TY - JOUR

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 - Meier, Sandra M.

AU - Lee, Phil H.

AU - Kendler, Kenneth S.

AU - Smoller, Jordan W.

AU - Tucker-Drob, Elliot M.

AU - Nivard, Michel G.

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

N1 - Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2022

Y1 - 2022

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.

U2 - 10.1038/s41588-022-01057-4

DO - 10.1038/s41588-022-01057-4

M3 - Journal article

C2 - 35513722

AN - SCOPUS:85130335728

VL - 54

SP - 548

EP - 559

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

ER -