Characterising the shared genetic influences between schizophrenia and subcortical brain regions
- Wooton, Olivia, Campbell, Megan M, Jahanshad, Neda, Thompson, Paul, Stein, Dan J, Dalvie, Shareefa
- Authors: Wooton, Olivia , Campbell, Megan M , Jahanshad, Neda , Thompson, Paul , Stein, Dan J , Dalvie, Shareefa
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/302450 , vital:58197 , xlink:href="https://doi.org/10.1016/j.euroneuro.2022.07.533"
- Description: Background: Abnormalities in brain structural volumes are well established in schizophrenia (SZ) and have been proposed as an endophenotype for the disorder. Despite increasing interest in the genetic relationship between brain structural volumes and SZ, our knowledge of the genetic overlap between the phenotypes is limited. This study aims to extend our current understanding of the shared genetic influences between SZ and subcortical brain volumes using data from the latest genome-wide association studies for the respective phenotypes (GWAS) and novel statistical approaches. Additionally, we will explore whether the association between schizophrenia and abnormal regional brain volumes is causal in nature. Methods: Summary statistics were obtained from the largest Psychiatric Genomic Consortium (PGC)-SZ GWAS (Ncase = 69,369, Ncontrol = 236,642) and the CHARGEENIGMA-UKBB GWAS of volumetric measures for eight subcortical brain regions (the nucleus accumbens, amygdala, brainstem, caudate nucleus, hippocampus, globus pallidus, putamen, and thalamus), and total intracranial volume (N = 30,983 - 40,380). Single nucleotide polymorphism (SNP) effect concordance analysis (SECA) was used to assess pleiotropy and concordance. Genetic correlation was assessed using linkage disequilibrium score regression (LDSR) and the pleiotropy informed conditional FDR approach was applied to identify SNPs associated with SZ conditional on their association with subcortical brain volumes. Mendelian randomization (MR) was used to test for causal association between SZ and each brain region. Results: There was evidence of global pleiotropy between SZ, and all examined subcortical brain regions. Inverse concordance between the genetic determinants of SZ and volumes of the nucleus accumbens, amygdala, brainstem, hippocampus, and thalamus was observed. Increased statistical power to detect SZ risk loci was shown when conditioning on subcortical brain volumes. There was no significant evidence for a causal effect of any of the examined brain regions on schizophrenia risk. Discussion: These data confirm the shared genetic basis of SZ and specific intracranial and subcortical brain volumes and provide evidence for negative concordance between SZ and volumes of the nucleus accumbens, amygdala, brainstem, hippocampus, and thalamus. Leveraging the genetic overlap between SZ and subcortical brain volumes has the potential to provide novel insights into the biological basis of the disorder.
- Full Text:
- Date Issued: 2022
- Authors: Wooton, Olivia , Campbell, Megan M , Jahanshad, Neda , Thompson, Paul , Stein, Dan J , Dalvie, Shareefa
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/302450 , vital:58197 , xlink:href="https://doi.org/10.1016/j.euroneuro.2022.07.533"
- Description: Background: Abnormalities in brain structural volumes are well established in schizophrenia (SZ) and have been proposed as an endophenotype for the disorder. Despite increasing interest in the genetic relationship between brain structural volumes and SZ, our knowledge of the genetic overlap between the phenotypes is limited. This study aims to extend our current understanding of the shared genetic influences between SZ and subcortical brain volumes using data from the latest genome-wide association studies for the respective phenotypes (GWAS) and novel statistical approaches. Additionally, we will explore whether the association between schizophrenia and abnormal regional brain volumes is causal in nature. Methods: Summary statistics were obtained from the largest Psychiatric Genomic Consortium (PGC)-SZ GWAS (Ncase = 69,369, Ncontrol = 236,642) and the CHARGEENIGMA-UKBB GWAS of volumetric measures for eight subcortical brain regions (the nucleus accumbens, amygdala, brainstem, caudate nucleus, hippocampus, globus pallidus, putamen, and thalamus), and total intracranial volume (N = 30,983 - 40,380). Single nucleotide polymorphism (SNP) effect concordance analysis (SECA) was used to assess pleiotropy and concordance. Genetic correlation was assessed using linkage disequilibrium score regression (LDSR) and the pleiotropy informed conditional FDR approach was applied to identify SNPs associated with SZ conditional on their association with subcortical brain volumes. Mendelian randomization (MR) was used to test for causal association between SZ and each brain region. Results: There was evidence of global pleiotropy between SZ, and all examined subcortical brain regions. Inverse concordance between the genetic determinants of SZ and volumes of the nucleus accumbens, amygdala, brainstem, hippocampus, and thalamus was observed. Increased statistical power to detect SZ risk loci was shown when conditioning on subcortical brain volumes. There was no significant evidence for a causal effect of any of the examined brain regions on schizophrenia risk. Discussion: These data confirm the shared genetic basis of SZ and specific intracranial and subcortical brain volumes and provide evidence for negative concordance between SZ and volumes of the nucleus accumbens, amygdala, brainstem, hippocampus, and thalamus. Leveraging the genetic overlap between SZ and subcortical brain volumes has the potential to provide novel insights into the biological basis of the disorder.
