncovers broader organizing principles for the way genetic variation shapes human brain organization to modify psychiatric risk.

Theme 2. Studying sex as a neurobiological variable that influences psychiatric risk. Many psychiatric disorders show profound sex differences in their prevalence, symptomatology and course. These differences are likely shaped by a complex mix of societal, psychological and biological factors. We reason that characterizing sex-differences in human brain organization may identify pathways that are enriched for determinants of psychiatric risk and resiliency. In pursuing this research we pay special attention to the distinction between sex (a biological concept) and gender (a societal construct). We use a combination of behavioral, neuroimaging and postmortem-derived -omic data to map normative sex-differences in the human brain and intersect these differences with findings from psychiatric research. We are particularly interested in the potential role of gonads and sex chromosomes in shaping brain sex differences, so we complement our human studies with collaborative studies using mouse models that provide experimental control of these factors.

Theme 3. Developing and applying tools to bridge different levels of human brain organization. Many questions in basic and clinical questions regarding the human brain are best addressed using observations from a large number of individuals. To date, in vivo neuroimaging provides the main means of measuring the human brain at scale, but this technology offers very little information on cellular and molecular aspects of brain organization.  These microscale components of the brain are typically accessed through smaller postmortem datasets lacking brain-wide coverage. An integrated view of the brain requires an ability to connect and move between these macro- and micro-scale views of the human brain. We therefore develop and apply tools for aligning brain maps from neuroimaging and postmortem data – enabling the “decoding” of neuroimaging maps into correlated microscale features, and the “projection” of genetic information into neuroanatomical space. We use this flexible bridge to build multi-level models of the human brain in health, and refine hypothesis regarding the biological bases of psychiatric risk.