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

Nature Neuroscience volume 22, pages 353–361 (2019)Cite this article

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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.

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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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Authors and Affiliations

  1. Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark

    Andrew J. Schork, Vivek Appadurai, Ron Nudel, Alfonso Buil, Wesley K. Thompson & Thomas Werge

  2. The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark

    Andrew J. Schork, Vivek Appadurai, Ron Nudel, David M. Hougaard, Marie Bækved-Hansen, Jonas Bybjerg-Grauholm, Marianne Giørtz Pedersen, Esben Agerbo, Carsten Bøcker Pedersen, Merete Nordentoft, Ole Mors, Anders D. Børglum, Preben Bo Mortensen, Alfonso Buil, Wesley K. Thompson & Thomas Werge

  3. Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA

    Hyejung Won, Mike Gandal & Daniel H. Geschwind

  4. Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA

    Hyejung Won, Mike Gandal & Daniel H. Geschwind

  5. Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Hyejung Won, Mike Gandal & Daniel H. Geschwind

  6. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    Hyejung Won

  7. UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA

    Hyejung Won

  8. Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland

    Olivier Delaneau

  9. Swiss Institute of Bioinformatics (SIB), University of Geneva, Geneva, Switzerland

    Olivier Delaneau

  10. Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland

    Olivier Delaneau

  11. DTU Bioinformatics, Technical University of Denmark, Lyngby, Denmark

    Malene Revsbech Christiansen

  12. Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark

    David M. Hougaard, Marie Bækved-Hansen & Jonas Bybjerg-Grauholm

  13. NCRR - National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark

    Marianne Giørtz Pedersen, Esben Agerbo, Carsten Bøcker Pedersen & Preben Bo Mortensen

  14. Centre for Integrated Register-based Research (CIRRAU), Aarhus University, Aarhus, Denmark

    Marianne Giørtz Pedersen, Esben Agerbo, Carsten Bøcker Pedersen & Preben Bo Mortensen

  15. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA

    Benjamin M. Neale & Mark J. Daly

  16. Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Benjamin M. Neale & Mark J. Daly

  17. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Benjamin M. Neale & Mark J. Daly

  18. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia

    Naomi R. Wray

  19. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia

    Naomi R. Wray

  20. Copenhagen Mental Health Center, Mental Health Services Capital Region of Denmark Copenhagen, Copenhagen, Denmark

    Merete Nordentoft

  21. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Merete Nordentoft & Thomas Werge

  22. Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark

    Ole Mors

  23. Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark

    Anders D. Børglum

  24. Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark

    Anders D. Børglum & Preben Bo Mortensen

  25. Division of Biostatistics, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA

    Wesley K. Thompson

  26. Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Daniel H. Geschwind

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  1. Andrew J. Schork
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Contributions

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.

Corresponding author

Correspondence to Thomas Werge.

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The authors declare no competing interests.

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Supplementary information

Supplementary Figures 1–25

Supplementary Figures 1–25

Reporting Summary

Supplementary Tables 1–21

Supplementary Tables 1–21

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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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