A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment
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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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Mid-gestation is a critical window during neurodevelopment that may confer risk to multiple psychiatric disorders.
“This result highlights mid-gestation as a critical window during neurodevelopment that may confer risk to multiple psychiatric disorders, consistent with recent results from cross-disorder GWAS14,15.”
From A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles (2020) · cites this paper as [15]
These results are consistent with a smaller recent analysis in the Danish iPSYCH cohort.
“These results are consistent with those of a smaller recent analysis in the population-based Danish iPSYCH cohort (comprising 46,008 cases and 19,526 controls across six neuropsychiatric disorders) (Schork et al., 2019).”
From Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders (2019) · cites this paper as Schork et al., 2019
In the iPSYCH analysis, functional genomic characterization of cross-disorder loci implicated fetal neurodevelopmental processes, with greater prenatal than postnatal expression.
“In that analysis, consistent with the present findings, functional genomic characterization of cross-disorder loci implicated fetal neurodevelopmental processes, with greater prenatal than postnatal expression.”
From Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders (2019) · cites this paper as Schork et al., 2019
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Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders
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“These results are consistent with those of a smaller recent analysis in the population-based Danish iPSYCH cohort (comprising 46,008 cases and 19,526 controls across six neuropsychiatric disorders) (Schork et al., 2019).”
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Self-citationNeurodevelopmental pathways in bipolar disorder
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Pervasively Thinner Neocortex as a Transdiagnostic Feature of General Psychopathology
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- Authors
- Schork, A. J., Won, H., Appadurai, V., Nudel, R., Gandal, M., Delaneau, O., Revsbech Christiansen, M., Hougaard, D. M., Bækved-Hansen, M., Bybjerg-Grauholm, J., Giørtz Pedersen, M., Agerbo, E., Bøcker Pedersen, C., Neale, B. M., Daly, M. J., Wray, N. R., Nordentoft, M., Mors, O., Børglum, A. D., Bo Mortensen, P., Buil, A., Thompson, W. K., Geschwind, D. H., & Werge, T.
- Affiliations
- Sankt Hans Hospital (DK)
- University of North Carolina at Chapel Hill (US)
- University of California, Los Angeles (US)
- University of Geneva (CH)
- Statens Serum Institut (DK)
- Aarhus University (DK)
- Broad Institute (US)
- The University of Queensland (AU)
- University of Copenhagen (DK)
- Aarhus University Hospital (DK)
- Corresponding author
- Werge, Thomas
- ORCID
- Schork, Andrew J.
- Won, Hyejung
- Appadurai, Vivek
- Nudel, Ron
- Delaneau, Olivier
- Hougaard, David M.
- Bybjerg-Grauholm, Jonas
- Agerbo, Esben
- Bøcker Pedersen, Carsten
- Neale, Benjamin M.
- Daly, Mark J.
- Wray, Naomi R.
- Nordentoft, Merete
- Mors, Ole
- Børglum, Anders D.
- Buil, Alfonso
- Thompson, Wesley K.
- Geschwind, Daniel H.
- Werge, Thomas
- Venue
- Nature Neuroscience
- Published
- 2019-01-28
- Volume
- 22
- Issue
- 3
- Pages
- 353-361
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6497521
- OpenAlex
- W2912304870
- Cited by
- 223
- References
- 132
- Citations by year
- 2026: 16 · 2025: 22 · 2024: 17 · 2023: 28 · 2022: 41 · 2021: 32 · 2020: 38 · 2019: 23 · 2018: 5
- FWCI
- 20.12
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- IRIS (submittedVersion)
- Technical University of Denmark, DTU Orbit (Technical University of Denmark, DTU) (submittedVersion, other-oa)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- Simons Foundation (311789, SFARI 311789)
- Aarhus Universitet
- Simons Foundation Autism Research Initiative
- Lundbeckfonden (R155-2014-1724, R102‐A9118, R204-2015-4129, R248‐2017‐2003, R102-A9118 and R155-2014-1724)
- Novo Nordisk
- Region Hovedstaden
- Novo Nordisk Fonden
- H. Lundbeck A/S (R102-A9118, R155-2014-1724)
- National Institutes of Health (5r01mh094714-04, 5u01mh094432-04)
- National Institute of Mental Health (U01 MH094432, R01MH109912, R01-MH094714, R01MH110927, R00MH113823, 5U01MH094432‐02)
- National Institute of General Medical Sciences (R01GM104400)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- mental illness, shared genetic risk, fetal brain development, gene expression regulation, radial glia, interneurons, neocortex development, genetic susceptibility loci
- MeSH terms
- Mental Disorders, Brain, Female, Gene Expression Regulation, Humans, Male, Risk Factors, Cohort Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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