Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis

A.D. Grotzinger; T.T. Mallard; W.A. Akingbuwa; H.F. Ip; M.G. Nivard; iPSYCH; Tourette Syndrome and Obsessive Compulsive Disorder Working Group of the Psychiatric Genetics Consortium; Bipolar Disorder Working Group of the Psychiatric Genetics Consortium; Major Depressive Disorder Working Group of the Psychiatric Genetics Consortium; Schizophrenia Working Group of the Psychiatric Genetics Consortium

doi:10.1038/s41588-022-01057-4

Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis

A.D. Grotzinger, T.T. Mallard, W.A. Akingbuwa, H.F. Ip, M.G. Nivard, iPSYCH, Tourette Syndrome and Obsessive Compulsive Disorder Working Group of the Psychiatric Genetics Consortium, Bipolar Disorder Working Group of the Psychiatric Genetics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genetics Consortium, Schizophrenia Working Group of the Psychiatric Genetics Consortium

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Abstract

We interrogate the joint genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis. We identify four broad factors (neurodevelopmental, compulsive, psychotic and internalizing) that underlie genetic correlations among the disorders and test whether these factors adequately explain their genetic correlations with biobehavioral traits. We introduce stratified genomic structural equation modeling, which we use to identify gene sets that disproportionately contribute to genetic risk sharing. This includes protein-truncating variant-intolerant genes expressed in excitatory and GABAergic brain cells that are enriched for genetic overlap across disorders with psychotic features. Multivariate association analyses detect 152 (20 new) independent loci that act on the individual factors and identify nine loci that act heterogeneously across disorders within a factor. Despite moderate-to-high genetic correlations across all 11 disorders, we find little utility of a single dimension of genetic risk across psychiatric disorders either at the level of biobehavioral correlates or at the level of individual variants.

Original language	English
Pages (from-to)	548-559
Number of pages	12
Journal	Nature genetics
Volume	54
Issue number	5
Early online date	5 May 2022
DOIs	https://doi.org/10.1038/s41588-022-01057-4
Publication status	Published - May 2022

Bibliographical note

Publisher copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding

This work presented here would not have been possible without the enormous efforts put forth by the investigators and participants from Psychiatric Genetics Consortium, iPSYCH, UK Biobank and 23andMe. The work from these contributing groups was supported by numerous grants from governmental and charitable bodies as well as philanthropic donation. Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health (NIH) under Award Number R01MH120219. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. A.D.G. was additionally supported by NIH grant R01HD083613. E.M.T.-D. was additionally supported by NIH grants R01AG054628 and R01HD083613 and the Jacobs Foundation. E.M.T.-D. is a faculty associate of the Population Research Center at the University of Texas, which is supported by NIH grant P2CHD042849, and the Center on Aging and Population Sciences, which is supported by NIH grant P30AG066614. M.G.N. is additionally supported by ZonMW grants 849200011 and 531003014 from The Netherlands Organisation for Health Research and Development and a VENI grant awarded by NWO (VI.Veni.191\u2009G.030) and is a Jacobs Foundation Fellow. W.A.A. is supported by the European Union\u2019s Horizon 2020 Research and Innovation Programme, Marie Sklodowska Curie Actions \u2013 MSCA-ITN-2016 \u2013 Innovative Training Networks under grant agreement 721567. H.F.I. is supported by the Aggression in Children: unraveling gene-environment interplay to inform Treatment and InterventiON strategies (ACTION) project. ACTION receives funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement 602768. C.M.L. is supported by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King\u2019s College London. A.M.M. is supported by the Wellcome Trust (104036/Z/14/Z, 216767/Z/19/Z), UKRI MRC (MC_PC_17209, MR/S035818/1). K.-P.L. is supported by the Deutsche Forschungsgemeinschaft (DFG: CRU 125, CRC TRR 58 A1/A5, No. 44541416), the European Union\u2019s Seventh Framework Programme under grant 602805 (Aggressotype), the Horizon 2020 Research and Innovation Programme under grant 728018 (Eat2beNICE) and 643051 (MiND), Fritz Thyssen Foundation (10.13.1185), ERA-Net NEURON/RESPOND 01EW1602B, ERA-Net NEURON/DECODE FKZ01EW1902 and 5-100 Russian Academic Excellence Project. G.B. is supported by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King\u2019s College London. P.H.L. is supported by NIH grants R01MH119243 and R00MH101367. The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), the EU FP7 Program (grant 602805, \u2018Aggressotype\u2019) and H2020 Program (grant 667302, \u2018CoCA\u2019), NIMH (1U01MH109514-01 to ADB) and the universities and university hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing (Aarhus University, Denmark) (grant to A.D.B.). This work presented here would not have been possible without the enormous efforts put forth by the investigators and participants from Psychiatric Genetics Consortium, iPSYCH, UK Biobank and 23andMe. The work from these contributing groups was supported by numerous grants from governmental and charitable bodies as well as philanthropic donation. Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health (NIH) under Award Number R01MH120219. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. A.D.G. was additionally supported by NIH grant R01HD083613. E.M.T.-D. was additionally supported by NIH grants R01AG054628 and R01HD083613 and the Jacobs Foundation. E.M.T.-D. is a faculty associate of the Population Research Center at the University of Texas, which is supported by NIH grant P2CHD042849, and the Center on Aging and Population Sciences, which is supported by NIH grant P30AG066614.

