A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment

Abstract

There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during mid-gestation. This epoch is supported by partitioning cross-disorder single-nucleotide polymorphism heritability, which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.

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Fig. 1: SNP heritability and genetic correlation estimates for iPSYCH indications.
Fig. 2: Cross-diagnosis genome-wide association study results.
Fig. 3: Consistency of effects in independent studies.
Fig. 4: LDSC-SEG heritability partitioning.
Fig. 5: Candidate geneset enrichments for neurodevelopmental processes.

Code availability

Code and scripts available by request from authors.

Data availability

In accordance with the consent structure of iPSYCH and Danish law, individual level genotype and phenotype data are not able to be shared publicly. Cross-disorder (XDX) GWAS summary statistics are available for download (https://ipsych.au.dk/downloads/). Summary statistics from secondary GWAS of single disorders are available upon request from the corresponding author. BrainSpan RNA data are available in the GEO with the accession code GSE25219. Fetal Brain Hi-C data are available in the GEO with the accession code GSE77565.

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Acknowledgments

The iPSYCH Initiative is funded by the Lundbeck Foundation (grant nos. R102-A9118 and R155-2014-1724), the Mental Health Services Capital Region of Denmark, University of Copenhagen, Aarhus University and the university hospital in Aarhus. Genotyping of iPSYCH samples was supported by grants from the Lundbeck Foundation, the Stanley Foundation, the Simons Foundation (SFARI 311789) and NIMH (5U01MH094432-02). The iPSYCH Initiative use the Danish National Biobank resource that is supported by the Novo Nordisk Foundation. iPSYCH data was stored and analysed at the Computerome HPC facility (http://www.computerome.dtu.dk/) and the authors are grateful for continuous support from the HPC team led by A. Syed of DTU Bioinformatics, Technical University of Denmark. The following grants provided support for this work: NIH grant nos. R00MH113823 (H.W.), R01GM104400 (W.K.T.), 1R01MH109912 (D.G.), 1R01MH110927 (D.G.) and 1R01MH094714 (D.G.). Australian National Health and Medical Research Council grant nos. 1113400, 1078901, 1087889 (N.R.W).

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D.G. and T.W. conceived of and supervised the study. A.J.S., H.W., D.G. and T.W. designed the analysis plan. A.J.S., V.A., A.B and W.K.T. prepared the data. A.J.S. performed the GWAS, (partitioned) SNP-(co)heritability, fine mapping and replication analyses. H.W. performed the candidate gene identification and enrichment analyses. R.N., M.G. and N.R.W. provided interpretive support. O.D. contributed imputation software and protocols. M.R.C. contributed analytic support. D.M.H., M.B.-H., J.B.-G., M.G.P., E.A., C.B.P., B.M.N., M.J.D., M.N., O.M., A.D.B., P.B.M. and T.W. designed, implemented and/or oversaw the collection and generation of the iPSYCH data. A.J.S., H.W., D.G. and T.W. wrote the manuscript. All authors discussed the results and contributed to the revision of the manuscript.

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Correspondence to Thomas Werge.

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Schork, A.J., Won, H., Appadurai, V. et al. A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment. Nat Neurosci 22, 353–361 (2019). https://doi.org/10.1038/s41593-018-0320-0

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