Genetic identification of brain cell types underlying schizophrenia

Abstract

With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. By applying knowledge of the cellular taxonomy of the brain from single-cell RNA sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. We found that the common-variant genomic results consistently mapped to pyramidal cells, medium spiny neurons (MSNs) and certain interneurons, but far less consistently to embryonic, progenitor or glial cells. These enrichments were due to sets of genes that were specifically expressed in each of these cell types. We also found that many of the diverse gene sets previously associated with schizophrenia (genes involved in synaptic function, those encoding mRNAs that interact with FMRP, antipsychotic targets, etc.) generally implicated the same brain cell types. Our results suggest a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. The genetic risk associated with MSNs did not overlap with that of glutamatergic pyramidal cells and interneurons, suggesting that different cell types have biologically distinct roles in schizophrenia.

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Fig. 1: Specificity metric calculated from single-cell transcriptome sequencing data can be used to test for increased burden of schizophrenia-SNP heritability in brain cell types.
Fig. 2: Evaluation of enrichment of common-variant CLOZUK schizophrenia GWAS results in the KI brain scRNA-seq dataset from mouse.
Fig. 3: Comparison of scRNA-seq and snRNA-seq, and evaluation of enrichment of common-variant CLOZUK schizophrenia genome-wide association results in brain snRNA-seq datasets from adult humans.
Fig. 4: Cell-type enrichment of gene sets associated with schizophrenia, neurological disorders and the evolutionary divergence between human and mouse.
Fig. 5: CA1 pyramidal neurons, medium spiny neurons and cortical interneurons are independently associated with schizophrenia, and distinct molecular pathways contribute to each cell type.

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Acknowledgements

J.H.-L. was funded by the Swedish Research Council (Vetenskapsrådet, award 2014-3863), StratNeuro, the Wellcome Trust (108726/Z/15/Z) and the Swedish Brain Foundation (Hjärnfonden). P.F.S. gratefully acknowledges support from the Swedish Research Council (Vetenskapsrådet, award D0886501). N.G.S. was supported by the Wellcome Trust (108726/Z/15/Z). J.B. was supported by the Swiss National Science Foundation. The PGC has received major funding from the US National Institute of Mental Health (U01 MH109528 and U01 MH109532). H.A.G. was supported by PGC grant 1U01MH109514-01. Primary schizophrenia GWAS data were generated with support from the Medical Research Council (MRC) Centre (MR/L010305/1), program grant G0800509 and project grant MR/L011794/1, and funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 279227 (CRESTAR Consortium).

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N.G.S., J.B., P.F.S. and J.H.-L. designed the study and wrote and reviewed the manuscript; N.G.S. performed the LDSC analyses; J.B. performed the MAGMA analyses; T.E.B., R.D.H., J.A.M. and E.S.L. generated the human mid-temporal cortex data; A.B.M.-M., J.R., S.L. and J.H.-L. generated the KI single-cell data; the Major Depressive Disorder Working Group of the PGC performed the MDD GWAS; J.T.R.W., J.J.C., P.G.-R., M.C.O., M.J.O. and A.F.P. performed the schizophrenia CLOZUK GWAS; G.B. and H.A.G. analyzed the antipsychotic drug targets; and all authors read and approved the manuscript.

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Correspondence to Patrick F. Sullivan or Jens Hjerling-Leffler.

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P.F.S. is on the advisory committee at Lundbeck, is a Scientific Advisory Board member at Pfizer and has received speaker reimbursement and grant funding from Roche. J.H.-L. is a Scientific Advisor at Cartana and has received grant funding from Roche.

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Supplementary Table 4

Specificity values for Karolinska scRNA-seq superset

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Skene, N.G., Bryois, J., Bakken, T.E. et al. Genetic identification of brain cell types underlying schizophrenia. Nat Genet 50, 825–833 (2018). https://doi.org/10.1038/s41588-018-0129-5

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