Funders	Funder number
Aggression in Children
Center on Aging	P30AG066614
H2020 Program	667302
MSCA-ITN-2016	721567
Mind
National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust
UKRI MRC	MR/S035818/1, MC_PC_17209
National Institutes of Health	R01AG054628, R01HD083613
National Institute of Mental Health	R00MH101367, R01MH119243, R01MH120219, 1U01MH109514-01
California Department of Fish and Game	CRU 125, 44541416, CRC TRR 58 A1/A5
King’s College London
Wellcome Trust	104036/Z/14/Z, 216767/Z/19/Z
Horizon 2020 Framework Programme
Seventh Framework Programme	602768, 602805
HORIZON EUROPE Marie Sklodowska-Curie Actions
Deutsche Forschungsgemeinschaft
ZonMw	531003014, 849200011
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	VI.Veni.191 G.030
Fritz Thyssen Stiftung	01EW1602B, FKZ01EW1902, 10.13.1185
Lundbeckfonden	R155-2014-1724, R248-2017-2003, R102-A9118
Jacobs Foundation	P2CHD042849
Seventh Framework Programme
Horizon 2020	Eat2beNICE, 643051, 728018
Novo Nordisk Fonden

UN SDGs

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Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysisFinal published version, 4.32 MBLicence: Article 25fa Dutch Copyright Act

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Grotzinger, A. D., Mallard, T. T., Akingbuwa, W. A., Ip, H. F., Nivard, M. G., iPSYCH, Tourette Syndrome and Obsessive Compulsive Disorder Working Group of the Psychiatric Genetics Consortium, Bipolar Disorder Working Group of the Psychiatric Genetics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genetics Consortium, & Schizophrenia Working Group of the Psychiatric Genetics Consortium (2022). Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis. Nature genetics, 54(5), 548-559. https://doi.org/10.1038/s41588-022-01057-4

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abstract = "We interrogate the joint genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis. We identify four broad factors (neurodevelopmental, compulsive, psychotic and internalizing) that underlie genetic correlations among the disorders and test whether these factors adequately explain their genetic correlations with biobehavioral traits. We introduce stratified genomic structural equation modeling, which we use to identify gene sets that disproportionately contribute to genetic risk sharing. This includes protein-truncating variant-intolerant genes expressed in excitatory and GABAergic brain cells that are enriched for genetic overlap across disorders with psychotic features. Multivariate association analyses detect 152 (20 new) independent loci that act on the individual factors and identify nine loci that act heterogeneously across disorders within a factor. Despite moderate-to-high genetic correlations across all 11 disorders, we find little utility of a single dimension of genetic risk across psychiatric disorders either at the level of biobehavioral correlates or at the level of individual variants.",

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Grotzinger, AD, Mallard, TT, Akingbuwa, WA, Ip, HF, Nivard, MG, iPSYCH, Tourette Syndrome and Obsessive Compulsive Disorder Working Group of the Psychiatric Genetics Consortium, Bipolar Disorder Working Group of the Psychiatric Genetics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genetics Consortium & Schizophrenia Working Group of the Psychiatric Genetics Consortium 2022, 'Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis', Nature genetics, vol. 54, no. 5, pp. 548-559. https://doi.org/10.1038/s41588-022-01057-4

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AU - Tourette Syndrome and Obsessive Compulsive Disorder Working Group of the Psychiatric Genetics Consortium

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JO - Nature genetics

JF - Nature genetics

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Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis

Abstract

Bibliographical note

Funding

UN SDGs

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