Maximizing the Potential of Whole Genome Sequencing in Psychiatry: Deep Phenotyping, Extended Pedigrees and Extreme Traits

The landscape of psychiatric genetics, like that of other complex genetic phenotypes, is undergoing a transformative shift with the increased availability of Whole Genome Sequencing (WGS). WGS allows one to detect rare genetic mutations at any position in the genome, allowing for an unprecedented complete genomic characterization of an individual. However, by their very nature, rare genetic mutations are difficult to study as they either require very large samples or experimental approaches that differ from the current case-control zeitgeist. After reviewing the current state of psychiatric genetics, my talk delves into alternate strategies and methodologies aimed at harnessing the full potential of WGS in psychiatry. First, the discussion revolves around the importance of Deep Phenotyping, emphasizing the need for detailed and nuanced clinical characterization, coupled with neurocognitive, environmental, trauma and, when possible, neuroimaging assessments. By incorporating a wealth of phenotypic data, we aim to unravel the intricate interplay between genetic variations and psychiatric manifestations, fostering a more personalized and precise approach to diagnosis and treatment. The integration of comprehensive phenotyping with Extended Pedigrees provides an unprecedented opportunity to trace the heritability of and genetic relationships between psychiatric traits and allied phenotypes of endophenotypes across multiple generations. This approach enables the identification of rare variants and facilitates the understanding of complex inheritance patterns, thereby enriching our understanding of the genetic underpinnings of psychiatric conditions. Finally, a focus on Extreme Traits (Phenotypes) provides an additional strategy for maximining rare genetic signals. By scrutinizing individuals with uncommon or severe psychiatric conditions, we can uncover unique genetic markers and pathways that may hold the key to unlocking broader insights into the genetic architecture of common psychiatric disorders. By adopting a multifaceted approach with various experimental designs, we aim to pave the way for advancements in diagnosis, treatment, and the overall understanding of psychiatric disorders at the genetic level.

David Glahn, PhD, is a Professor at Harvard Medical School and serves as the Chief for Research in the Department of Psychiatry at Boston Children’s Hospital (BCH). Within BCH, he leads the Tommy Fuss Center for Developmental Neuropsychiatric Disease Research and the Early Psychosis Investigation Center. Dr. Glahn earned a PhD in clinical psychology from the University of Pennsylvania, undertook a postdoctoral fellowship at UCLA, and held faculty positions at the University of Texas Health Science Center San Antonio and Yale University before joining Harvard/BCH in 2018. The overarching goals of Dr. Glahn's research program are twofold. First, he aims to elucidate the biological antecedents of psychotic and affective disorders by integrating a diverse array of data, including clinical, cognitive, developmental, neuroimaging, peripheral blood, and molecular genetic information. Second, his research strives to determine the impact of genetic and environmental variation on normative brain structure and function throughout the lifespan. Dr. Glahn's has published of over 400 peer-reviewed papers. He oversees a research team comprising junior faculty, postdoctoral fellows, graduate students, and research assistants, totaling 15 members. He has been consistently funded by the National Institutes of Health (NIH) since 2004. Dr. Glahn's collaborates extensively with investigators locally, nationally, and internationally, fostering a network of researchers committed to pushing the boundaries of neuropsychiatric research.