Multivariate GWAS of psychiatric disorders and their cardinal symptoms reveal two dimensions of cross-cutting genetic liabilities

Bipolar Disorder Working Group of the Psychiatric Genomics Consortium

doi:10.1016/j.xgen.2022.100140

Multivariate GWAS of psychiatric disorders and their cardinal symptoms reveal two dimensions of cross-cutting genetic liabilities

Bipolar Disorder Working Group of the Psychiatric Genomics Consortium

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Understanding which biological pathways are specific versus general across diagnostic categories and levels of symptom severity is critical to improving nosology and treatment of psychopathology. Here, we combine transdiagnostic and dimensional approaches to genetic discovery for the first time, conducting a novel multivariate genome-wide association study of eight psychiatric symptoms and disorders broadly related to mood disturbance and psychosis. We identify two transdiagnostic genetic liabilities that distinguish between common forms of psychopathology versus rarer forms of serious mental illness. Biological annotation revealed divergent genetic architectures that differentially implicated prenatal neurodevelopment and neuronal function and regulation. These findings inform psychiatric nosology and biological models of psychopathology, as they suggest that the severity of mood and psychotic symptoms present in serious mental illness may reflect a difference in kind rather than merely in degree.

Original language	English
Article number	100140
Pages (from-to)	1-19
Number of pages	19
Journal	Cell Genomics
Volume	2
Issue number	6
Early online date	8 Jun 2022
DOIs	https://doi.org/10.1016/j.xgen.2022.100140
Publication status	Published - 8 Jun 2022

Bibliographical note

Funding Information:
T.T.M. is supported by funds from NIH T32HG010464 . S.S.-R. was supported by funds from the California Tobacco-Related Disease Research Program (TRDRP; grant number T29KT0526 ) and NIDA DP1DA054394 . J.S. was supported by NIH T32MH019112 . A.O. was supported by the Netherlands Organisation for Scientific Research VENI (016.Veni.198.058). A.A.P. was supported by a grant from the TRDRP ( 28IR-0070 ) and by NIH P50DA037844 . K.P.H. and E.M.T.-D. were supported in part by Jacobs Foundation Research Fellowships and are faculty research associates of the Population Research Center at the University of Texas at Austin , which is supported by NIH grant P2CHD04284 . K.P.H. and E.M.T.-D. were also supported by NIH grants R01-HD083613 and R01-HD092548 . E.M.T.-D. was also supported by NIH grant R01-MH120219 and is a member of the Center for Aging and Population Studies at the University of Texas at Austin , which is supported by NIH grant P30AG066614 . M.C.K. was supported by funds from NIH grants MH100141 and DA044283 . P.D.K. was supported by an ERC consolidator grant ( 647648 EdGe ). The dataset(s) used for the PheWAS/LabWAS analyses described were obtained from Vanderbilt University Medical Center’s BioVU, which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH -funded Shared Instrumentation Grant S10RR025141 and CTSA grants UL1TR002243 , UL1TR000445 , and UL1RR024975 . Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711, and additional funding sources are listed at https://victr.vumc.org/biovu-funding/ . L.K.D. obtained support from 1R01MH113362, 1R01MH118233, and 1R56MH120736. The project was approved by the VUMC Institutional Review Board (IRB #160302, #172020, and #190418). Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. This research was conducted with the UK Biobank Resource under application number 11425 and with the support and collaboration from all investigators who make up the Bipolar Disorder Working Group of the PGC. We would like to thank the many studies that made these consortia possible, the researchers involved, and the participants in those studies, without whom this effort would not be possible. We would also like to thank the research participants and employees of 23andMe for making this work possible.

Funding Information:
T.T.M. is supported by funds from NIH T32HG010464. S.S.-R. was supported by funds from the California Tobacco-Related Disease Research Program (TRDRP; grant number T29KT0526) and NIDA DP1DA054394. J.S. was supported by NIH T32MH019112. A.O. was supported by the Netherlands Organisation for Scientific Research VENI (016.Veni.198.058). A.A.P. was supported by a grant from the TRDRP (28IR-0070) and by NIH P50DA037844. K.P.H. and E.M.T.-D. were supported in part by Jacobs Foundation Research Fellowships and are faculty research associates of the Population Research Center at the University of Texas at Austin, which is supported by NIH grant P2CHD04284. K.P.H. and E.M.T.-D. were also supported by NIH grants R01-HD083613 and R01-HD092548. E.M.T.-D. was also supported by NIH grant R01-MH120219and is a member of the Center for Aging and Population Studies at the University of Texas at Austin, which is supported by NIH grant P30AG066614. M.C.K. was supported by funds from NIH grants MH100141 and DA044283. P.D.K. was supported by an ERC consolidator grant (647648 EdGe). The dataset(s) used for the PheWAS/LabWAS analyses described were obtained from Vanderbilt University Medical Center's BioVU, which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH-funded Shared Instrumentation Grant S10RR025141 and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711, and additional funding sources are listed at https://victr.vumc.org/biovu-funding/. L.K.D. obtained support from 1R01MH113362, 1R01MH118233, and 1R56MH120736. The project was approved by the VUMC Institutional Review Board (IRB #160302, #172020, and #190418). Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. This research was conducted with the UK Biobank Resource under application number 11425 and with the support and collaboration from all investigators who make up the Bipolar Disorder Working Group of the PGC. We would like to thank the many studies that made these consortia possible, the researchers involved, and the participants in those studies, without whom this effort would not be possible. We would also like to thank the research participants and employees of 23andMe for making this work possible. T.T.M. P.D.K. and K.P.H. conceived and designed the study. P.D.K. and K.P.H. oversaw the study. T.T.M. and K.P.H. led the writing of the manuscript with substantive contributions from P.D.K. and M.C.K. A.A.P. E.M.T.-D. and K.S.K. provided valuable feedback on the framing and interpretation of the results. T.T.M. was the lead analyst, responsible for conducting GWASs, quality control, genetic correlations, multivariate analyses with Genomic SEM, and biological annotation with assistance from R.K.L. A.D.G. S.S.-R. and J.S. T.T.M. prepared the data for analysis with assistance from R.K.L. A.O. R.d.V. and S.F.W.M. S.S.-R. performed the phenome-wide association study with assistance from L.K.D. T.T.M. prepared the figures and tables. Investigators from the Bipolar Disorder Working Group of the PGC contributed data for BD1, BD2, and SZA. All authors provided valuable feedback and advice during preparation of the manuscript. The authors declare no competing interests.

Publisher Copyright:
© 2022 The Author(s)

Funding

T.T.M. is supported by funds from NIH T32HG010464 . S.S.-R. was supported by funds from the California Tobacco-Related Disease Research Program (TRDRP; grant number T29KT0526 ) and NIDA DP1DA054394 . J.S. was supported by NIH T32MH019112 . A.O. was supported by the Netherlands Organisation for Scientific Research VENI (016.Veni.198.058). A.A.P. was supported by a grant from the TRDRP ( 28IR-0070 ) and by NIH P50DA037844 . K.P.H. and E.M.T.-D. were supported in part by Jacobs Foundation Research Fellowships and are faculty research associates of the Population Research Center at the University of Texas at Austin , which is supported by NIH grant P2CHD04284 . K.P.H. and E.M.T.-D. were also supported by NIH grants R01-HD083613 and R01-HD092548 . E.M.T.-D. was also supported by NIH grant R01-MH120219 and is a member of the Center for Aging and Population Studies at the University of Texas at Austin , which is supported by NIH grant P30AG066614 . M.C.K. was supported by funds from NIH grants MH100141 and DA044283 . P.D.K. was supported by an ERC consolidator grant ( 647648 EdGe ). The dataset(s) used for the PheWAS/LabWAS analyses described were obtained from Vanderbilt University Medical Center’s BioVU, which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH -funded Shared Instrumentation Grant S10RR025141 and CTSA grants UL1TR002243 , UL1TR000445 , and UL1RR024975 . Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711, and additional funding sources are listed at https://victr.vumc.org/biovu-funding/ . L.K.D. obtained support from 1R01MH113362, 1R01MH118233, and 1R56MH120736. The project was approved by the VUMC Institutional Review Board (IRB #160302, #172020, and #190418). Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. This research was conducted with the UK Biobank Resource under application number 11425 and with the support and collaboration from all investigators who make up the Bipolar Disorder Working Group of the PGC. We would like to thank the many studies that made these consortia possible, the researchers involved, and the participants in those studies, without whom this effort would not be possible. We would also like to thank the research participants and employees of 23andMe for making this work possible. T.T.M. is supported by funds from NIH T32HG010464. S.S.-R. was supported by funds from the California Tobacco-Related Disease Research Program (TRDRP; grant number T29KT0526) and NIDA DP1DA054394. J.S. was supported by NIH T32MH019112. A.O. was supported by the Netherlands Organisation for Scientific Research VENI (016.Veni.198.058). A.A.P. was supported by a grant from the TRDRP (28IR-0070) and by NIH P50DA037844. K.P.H. and E.M.T.-D. were supported in part by Jacobs Foundation Research Fellowships and are faculty research associates of the Population Research Center at the University of Texas at Austin, which is supported by NIH grant P2CHD04284. K.P.H. and E.M.T.-D. were also supported by NIH grants R01-HD083613 and R01-HD092548. E.M.T.-D. was also supported by NIH grant R01-MH120219and is a member of the Center for Aging and Population Studies at the University of Texas at Austin, which is supported by NIH grant P30AG066614. M.C.K. was supported by funds from NIH grants MH100141 and DA044283. P.D.K. was supported by an ERC consolidator grant (647648 EdGe). The dataset(s) used for the PheWAS/LabWAS analyses described were obtained from Vanderbilt University Medical Center's BioVU, which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH-funded Shared Instrumentation Grant S10RR025141 and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711, and additional funding sources are listed at https://victr.vumc.org/biovu-funding/. L.K.D. obtained support from 1R01MH113362, 1R01MH118233, and 1R56MH120736. The project was approved by the VUMC Institutional Review Board (IRB #160302, #172020, and #190418). Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. This research was conducted with the UK Biobank Resource under application number 11425 and with the support and collaboration from all investigators who make up the Bipolar Disorder Working Group of the PGC. We would like to thank the many studies that made these consortia possible, the researchers involved, and the participants in those studies, without whom this effort would not be possible. We would also like to thank the research participants and employees of 23andMe for making this work possible. T.T.M. P.D.K. and K.P.H. conceived and designed the study. P.D.K. and K.P.H. oversaw the study. T.T.M. and K.P.H. led the writing of the manuscript with substantive contributions from P.D.K. and M.C.K. A.A.P. E.M.T.-D. and K.S.K. provided valuable feedback on the framing and interpretation of the results. T.T.M. was the lead analyst, responsible for conducting GWASs, quality control, genetic correlations, multivariate analyses with Genomic SEM, and biological annotation with assistance from R.K.L. A.D.G. S.S.-R. and J.S. T.T.M. prepared the data for analysis with assistance from R.K.L. A.O. R.d.V. and S.F.W.M. S.S.-R. performed the phenome-wide association study with assistance from L.K.D. T.T.M. prepared the figures and tables. Investigators from the Bipolar Disorder Working Group of the PGC contributed data for BD1, BD2, and SZA. All authors provided valuable feedback and advice during preparation of the manuscript. The authors declare no competing interests.

Funders	Funder number
Bipolar Disorder Working Group
California Tobacco-Related Disease Research Program
National Institutes of Health	T32HG010464
National Institutes of Health
National Institute on Drug Abuse	T32MH019112, 28IR-0070, P50DA037844, DP1DA054394
National Institute on Drug Abuse
Tobacco-Related Disease Research Program	T29KT0526
Tobacco-Related Disease Research Program
National Center for Advancing Translational Sciences	11425
National Center for Advancing Translational Sciences
Vanderbilt University Medical Center	UL1TR000445, S10RR025141, UL1RR024975, UL1TR002243
Vanderbilt University Medical Center
Pennsylvania Game Commission
Engineering Research Centers	647648 EdGe
Engineering Research Centers
Jacobs Foundation	P30AG066614, R01-HD083613, DA044283, R01-HD092548, MH100141, P2CHD04284, R01-MH120219
Jacobs Foundation

Keywords

genetic correlation
genome-wide association study
genomics
neurodevelopment
pleiotropy
psychiatric disorders
psychiatric genetics
transdiagnostic

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10.1016/j.xgen.2022.100140

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Cite this

@article{2c83701d52da444fb8ff6b1b93888401,

title = "Multivariate GWAS of psychiatric disorders and their cardinal symptoms reveal two dimensions of cross-cutting genetic liabilities",

abstract = "Understanding which biological pathways are specific versus general across diagnostic categories and levels of symptom severity is critical to improving nosology and treatment of psychopathology. Here, we combine transdiagnostic and dimensional approaches to genetic discovery for the first time, conducting a novel multivariate genome-wide association study of eight psychiatric symptoms and disorders broadly related to mood disturbance and psychosis. We identify two transdiagnostic genetic liabilities that distinguish between common forms of psychopathology versus rarer forms of serious mental illness. Biological annotation revealed divergent genetic architectures that differentially implicated prenatal neurodevelopment and neuronal function and regulation. These findings inform psychiatric nosology and biological models of psychopathology, as they suggest that the severity of mood and psychotic symptoms present in serious mental illness may reflect a difference in kind rather than merely in degree.",

keywords = "genetic correlation, genome-wide association study, genomics, neurodevelopment, pleiotropy, psychiatric disorders, psychiatric genetics, transdiagnostic",

author = "Mallard, {Travis T.} and {Karlsson Linn{\'e}r}, Richard and Grotzinger, {Andrew D.} and Sandra Sanchez-Roige and Jakob Seidlitz and Aysu Okbay and {de Vlaming}, Ronald and Meddens, {S. Fleur W.} and Palmer, {Abraham A.} and Davis, {Lea K.} and Tucker-Drob, {Elliot M.} and Kendler, {Kenneth S.} and Keller, {Matthew C.} and Koellinger, {Philipp D.} and Harden, {K. Paige} and {Bipolar Disorder Working Group of the Psychiatric Genomics Consortium}",

note = "Funding Information: T.T.M. is supported by funds from NIH T32HG010464 . S.S.-R. was supported by funds from the California Tobacco-Related Disease Research Program (TRDRP; grant number T29KT0526 ) and NIDA DP1DA054394 . J.S. was supported by NIH T32MH019112 . A.O. was supported by the Netherlands Organisation for Scientific Research VENI (016.Veni.198.058). A.A.P. was supported by a grant from the TRDRP ( 28IR-0070 ) and by NIH P50DA037844 . K.P.H. and E.M.T.-D. were supported in part by Jacobs Foundation Research Fellowships and are faculty research associates of the Population Research Center at the University of Texas at Austin , which is supported by NIH grant P2CHD04284 . K.P.H. and E.M.T.-D. were also supported by NIH grants R01-HD083613 and R01-HD092548 . E.M.T.-D. was also supported by NIH grant R01-MH120219 and is a member of the Center for Aging and Population Studies at the University of Texas at Austin , which is supported by NIH grant P30AG066614 . M.C.K. was supported by funds from NIH grants MH100141 and DA044283 . P.D.K. was supported by an ERC consolidator grant ( 647648 EdGe ). The dataset(s) used for the PheWAS/LabWAS analyses described were obtained from Vanderbilt University Medical Center{\textquoteright}s BioVU, which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH -funded Shared Instrumentation Grant S10RR025141 and CTSA grants UL1TR002243 , UL1TR000445 , and UL1RR024975 . Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711, and additional funding sources are listed at https://victr.vumc.org/biovu-funding/ . L.K.D. obtained support from 1R01MH113362, 1R01MH118233, and 1R56MH120736. The project was approved by the VUMC Institutional Review Board (IRB #160302, #172020, and #190418). Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. This research was conducted with the UK Biobank Resource under application number 11425 and with the support and collaboration from all investigators who make up the Bipolar Disorder Working Group of the PGC. We would like to thank the many studies that made these consortia possible, the researchers involved, and the participants in those studies, without whom this effort would not be possible. We would also like to thank the research participants and employees of 23andMe for making this work possible. Funding Information: T.T.M. is supported by funds from NIH T32HG010464. S.S.-R. was supported by funds from the California Tobacco-Related Disease Research Program (TRDRP; grant number T29KT0526) and NIDA DP1DA054394. J.S. was supported by NIH T32MH019112. A.O. was supported by the Netherlands Organisation for Scientific Research VENI (016.Veni.198.058). A.A.P. was supported by a grant from the TRDRP (28IR-0070) and by NIH P50DA037844. K.P.H. and E.M.T.-D. were supported in part by Jacobs Foundation Research Fellowships and are faculty research associates of the Population Research Center at the University of Texas at Austin, which is supported by NIH grant P2CHD04284. K.P.H. and E.M.T.-D. were also supported by NIH grants R01-HD083613 and R01-HD092548. E.M.T.-D. was also supported by NIH grant R01-MH120219and is a member of the Center for Aging and Population Studies at the University of Texas at Austin, which is supported by NIH grant P30AG066614. M.C.K. was supported by funds from NIH grants MH100141 and DA044283. P.D.K. was supported by an ERC consolidator grant (647648 EdGe). The dataset(s) used for the PheWAS/LabWAS analyses described were obtained from Vanderbilt University Medical Center's BioVU, which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH-funded Shared Instrumentation Grant S10RR025141 and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711, and additional funding sources are listed at https://victr.vumc.org/biovu-funding/. L.K.D. obtained support from 1R01MH113362, 1R01MH118233, and 1R56MH120736. The project was approved by the VUMC Institutional Review Board (IRB #160302, #172020, and #190418). Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. This research was conducted with the UK Biobank Resource under application number 11425 and with the support and collaboration from all investigators who make up the Bipolar Disorder Working Group of the PGC. We would like to thank the many studies that made these consortia possible, the researchers involved, and the participants in those studies, without whom this effort would not be possible. We would also like to thank the research participants and employees of 23andMe for making this work possible. T.T.M. P.D.K. and K.P.H. conceived and designed the study. P.D.K. and K.P.H. oversaw the study. T.T.M. and K.P.H. led the writing of the manuscript with substantive contributions from P.D.K. and M.C.K. A.A.P. E.M.T.-D. and K.S.K. provided valuable feedback on the framing and interpretation of the results. T.T.M. was the lead analyst, responsible for conducting GWASs, quality control, genetic correlations, multivariate analyses with Genomic SEM, and biological annotation with assistance from R.K.L. A.D.G. S.S.-R. and J.S. T.T.M. prepared the data for analysis with assistance from R.K.L. A.O. R.d.V. and S.F.W.M. S.S.-R. performed the phenome-wide association study with assistance from L.K.D. T.T.M. prepared the figures and tables. Investigators from the Bipolar Disorder Working Group of the PGC contributed data for BD1, BD2, and SZA. All authors provided valuable feedback and advice during preparation of the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = jun,

day = "8",

doi = "10.1016/j.xgen.2022.100140",

language = "English",

volume = "2",

pages = "1--19",

journal = "Cell Genomics",

issn = "2666-979X",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - Multivariate GWAS of psychiatric disorders and their cardinal symptoms reveal two dimensions of cross-cutting genetic liabilities

AU - Mallard, Travis T.

AU - Karlsson Linnér, Richard

AU - Grotzinger, Andrew D.

AU - Sanchez-Roige, Sandra

AU - Seidlitz, Jakob

AU - Okbay, Aysu

AU - de Vlaming, Ronald

AU - Meddens, S. Fleur W.

AU - Palmer, Abraham A.

AU - Davis, Lea K.

AU - Tucker-Drob, Elliot M.

AU - Kendler, Kenneth S.

AU - Keller, Matthew C.

AU - Koellinger, Philipp D.

AU - Harden, K. Paige

AU - Bipolar Disorder Working Group of the Psychiatric Genomics Consortium

N1 - Funding Information: T.T.M. is supported by funds from NIH T32HG010464 . S.S.-R. was supported by funds from the California Tobacco-Related Disease Research Program (TRDRP; grant number T29KT0526 ) and NIDA DP1DA054394 . J.S. was supported by NIH T32MH019112 . A.O. was supported by the Netherlands Organisation for Scientific Research VENI (016.Veni.198.058). A.A.P. was supported by a grant from the TRDRP ( 28IR-0070 ) and by NIH P50DA037844 . K.P.H. and E.M.T.-D. were supported in part by Jacobs Foundation Research Fellowships and are faculty research associates of the Population Research Center at the University of Texas at Austin , which is supported by NIH grant P2CHD04284 . K.P.H. and E.M.T.-D. were also supported by NIH grants R01-HD083613 and R01-HD092548 . E.M.T.-D. was also supported by NIH grant R01-MH120219 and is a member of the Center for Aging and Population Studies at the University of Texas at Austin , which is supported by NIH grant P30AG066614 . M.C.K. was supported by funds from NIH grants MH100141 and DA044283 . P.D.K. was supported by an ERC consolidator grant ( 647648 EdGe ). The dataset(s) used for the PheWAS/LabWAS analyses described were obtained from Vanderbilt University Medical Center’s BioVU, which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH -funded Shared Instrumentation Grant S10RR025141 and CTSA grants UL1TR002243 , UL1TR000445 , and UL1RR024975 . Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711, and additional funding sources are listed at https://victr.vumc.org/biovu-funding/ . L.K.D. obtained support from 1R01MH113362, 1R01MH118233, and 1R56MH120736. The project was approved by the VUMC Institutional Review Board (IRB #160302, #172020, and #190418). Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. This research was conducted with the UK Biobank Resource under application number 11425 and with the support and collaboration from all investigators who make up the Bipolar Disorder Working Group of the PGC. We would like to thank the many studies that made these consortia possible, the researchers involved, and the participants in those studies, without whom this effort would not be possible. We would also like to thank the research participants and employees of 23andMe for making this work possible. Funding Information: T.T.M. is supported by funds from NIH T32HG010464. S.S.-R. was supported by funds from the California Tobacco-Related Disease Research Program (TRDRP; grant number T29KT0526) and NIDA DP1DA054394. J.S. was supported by NIH T32MH019112. A.O. was supported by the Netherlands Organisation for Scientific Research VENI (016.Veni.198.058). A.A.P. was supported by a grant from the TRDRP (28IR-0070) and by NIH P50DA037844. K.P.H. and E.M.T.-D. were supported in part by Jacobs Foundation Research Fellowships and are faculty research associates of the Population Research Center at the University of Texas at Austin, which is supported by NIH grant P2CHD04284. K.P.H. and E.M.T.-D. were also supported by NIH grants R01-HD083613 and R01-HD092548. E.M.T.-D. was also supported by NIH grant R01-MH120219and is a member of the Center for Aging and Population Studies at the University of Texas at Austin, which is supported by NIH grant P30AG066614. M.C.K. was supported by funds from NIH grants MH100141 and DA044283. P.D.K. was supported by an ERC consolidator grant (647648 EdGe). The dataset(s) used for the PheWAS/LabWAS analyses described were obtained from Vanderbilt University Medical Center's BioVU, which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH-funded Shared Instrumentation Grant S10RR025141 and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD074711, and additional funding sources are listed at https://victr.vumc.org/biovu-funding/. L.K.D. obtained support from 1R01MH113362, 1R01MH118233, and 1R56MH120736. The project was approved by the VUMC Institutional Review Board (IRB #160302, #172020, and #190418). Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. This research was conducted with the UK Biobank Resource under application number 11425 and with the support and collaboration from all investigators who make up the Bipolar Disorder Working Group of the PGC. We would like to thank the many studies that made these consortia possible, the researchers involved, and the participants in those studies, without whom this effort would not be possible. We would also like to thank the research participants and employees of 23andMe for making this work possible. T.T.M. P.D.K. and K.P.H. conceived and designed the study. P.D.K. and K.P.H. oversaw the study. T.T.M. and K.P.H. led the writing of the manuscript with substantive contributions from P.D.K. and M.C.K. A.A.P. E.M.T.-D. and K.S.K. provided valuable feedback on the framing and interpretation of the results. T.T.M. was the lead analyst, responsible for conducting GWASs, quality control, genetic correlations, multivariate analyses with Genomic SEM, and biological annotation with assistance from R.K.L. A.D.G. S.S.-R. and J.S. T.T.M. prepared the data for analysis with assistance from R.K.L. A.O. R.d.V. and S.F.W.M. S.S.-R. performed the phenome-wide association study with assistance from L.K.D. T.T.M. prepared the figures and tables. Investigators from the Bipolar Disorder Working Group of the PGC contributed data for BD1, BD2, and SZA. All authors provided valuable feedback and advice during preparation of the manuscript. The authors declare no competing interests. Publisher Copyright: © 2022 The Author(s)

