Transcriptional and imaging-genetic association of cortical interneurons, brain function, and schizophrenia risk

Kevin M Anderson,Avram J Holmes,Rowena Chin,Meghan A Collins,Monica D Rosenberg,Tian Ge

doi:10.1038/s41467-020-16710-x

Abstract

Inhibitory interneurons orchestrate information flow across the cortex and are implicated in psychiatric illness. Although interneuron classes have unique functional properties and spatial distributions, the influence of interneuron subtypes on brain function, cortical specialization, and illness risk remains elusive. Here, we demonstrate stereotyped negative correlation of somatostatin and parvalbumin transcripts within human and non-human primates. Cortical distributions of somatostatin and parvalbumin cell gene markers are strongly coupled to regional differences in functional MRI variability. In the general population (n = 9,713), parvalbumin-linked genes account for an enriched proportion of heritable variance in in-vivo functional MRI signal amplitude. Single-marker and polygenic cell deconvolution establish that this relationship is spatially dependent, following the topography of parvalbumin expression in post-mortem brain tissue. Finally, schizophrenia genetic risk is enriched among interneuron-linked genes and predicts cortical signal amplitude in parvalbumin-biased regions. These data indicate that the molecular-genetic basis of brain function is shaped by interneuron-related transcripts and may capture individual differences in schizophrenia risk.

Highlights

Inhibitory interneurons orchestrate information flow across the cortex and are implicated in psychiatric illness
Prior research suggests that SST and PVALB markers are differentially expressed across cortex[9,10], the current work directly establishes transcriptional anti-correlation between these two cell types across multiple techniques, human datasets, non-human primate data, and human neurodevelopment
Integrating genetic, transcriptional, and neuroimaging data, we demonstrate that spatial distributions of interneurons are stereotyped across species and development, and explain a substantial portion of the heritable variation in resting-state functional amplitude (RSFA), a measure of in-vivo brain activity

Summary

Introduction

Inhibitory interneurons orchestrate information flow across the cortex and are implicated in psychiatric illness. Schizophrenia genetic risk is enriched among interneuron-linked genes and predicts cortical signal amplitude in parvalbumin-biased regions These data indicate that the molecular-genetic basis of brain function is shaped by interneuron-related transcripts and may capture individual differences in schizophrenia risk. The transcriptional correlates of brain function have rarely been validated in-vivo[6] and little is known about how the spatial distribution of specific interneuron subtypes shapes cortical function and associated risk for psychiatric illness in humans. SST and PVALB interneuron markers are differentially expressed within distributed limbic and somato-motor cortico-striatal networks, respectively[9] These observations suggest that spatial distributions of interneuron subtypes could underlie regional signaling differences across the cortical sheet, as indexed by blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI). Linking cortical interneurons to individual differences in human brain function would yield deep biological insight into the hemodynamic BOLD signal, providing an engine for the discovery of functional connectome-linked genes and associated risk for illness onset

Methods

Results

Conclusion