Research

Our research leverages genetic and genomic tools to identify the underlying neurobiological mechanisms and novel therapeutic targets for neurodevelopmental and psychiatric disorders, including autism and schizophrenia. Further, we strive to translate biological insights from basic research into the clinic.

Research Projects

Defining the Cellular and Molecular Neuropathology in Autism

We profile human brain tissue samples using genomic sequencing, including bulk and single cell RNA-sequencing, to characterize the brain-level molecular pathology of major neuropsychiatric disorders, including autism (ASD), schizophrenia, bipolar disorder, and depression. Our work has identified patterns of shared and distinct transcriptomic changes across disorders, including shared neuronal and synaptic pathways downregulated in ASD, schizophrenia, and bipolar disorder, activation of astrocytes in ASD and schizophrenia, and upregulation of microglia in ASD.

See: Gandal et al., Science 2018a;  Gandal, Haney, Wamsley et al., Nature 2022

Human Brain Integrative Genomics to Prioritize Psychiatric Risk Genes

Large-scale genetic association studies have identified hundreds of loci associated with neurodevelopmental, psychiatric disorders but the vast majority of these variants lie in non-coding regions of the genome. Consequently, the target genes and mechanisms through which these variant remain largely unknown. To address this, we develop large-scale functional genomic reference panels using human brain tissue samples which we integrate with GWAS associations to prioritize candidate risk genes.

See: Gandal et al., Science, 2018b ; Walker et al., Cell 2019

Isoform-Level Functional Mapping of Psychiatric GWAS

Identifying the biological mechanisms through which disease-associated genetic variants impart risk remains among the major challenges for GWAS. To address this, TWAS and related approaches integrate GWAS associations with tissue-specific eQTL to prioritize candidate risk genes. Most previous work, however, has been gene-centric, largely ignoring the many distinct transcript-isoforms that can be generated from a single gene. Here, in collaboration with Bogdan Pasaniuc, we are working to extend the statistical genetic framework of TWAS to capture and probabilistically fine-map associations at the transcript-isoform level. 

See: Bhattacharya et al., medRxiv 2022

Neural-Immune Contributions to Psychiatric Traits

Substantial epidemiologic associations have been observed between psychiatric diagnoses, family history of autoimmune disorders, and early infectious exposures. We are integrating results from human brain RNA-seq with imaging genetics in large-scale population biobanks to identify the mechanistic underpinnings for these neural-immune-psychiatric connections.

See: Kim et al., Nature Neuroscience 2021

Systems-Level and Integrative Genomics in Brain

We use a variety of systems-level, network-based approaches to capture meaningful biological signals from large-scale datasets. 

See: Hernandez, Biological Psychiatry 2021; Parikshak et al., Nat Rev Genetics, 2015