Spatial Mapping of Genetic Liability to Psychiatric Disorders in the Adult Human Hippocampus

Background: Common genetic variants associated with psychiatric disorders are enriched in genes with high expression specificity for hippocampal neurons. However, to date, these studies have been based on measures of gene expression from nuclei in liquid suspensions, where information on the precise location of cells within the assayed tissue is lost. Methods: We applied genetically informed spatial mapping of cells for complex traits (gsMAP) to test enrichment of common-variant genetic liability to schizophrenia, bipolar disorder, and major depressive disorder (MDD) in 13 hippocampal subregions according to expression specificity of associated genes using spatial transcriptomic (ST) data from 10 neurotypical adult donors. Then we used cellular deconvolution data from ST spots to perform further gsMAP analyses on cell populations within enriched subregions. Results: Compared with other hippocampal subregions, common-variant liability to schizophrenia, bipolar disorder, and, to a lesser extent, MDD, was significantly enriched in genes with higher expression specificity for the subiculum and neuron-rich areas of the cornu ammonis subfields and dentate gyrus. Within implicated regions, enrichments for schizophrenia and bipolar disorder were pronounced in ST spots containing glutamatergic neurons. Genes with higher expression specificity for the granule cell layer and subgranular zone of the dentate gyrus were more significantly enriched for association with bipolar disorder than for schizophrenia. Conclusions: Our findings support a role for glutamatergic neurons in all major subregions of the hippocampus in mediating common-variant liability to schizophrenia and bipolar disorder and provide evidence for the greater relative importance of the dentate gyrus in bipolar disorder.