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

Andrew D. Grotzinger; Travis T. Mallard; Wonuola A. Akingbuwa; Hill F. Ip; Mark J. Adams; Cathryn M. Lewis; Andrew M. McIntosh; Jakob Grove; Søren Dalsgaard; Klaus Peter Lesch; Nora Strom; Sandra M. Meier; Manuel Mattheisen; Anders D. Børglum; Ole Mors; Gerome Breen; 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; Phil H. Lee; Kenneth S. Kendler; Jordan W. Smoller; Elliot M. Tucker-Drob; Michel G. Nivard

doi:10.1038/s41588-022-01057-4

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

Andrew D. Grotzinger^*, Travis T. Mallard, Wonuola A. Akingbuwa, Hill F. Ip, Mark J. Adams, Cathryn M. Lewis, Andrew M. McIntosh, Jakob Grove, Søren Dalsgaard, Klaus Peter Lesch, Nora Strom, Sandra M. Meier, Manuel Mattheisen, Anders D. Børglum, Ole Mors, Gerome Breen, 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 ConsortiumSchizophrenia Working Group of the Psychiatric Genetics Consortium, Phil H. Lee, Kenneth S. Kendler, Jordan W. Smoller, Elliot M. Tucker-Drob, Michel G. Nivard

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

107 Citations (Scopus)

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
Journal	Nature Genetics
Volume	54
Issue	5
Pages (from-to)	548-559
Number of pages	12
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-022-01057-4
Publication status	Published - May 2022

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9117465/pdf/nihms-1791507.pdf

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Grotzinger, A. D., Mallard, T. T., Akingbuwa, W. A., Ip, H. F., Adams, M. J., Lewis, C. M., McIntosh, A. M., Grove, J., Dalsgaard, S., Lesch, K. P., Strom, N., Meier, S. M., Mattheisen, M., Børglum, A. D., Mors, O., Breen, G., iPSYCH, Tourette Syndrome and Obsessive Compulsive Disorder Working Group of the Psychiatric Genetics Consortium, Bipolar Disorder Working Group of the Psychiatric Genetics Consortium, ... Nivard, M. G. (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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title = "Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis",

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.",

author = "Grotzinger, {Andrew D.} and Mallard, {Travis T.} and Akingbuwa, {Wonuola A.} and Ip, {Hill F.} and Adams, {Mark J.} and Lewis, {Cathryn M.} and McIntosh, {Andrew M.} and Jakob Grove and S{\o}ren Dalsgaard and Lesch, {Klaus Peter} and Nora Strom and Meier, {Sandra M.} and Manuel Mattheisen and B{\o}rglum, {Anders D.} and Ole Mors and Gerome Breen and iPSYCH and {Tourette Syndrome and Obsessive Compulsive Disorder Working Group of the Psychiatric Genetics Consortium} and {Bipolar Disorder Working Group of the Psychiatric Genetics Consortium} and {Major Depressive Disorder Working Group of the Psychiatric Genetics Consortium} and {Schizophrenia Working Group of the Psychiatric Genetics Consortium} and Lee, {Phil H.} and Kendler, {Kenneth S.} and Smoller, {Jordan W.} and Tucker-Drob, {Elliot M.} and Nivard, {Michel G.}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = may,

doi = "10.1038/s41588-022-01057-4",

language = "English",

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Grotzinger, AD, Mallard, TT, Akingbuwa, WA, Ip, HF, Adams, MJ, Lewis, CM, McIntosh, AM, Grove, J , Dalsgaard, S, Lesch, KP, Strom, N, Meier, SM, Mattheisen, M, Børglum, AD , Mors, O, Breen, 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, Lee, PH, Kendler, KS, Smoller, JW, Tucker-Drob, EM & Nivard, MG 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

Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis. / Grotzinger, Andrew D.; Mallard, Travis T.; Akingbuwa, Wonuola A. et al.
In: Nature Genetics, Vol. 54, No. 5, 05.2022, p. 548-559.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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T1 - Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis

AU - Grotzinger, Andrew D.

AU - Mallard, Travis T.

AU - Akingbuwa, Wonuola A.

AU - Ip, Hill F.

AU - Adams, Mark J.

AU - Lewis, Cathryn M.

AU - McIntosh, Andrew M.

AU - Grove, Jakob

AU - Dalsgaard, Søren

AU - Lesch, Klaus Peter

AU - Strom, Nora

AU - Meier, Sandra M.

AU - Mattheisen, Manuel

AU - Børglum, Anders D.

AU - Mors, Ole

AU - Breen, Gerome

AU - iPSYCH

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

AU - Bipolar Disorder Working Group of the Psychiatric Genetics Consortium

AU - Major Depressive Disorder Working Group of the Psychiatric Genetics Consortium

AU - Schizophrenia Working Group of the Psychiatric Genetics Consortium

AU - Lee, Phil H.

AU - Kendler, Kenneth S.

AU - Smoller, Jordan W.

AU - Tucker-Drob, Elliot M.

AU - Nivard, Michel G.

PY - 2022/5

Y1 - 2022/5

N2 - 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.

AB - 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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U2 - 10.1038/s41588-022-01057-4

DO - 10.1038/s41588-022-01057-4

M3 - Journal article

C2 - 35513722

AN - SCOPUS:85130335728

SN - 1061-4036

VL - 54

SP - 548

EP - 559

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

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

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