Abstract
The widespread comorbidity among psychiatric disorders demonstrated in epidemiological studies1–5 is mirrored by non-zero, positive genetic correlations from large-scale genetic studies6–10. To identify shared biological processes underpinning this observed phenotypic and genetic covariance and enhance molecular characterization of general psychiatric disorder liability11–13, we used several strategies aimed at uncovering pleiotropic, that is, cross-trait-associated, single-nucleotide polymorphisms (SNPs), genes and biological pathways. We conducted cross-trait meta-analysis on 12 psychiatric disorders to identify pleiotropic SNPs. The meta-analytic signal was driven by schizophrenia, hampering interpretation and joint biological characterization of the cross-trait meta-analytic signal. Subsequent pairwise comparisons of psychiatric disorders identified substantial pleiotropic overlap, but mainly among pairs of psychiatric disorders, and mainly at less stringent P-value thresholds. Only annotations related to evolutionarily conserved genomic regions were significant for multiple (9 out of 12) psychiatric disorders. Overall, identification of shared biological mechanisms remains challenging due to variation in power and genetic architecture between psychiatric disorders.
| Original language | English |
|---|---|
| Pages (from-to) | 1795-1802 |
| Number of pages | 8 |
| Journal | Nature genetics |
| Volume | 54 |
| Issue number | 12 |
| Early online date | 5 Dec 2022 |
| DOIs | |
| Publication status | Published - Dec 2022 |
Bibliographical note
Funding Information:C.d.L. is funded by Hoffman-La Roche. The other authors declare no competing interests.
Funding Information:
C.R., D.P. and S.v.d.S were funded by Netherlands Organization for Scientific Research (NWO; Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology; grant 024.004.012 to D.P.). P.R.J. was funded by the Netherlands Organization for Scientific Research (ZonMW VENI-09150162010138 to P.R.J.). D.P., J.W. and C.d.L. were funded by the Netherlands Organization for Scientific Research (NWO VICI 453-14-005 to D.P.), and M.N., D.P., J.W. and C.d.L. were funded a European Research Council advanced grant (ERC-2018-AdG GWAS2FUNC 834057 to D.P.). The analyses were carried out on the Genetic Cluster Computer, which is financed by the Netherlands Scientific Organization (NWO 480-05-003), VU University (Amsterdam, the Netherlands) and the Dutch Brain Foundation and hosted by the Dutch National Computing and Networking Services SurfSARA. This research was conducted using the UK Biobank resource under application number 16406 and is based in part on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, supported by awards CSP 575B and Merit 1|01CX001849.e. We thank the numerous participants, researchers and staff from many studies who collected and contributed to the data. In particular, we would like to express our gratitude to all UK Biobank and Million Veteran Program participants who have been so generous to share their data for analysis. Figure and Supplementary Figure were created with BioRender.com. These figures were, in part, adapted from the ‘Central Dogma’, ‘Expression of ACE2 Receptor in Human Host Tissues’ and ‘Notch Signaling Pathway’ templates by BioRender.com (2020) and can be retrieved from https://app.biorender.com/biorender-templates .
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
Funding
C.d.L. is funded by Hoffman-La Roche. The other authors declare no competing interests. C.R., D.P. and S.v.d.S were funded by Netherlands Organization for Scientific Research (NWO; Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology; grant 024.004.012 to D.P.). P.R.J. was funded by the Netherlands Organization for Scientific Research (ZonMW VENI-09150162010138 to P.R.J.). D.P., J.W. and C.d.L. were funded by the Netherlands Organization for Scientific Research (NWO VICI 453-14-005 to D.P.), and M.N., D.P., J.W. and C.d.L. were funded a European Research Council advanced grant (ERC-2018-AdG GWAS2FUNC 834057 to D.P.). The analyses were carried out on the Genetic Cluster Computer, which is financed by the Netherlands Scientific Organization (NWO 480-05-003), VU University (Amsterdam, the Netherlands) and the Dutch Brain Foundation and hosted by the Dutch National Computing and Networking Services SurfSARA. This research was conducted using the UK Biobank resource under application number 16406 and is based in part on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, supported by awards CSP 575B and Merit 1|01CX001849.e. We thank the numerous participants, researchers and staff from many studies who collected and contributed to the data. In particular, we would like to express our gratitude to all UK Biobank and Million Veteran Program participants who have been so generous to share their data for analysis. Figure and Supplementary Figure were created with BioRender.com. These figures were, in part, adapted from the ‘Central Dogma’, ‘Expression of ACE2 Receptor in Human Host Tissues’ and ‘Notch Signaling Pathway’ templates by BioRender.com (2020) and can be retrieved from https://app.biorender.com/biorender-templates .
| Funders | Funder number |
|---|---|
| Dutch Brain Foundation | |
| Dutch National Computing and Networking Services | 16406 |
| Million Veteran Program | |
| Office of Research and Development | |
| F. Hoffmann-La Roche | |
| Health Services Research and Development | 01CX001849 |
| Health Services Research and Development | |
| European Research Council | ERC-2018-AdG GWAS2FUNC 834057 |
| European Research Council | |
| ZonMw | VENI-09150162010138, VICI 453-14-005 |
| ZonMw | |
| Vrije Universiteit Amsterdam | |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | 480-05-003, 024.004.012 |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek |
