The genetic relationship between the corpus callosum, bipolar disorder and alcohol use

Campbell, Megan Loraine

The genetic relationship between the corpus callosum, bipolar disorder and alcohol use

Thesis / Dissertation

2025

Publisher

University of Cape Town

Department

Department of Psychiatry and Mental Health

Faculty

Faculty of Health Sciences

Abstract

Background: The corpus callosum (CC) is a brain structure responsible for the integration of information across the two cerebral hemispheres to facilitate language, affective- and sensorimotor function. Morphological alterations in sub-regions of this structure have been observed in various psychiatric disorders, particularly bipolar disorder and alcohol consumption. Although the CC has a high heritability (0.67 for total CC; family study) the genetic architecture of the entire structure, its subregions, and any genetic links with psychiatric disorders remain largely unclear. Therefore, the aim of this study was to investigate the genetic architecture of the CC, and this was accomplished by the following objectives: elucidating the single nucleotide polymorphism (SNP)- based heritability and polygenic architecture of the CC and its subregions, and by investigating the genetic overlap between the CC and its subregions with psychiatric disorders, including bipolar disorder and alcohol consumption. Methods: Multivariate and univariate genome-wide association studies (GWAS) were conducted utilizing genetic and T1-weighted magnetic resonance imaging (MRI) data of 40,894 individuals from the UK Biobank. The volume of the five subregions of the CC (posterior, mid-posterior, central, mid-anterior and anterior) were extracted using FreeSurfer v7.1. Multivariate GWAS was run combining volumes of all CC subregions. Multivariate GWAS was conducted to boost genetic discovery and to assess the pleiotropic effects across volumes of the five subregions of the CC. Univariate GWAS was conducted across CC subregion volumes and the 28 diffusion weighted imaging modalities. All analyses were co varied for age, age squared, sex, scanning site, Euler score (a proxy of image quality), total intracranial volume and the first 20 genetic principal components. Annotations of GWAS summary statistics were conducted using OpenTargets and gene-set enrichment analyses were performed using hypergeometric tests. Linkage disequilibrium score regression (LDSC) was 5 used to determine SNP-based heritability of the CC and subregions (for both volume and diffusion weighted modalities), as well as to assess genetic correlations between these subregions and relevant psychiatric and substance use phenotypes. A causal mixture model framework was employed to determine the polygenicity of each subregion and related psychiatric traits and, leveraging pleiotropy using the conjunctional false discovery rate (cFDR) framework, shared loci between the CC and psychiatric phenotypes were identified. Results: This study identified seventy independent loci with distributed effects across volumes of the CC subregions, with additional loci showing subregion-specific associations. Univariate GWAS analysis of diffusion metrics revealed a total of 1,520 significant genetic loci associated with diffusion metrics in the subregions of the CC. The polygenicity varied across diffusion modalities and subregions, ranging from 268 to 7,069 trait-influencing variants. The mean number of trait-influencing variants ranged from 1,560 to 2,865 across different diffusion metric groups and 2,385 to 3,108 across subregions. It was found that CC subregion volumes are influenced by approximately 1,400 to 1,800 genetic variants, with approximately 1,800 variants influencing total CC volume. The SNP-based heritability estimates varied, with CC volume showing a relatively high heritability (h2 snp=0.38, SE=0.03) and subregion volumes ranging from 0.22 (SE=0.02; mid-posterior) to 0.37 (SE=0.03; posterior). Significant genetic correlations were observed between CC volume and bipolar disorder, major depressive disorder, drinks per week, cannabis use. The diffusion metrics also showed subregion-specific correlations with CC volume, bipolar disorder and alcohol consumption. The genetic overlap between the CC and psychiatric phenotypes differed across subregions, with anterior regions showing almost complete overlap with bipolar disorder and schizophrenia, while the central region exhibited substantial overlap with drinks per week. In conjunctional analysis, I identified 138 significant independent variants between CC subregions and psychiatric 6 phenotypes, and gene-set enrichment analysis implicated antigen processing, regulation of the extracellular matrix, and hyaluronan metabolism as significant pathways. Conclusion: These results demonstrate that the CC possesses a polygenic architecture and has a substantial SNP-based heritability across its subregions. Distinct genetic loci were implicated in the CC's anterior and posterior subregions, which is in line with their different functional specializations. There was evidence of significant genetic correlation of the CC with BD, MDD, as well as between the CC and substance use phenotypes (drinks per week and cannabis consumption). Moreover, substantial genetic overlap was observed between the CC with SCZ and BD, and alcohol consumption. These findings of overlapping genetic architectures of the CC and these psychiatric phenotypes suggest the existence of shared biological pathways that may have value in the development of targeted treatment strategies

Keywords

Psychiatry and Mental Health

Reference:

Collections

PhD / Doctoral

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