Abstract
Inhibitory interneurons orchestrate information flow across cortex and are implicated in psychiatric illness. Although classes of interneurons have unique functional properties and spatial distributions throughout the brain, the relative influence of interneuron subtypes on brain function, cortical specialization, and illness risk remains elusive. Here, we demonstrate stereotyped organizational properties of somatostatin and parvalbumin related transcripts within human and non-human primates. Interneuron spatial distributions recapitulate cortico-striato-thalamic functional networks and track regional differences in functional MRI signal amplitude. In the general population (n=9,627), parvalbumin-linked genes account for an enriched proportion of genome-wide heritable variance in in-vivo functional MRI signal amplitude. This relationship is spatially dependent, following the topographic organization of parvalbumin expression in independent post-mortem brain tissue. Finally, genetic risk for schizophrenia is enriched among interneuron-linked genes and predictive of cortical signal amplitude in parvalbumin-biased regions. These data indicate that the molecular genetic basis of resting-state brain function across cortex is shaped by the spatial distribution of interneuron-related transcripts and underlies individual differences in risk for schizophrenia.
Key Findings
Spatial distributions of somatostatin (SST) and parvalbumin (PVALB) are negatively correlated in mature human and non-human primate cortex, paralleling patterns observed in utero.
SST and PVALB are differentially expressed within distinct limbic and somato/motor cortico-striato-thalamic networks, respectively.
In-vivo resting-state signal amplitude is heritable in the general population and tracks relative SST/PVALB expression across cortex.
Single-nucleotide polymorphisms tied to PVALB-related genes account for an enriched proportion of the heritable variance in resting-state signal amplitude.
PVALB-mediated heritability of resting-state signal amplitude in the general population is spatially heterogeneous, mirroring the cortical expression of PVALB in independent post-mortem brain tissue.
Polygenic risk for schizophrenia is enriched among interneuron-linked genes and predicts resting-state signal amplitude in a manner that also follows the cortical expression of PVALB.
Author contributions. KMA and AJH designed the research. KMA conducted the research. MAC, RC, MDR, TG provided analytic support. KMA and AJH wrote the manuscript and made figures. All authors edited the manuscript.
Acknowledgements
This work was supported by the National Institute of Mental Health (Grant K01MH099232 to A.J.H.), the National Science Foundation (DGE-1122492 to K.M.A.), and the National Institute on Aging (K99AG054573 to T.G.). Analyses were made possible by the high-performance computing facilities provided through the Yale Center for Research Computing. We thank B.J. Casey, Danielle Gerhard, Lauren Patrick, and Erica Ho for their feedback on early versions of the project. This work used data from the Allen Institute for Brain Science, NIH Blueprint Non-Human Primate Atlas, CommonMind Consortium, Brainspan Atlas of the Developing Human Brain, and has been conducted using the UK Biobank Resource under Application Number 25163. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 01/16/2018.