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Multivariate genomic architecture of cortical thickness and surface area at multiple levels of analysis.

ABSTRACT: Recent work in imaging genetics suggests high levels of genetic overlap within cortical regions for cortical thickness (CT) and surface area (SA). We model this multivariate system of genetic relationships by applying Genomic Structural Equation Modeling (Genomic SEM) and parsimoniously define five genomic brain factors underlying both CT and SA along with a general factor capturing genetic overlap across all brain regions. We validate these factors by demonstrating the generalizability of the model to a semi-independent sample and show that the factors align with biologically and functionally relevant parcellations of the cortex. We apply Stratified Genomic SEM to identify specific categories of genes (e.g., neuronal cell types) that are disproportionately associated with pleiotropy across specific subclusters of brain regions, as indexed by the genomic factors. Finally, we examine genetic associations with psychiatric and cognitive correlates, finding that broad aspects of cognitive function are associated with a general factor for SA and that psychiatric associations are null. These analyses provide key insights into the multivariate genomic architecture of two critical features of the cerebral cortex.

SUBMITTER: Grotzinger AD

PROVIDER: S-EPMC9941500 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Multivariate genomic architecture of cortical thickness and surface area at multiple levels of analysis.

Grotzinger Andrew D AD Mallard Travis T TT Liu Zhaowen Z Seidlitz Jakob J Ge Tian T Smoller Jordan W JW

Nature communications 20230220 1

Recent work in imaging genetics suggests high levels of genetic overlap within cortical regions for cortical thickness (CT) and surface area (SA). We model this multivariate system of genetic relationships by applying Genomic Structural Equation Modeling (Genomic SEM) and parsimoniously define five genomic brain factors underlying both CT and SA along with a general factor capturing genetic overlap across all brain regions. We validate these factors by demonstrating the generalizability of the m ...[more]

PMID: 36806290

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Project description:ImportanceSchizophrenia is a complex heritable disorder associated with many genetic variants, each with a small effect. While cortical differences between patients with schizophrenia and healthy controls are consistently reported, the underlying molecular mechanisms remain elusive.ObjectiveTo investigate the extent of shared genetic architecture between schizophrenia and brain cortical surface area (SA) and thickness (TH) and to identify shared genomic loci.Design, setting, and participantsIndependent genome-wide association study data on schizophrenia (Psychiatric Genomics Consortium and CLOZUK: n = 105 318) and SA and TH (UK Biobank: n = 33 735) were obtained. The extent of polygenic overlap was investigated using MiXeR. The specific shared genomic loci were identified by conditional/conjunctional false discovery rate analysis and were further examined in 3 independent cohorts. Data were collected from December 2019 to February 2021, and data analysis was performed from May 2020 to February 2021.Main outcomes and measuresThe primary outcomes were estimated fractions of polygenic overlap between schizophrenia, total SA, and average TH and a list of functionally characterized shared genomic loci.ResultsBased on genome-wide association study data from 139 053 participants, MiXeR estimated schizophrenia to be more polygenic (9703 single-nucleotide variants [SNVs]) than total SA (2101 SNVs) and average TH (1363 SNVs). Most SNVs associated with total SA (1966 of 2101 [93.6%]) and average TH (1322 of 1363 [97.0%]) may be associated with the development of schizophrenia. Subsequent conjunctional false discovery rate analysis identified 44 and 23 schizophrenia risk loci shared with total SA and average TH, respectively. The SNV associations of shared loci between schizophrenia and total SA revealed en masse concordant association between the discovery and independent cohorts. After removing high linkage disequilibrium regions, such as the major histocompatibility complex region, the shared loci were enriched in immunologic signature gene sets. Polygenic overlap and shared loci between schizophrenia and schizophrenia-associated regions of interest for SA (superior frontal and middle temporal gyri) and for TH (superior temporal, inferior temporal, and superior frontal gyri) were also identified.Conclusions and relevanceThis study demonstrated shared genetic loci between cortical morphometry and schizophrenia, among which a subset are associated with immunity. These findings provide an insight into the complex genetic architecture and associated with schizophrenia.

Dataset Information

Multivariate genomic architecture of cortical thickness and surface area at multiple levels of analysis.

Publications

Multivariate genomic architecture of cortical thickness and surface area at multiple levels of analysis.

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