PY - 2022/6/8

Y1 - 2022/6/8

N2 - Understanding which biological pathways are specific versus general across diagnostic categories and levels of symptom severity is critical to improving nosology and treatment of psychopathology. Here, we combine transdiagnostic and dimensional approaches to genetic discovery for the first time, conducting a novel multivariate genome-wide association study of eight psychiatric symptoms and disorders broadly related to mood disturbance and psychosis. We identify two transdiagnostic genetic liabilities that distinguish between common forms of psychopathology versus rarer forms of serious mental illness. Biological annotation revealed divergent genetic architectures that differentially implicated prenatal neurodevelopment and neuronal function and regulation. These findings inform psychiatric nosology and biological models of psychopathology, as they suggest that the severity of mood and psychotic symptoms present in serious mental illness may reflect a difference in kind rather than merely in degree.

AB - Understanding which biological pathways are specific versus general across diagnostic categories and levels of symptom severity is critical to improving nosology and treatment of psychopathology. Here, we combine transdiagnostic and dimensional approaches to genetic discovery for the first time, conducting a novel multivariate genome-wide association study of eight psychiatric symptoms and disorders broadly related to mood disturbance and psychosis. We identify two transdiagnostic genetic liabilities that distinguish between common forms of psychopathology versus rarer forms of serious mental illness. Biological annotation revealed divergent genetic architectures that differentially implicated prenatal neurodevelopment and neuronal function and regulation. These findings inform psychiatric nosology and biological models of psychopathology, as they suggest that the severity of mood and psychotic symptoms present in serious mental illness may reflect a difference in kind rather than merely in degree.

KW - genetic correlation

KW - genome-wide association study

KW - genomics

KW - neurodevelopment

KW - pleiotropy

KW - psychiatric disorders

KW - psychiatric genetics

KW - transdiagnostic

UR - http://www.scopus.com/inward/record.url?scp=85136770259&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85136770259&partnerID=8YFLogxK

U2 - 10.1016/j.xgen.2022.100140

DO - 10.1016/j.xgen.2022.100140

M3 - Article

AN - SCOPUS:85136770259

SN - 2666-979X

VL - 2

SP - 1

EP - 19

JO - Cell Genomics

JF - Cell Genomics

IS - 6

M1 - 100140

ER -

Multivariate GWAS of psychiatric disorders and their cardinal symptoms reveal two dimensions of cross-cutting genetic liabilities

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