Exploration of genetic overlap of brain phenotypes with schizophrenia: different methods provide complementary insights

Wu, Xiao, Parekh, Pravesh, Lin, Bochao Danae, Pries, Lotta-Katrin, Guloksuz, Sinan, Rutten, Bart P F, Andreassen, Ole A, Linden, David E J ORCID: https://orcid.org/0000-0002-5638-9292 and van der Meer, Dennis 2025. Exploration of genetic overlap of brain phenotypes with schizophrenia: different methods provide complementary insights. Schizophrenia Bulletin: The Journal of Psychoses and Related Disorders , sbaf096. 10.1093/schbul/sbaf096

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Abstract

Background: Genetic studies have shown associations between genetic risk for schizophrenia and brain imaging phenotypes. However, prior studies focused on a single neuroimaging modality and/or employed methods that do not fully elucidate the shared genetic architecture between them, limiting our understanding of their complex genetic relationship. Study Design: We used genome-wide association study summary statistics for schizophrenia alongside 37 brain measurements, selected based on adequate SNP-based heritability and representing structural, microstructural, and functional brain features derived from T1, diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI). These were integrated with a clinical cohort (1065 cases, 1037 controls) to examine the polygenic overlap between schizophrenia and brain measurements. Polygenic overlap was assessed at genome-wide and individual locus levels through linkage disequilibrium score regression, polygenic scoring (PGS), bivariate MiXeR, and conjunctional false discovery rate. Study Results: Schizophrenia showed weak genetic correlations with all brain measures (rg = −0.131 to 0.146; PFDR = .069 to .019), and no significant correlation with brain PGS. Nonetheless, a substantial proportion of causal variants with mixed effect direction were shared between schizophrenia and brain traits. Genetic correlations and polygenic scores showed significant positive associations with the proportion of shared variants with concordant effect direction. Additionally, we identified 218 loci shared with schizophrenia in T1, 138 in DTI, and 24 in rs-fMRI measures. Conclusions: Our findings indicate shared genetic underpinnings between schizophrenia and brain structure and functional connectivity, emphasizing the necessity for complementary methodologies to investigate the genetic overlap between complex polygenic traits.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by-nc/4.0/, Type: cc-by-nc
Publisher:	Oxford University Press
ISSN:	0586-7614
Date of First Compliant Deposit:	3 July 2025
Last Modified:	03 Jul 2025 09:45
URI:	https://orca.cardiff.ac.uk/id/eprint/179508

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