UCLA

Psychiatric disorders are not well understood. Their diagnosis is based purely on behavioral symptoms and they lack a clearly defined pathology in brain, which challenges our ability to understand their biological roots. However, it is well established that psychiatric disorders are heritable, and large-scale genetic studies have begun to identify now thousands of psychiatric genetic risk variants.1 Discovering how these genetic variants converge within discrete neurobiological pathways is a critical next step for understanding psychiatric disorder mechanisms and identifying new targets for therapeutic development. In search for these convergent pathways, transcriptomic studies have started to identify gene expression changes within human postmortem brain samples from psychiatric patients compared to neurotypical controls. The transcriptome – the set of expressed RNA transcripts present in a given tissue or cellular samples – represents a snapshot of the cell-types and subcellular, molecular processes present and active in sequenced samples. As such, transcriptomic profiling of brain samples from psychiatric cases versus controls may provide increased resolution to identify a molecular pathology of disease not observed via traditional approaches. For example, in ASD, upregulation of microglial, astrocyte, and immune signaling genes, downregulation of specific synaptic genes, and attenuation of regional gene expression differences have been observed with transcriptomic analyses.2,3 While transcriptomic studies have substantially improved our understanding of psychiatric neuropathology, they are limited in scope to single psychiatric disorders and few brain regions. Considering the growing evidence for genetic overlap between distinct psychiatric disorders,4 it is a reasonable next step to determine if these disorders also share biological signatures in the brain. Comparing and contrasting gene expression changes across distinct psychiatric disorders – as well as across the entire cerebral cortex - will provide a fuller picture of the spatial landscape and specificity of molecular dysregulation in the psychiatric disease brain, pinpointing potential regions of particular vulnerability and biological pathways involved in psychiatric disease mechanisms.

To obtain this cross-disorder and multi-regional understanding of psychiatric gene expression changes, here I present a comprehensive set of transcriptomic investigations conducted by myself and others, spanning multiple psychiatric disorders and brain regions. In Chapter 2, I share our published mega-analysis of gene expression microarray datasets containing frontal cortex samples from subjects diagnosed with schizophrenia, bipolar disorder, ASD, and major depressive disorder subjects, compared with non-psychiatric controls.5 We find that polygenic overlap parallels transcriptomic overlap, and that psychiatric genetic risk variants are associated with downregulated neuronal genes found in ASD, schizophrenia, and bipolar disorder. In Chapter 3, I present my contributions to our published collaborative work with the PsychENCODE Consortium,6 in which we compiled and uniformly processed genotype and RNA-sequencing data from more than 2,000 postmortem human brain samples to gain an understanding of how the entire transcriptome is impacted in frontal cortex samples from subjects diagnosed with schizophrenia, bipolar disorder, and ASD. Here, I detail my work integrating polygenic risk scores --measures of common genetic burden for psychiatric disease -- with transcriptomic changes to obtain a deeper understanding of how genetic variants directly regulate psychiatric gene expression changes. In Chapter 4, I present our work characterizing ASD transcriptomic across 11 distinct regions spanning the ASD cerebral cortex. We find widespread dysregulation across the cerebral cortex, with this dysregulation exhibiting the greatest magnitude of effect in the occipital region. ASD genetic risk variants are associated with genes downregulated cortex-wide that contribute to neuronal synaptic plasticity pathways, heavily implicating neuronal synaptic plasticity in ASD neuropathology. Together, these transcriptomic analyses expand our understanding of the molecular pathology of psychiatric disorders across distinct disorders and the cerebral cortex, implicating specific genes, cell-types, and biological pathways in psychiatric neuropathology.

Abstract Bibliography1. Sullivan, P. F. & Geschwind, D. H. Defining the Genetic, Genomic, Cellular, and Diagnostic Architectures of Psychiatric Disorders. Cell 177, 162–183 (2019). 2. I. Voineagu et al., Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 474, 380–384 (2011). 3. Parikshak, N. N. et al. Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism. Nature 540, 423–427 (2016). 4. Bulik-Sullivan, B., Finucane, H., Anttila, V. et al. An atlas of genetic correlations across human diseases and traits. Nat Genet 47, 1236–1241 (2015). 5. Gandal, M. J. et al. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science 359, 693–697 (2018). 6. Gandal, M. J. et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science 362, (2018).