Precision brain charts for imaging-genomics of schizophrenia and the psychosis spectrum

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ABSTRACT An unmet need for psychiatric neuroimaging is a standard developmental frame of reference to benchmark studies of neurodevelopmental conditions such as schizophrenia the psychosis spectrum (PS). Using a modelling approach that has proven successful for non-imaging growth charts in clinical pediatrics, and in our preliminary work that was focused on a limited set of global brain MRI features, we propose to leverage data from our multi-site Brain Chart Consortium to produce computational charts of brain maturation for a far richer set of brain morphological features across anatomical scales. Our Consortium aims to be the largest and most inclusive possible, with preliminary data covering the entire lifespan, over 130,000 MRI scans, over 100,000 individuals and over 300 MR scanners. Using advanced, fully-reproducible pipelines for quality control, image processing and harmonization, multi-scale brain charts will define normative trends and milestones of growth which can be used to benchmark a new individual brain scan, or group of scans, while controlling for study- specific technical confounds. We will create and maintain an open resource to disseminate these charts for use by other researchers. We will use brain charts to identify clusters of developmental imaging phenotypes – brain profiles benchmarked by growth chart norms – with similarly-shaped maturational trajectories. Longitudinal analysis of twin datasets will specifically delineate heritable brain profiles, which we hypothesize will show genotype-by-age effects organized along the sensory-to-association (SA) axis of cortical maturation, in developmental epochs where risk for PS is hypothesized to emerge (Aim 1). We will perform genome- and transcriptome-wide association studies to identify brain profiles that are influenced by functionally active genetic variants associated with risk for PS (Aim 2). We will perform brain profile subtyping of individuals with PS diagnoses in our Consortium case-control studies (over 2000 MRIs), to characterize a PS subtype where deviations are most prominent along the SA axis in association cortices that undergo prolonged maturation through adolescence. Any individual’s chart-benchmarked brain profile, in a new study, can thus be characterized with a loading score that quantifies similarity to this PS subtype, and we will evaluate the association of the PS subtype loading score with the evolution of PS symptoms across multiple longitudinal follow-up studies of PS conducted at the University of Pennsylvania (over 2200 longitudinal MRIs, 800 participants, 450 with PS, age 8-35) that will be pooled and harmonized for this proposal (Aim 3). This proposal’s overarching goal is to create a practically useful brain chart resource and to demonstrate its transformative potential for studies of brain development in PS. This work capitalizes on the PI and assembled team’s expertise in psychiatric and developmental brain imaging, imaging-genetics and neuroinformatics. Cumulatively, the proposed research will provide a substantial advance in our understanding of typical brain development and altered neurodevelopment in PS.