- Full Text:
- Date Issued: 2022
Systematic review of genome-wide association studies of anxiety disorders and neuroticism
- Van Der Walt, Kristien, Campbell, Megan, Stein, Dan J, Dalvie, Shareefa
- Authors: Van Der Walt, Kristien , Campbell, Megan , Stein, Dan J , Dalvie, Shareefa
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/302532 , vital:58205 , xlink:href="https://doi.org//10.1080/15622975.2022.2099970"
- Description: Objectives: To summarise SNP associations identified by genome-wide association studies (GWASs) of anxiety disorders and neuroticism; to appraise the quality of individual studies, and to assess the ancestral diversity of study participants. Methods: We searched PubMed, Scopus, PsychInfo and PubPsych for GWASs of anxiety disorders, non-diagnostic traits (such as anxiety sensitivity), and neuroticism, and extracted all SNPs that surpassed genome-wide significance. We graded study quality using Q-genie scores and reviewed the ancestral diversity of included participants. Results: 32 studies met our inclusion criteria. A total of 563 independent significant variants were identified, of which 29 were replicated nominally in independent samples, and 3 were replicated significantly. The studies had good global quality, but many smaller studies were underpowered. Phenotypic heterogeneity for anxiety (and less so for neuroticism) seemed to reflect the complexity of capturing this trait. Ancestral diversity was poor, with 70% of studies including only populations of European ancestry. Conclusion: The functionality of genes identified by GWASs of anxiety and neuroticism deserves further investigation. Future GWASs should have larger sample sizes, more rigorous phenotyping and include more ancestrally diverse population groups.
- Full Text:
- Date Issued: 2022
- Authors: Van Der Walt, Kristien , Campbell, Megan , Stein, Dan J , Dalvie, Shareefa
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/302532 , vital:58205 , xlink:href="https://doi.org//10.1080/15622975.2022.2099970"
- Description: Objectives: To summarise SNP associations identified by genome-wide association studies (GWASs) of anxiety disorders and neuroticism; to appraise the quality of individual studies, and to assess the ancestral diversity of study participants. Methods: We searched PubMed, Scopus, PsychInfo and PubPsych for GWASs of anxiety disorders, non-diagnostic traits (such as anxiety sensitivity), and neuroticism, and extracted all SNPs that surpassed genome-wide significance. We graded study quality using Q-genie scores and reviewed the ancestral diversity of included participants. Results: 32 studies met our inclusion criteria. A total of 563 independent significant variants were identified, of which 29 were replicated nominally in independent samples, and 3 were replicated significantly. The studies had good global quality, but many smaller studies were underpowered. Phenotypic heterogeneity for anxiety (and less so for neuroticism) seemed to reflect the complexity of capturing this trait. Ancestral diversity was poor, with 70% of studies including only populations of European ancestry. Conclusion: The functionality of genes identified by GWASs of anxiety and neuroticism deserves further investigation. Future GWASs should have larger sample sizes, more rigorous phenotyping and include more ancestrally diverse population groups.
- Full Text:
- Date Issued: 2022
The genetic architecture of the corpus callosum and its subregions
- Campbell, Megan M, Dalvie, Shareefa, Shadrin, Alexey, Van der Meer, Dennis, Andreassen, Ola, Stein, Dan J, Rokicki, Jaroslav
- Authors: Campbell, Megan M , Dalvie, Shareefa , Shadrin, Alexey , Van der Meer, Dennis , Andreassen, Ola , Stein, Dan J , Rokicki, Jaroslav
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/302542 , vital:58206 , xlink:href="https://doi.org/10.1016/j.euroneuro.2022.07.263"
- Description: Background: Regional surface area and thickness of the cerebral cortex and volume of subcortical structures are highly heritable brain morphological features with complex genetic architectures, involving many common genetic variants with small effect sizes. However, the genetic architecture of the corpus callosum (CC) and its subregions remains largely unclear. We aim to determine the heritability and genetic architecture of CC volume and each subregion and the extent to which this overlaps with that of psychiatric disorders. Methods: Genetic and T1-weighted MRI data of 40,894 individuals from the UK-biobank was used to construct a multivariate GWAS. Here, we utilized a multivariate approach (Multivariate Omnibus Statistical Test, MOSTest) to assess the distributive effects of common variants across the five subregions of the CC (posterior, mid posterior, central, mid anterior and anterior) obtained by running the automatic subcortical segmentation algorithm in FreeSurfer 5.3. Gene-set enrichment analyses were performed using MAGMA. Linkage disequilibrium score regression was used to determine the SNP-based heritability of the CC and will be used to assess the genetic correlation between each subregion and a variety of psychiatric disorders. Results: Following MOSTest, 70 independent loci show pooled effects across the 5 subregions of the CC (p more than 5×10-8). Using LDSC, we found evidence to suggest that CC volume is heritable (h2SNP= 0.38, SE=0.03). Significant variants showed enrichment in pathways related to regulation of the nervous system and cell development, neurogenesis, and regulation of neuron differentiation. Gene-set analysis revealed 156 significant genes (p is less than 2.6x10-6). Many of the significant SNPs have been previously associated with white matter hyperintensity volume as well as a range of psychiatric disorders. Discussion: Here we provide the first preliminary evidence to suggest that volume of the CC is heritable. Gene set enrichment analyses identified pathways related to neuron development and neurogenesis, suggesting that CC alteration may have an independent developmental origin. Further investigation into the shared genetic architecture of CC subregions and psychiatric disorders may provide novel insight into disease manifestation.
- Full Text:
- Date Issued: 2022
- Authors: Campbell, Megan M , Dalvie, Shareefa , Shadrin, Alexey , Van der Meer, Dennis , Andreassen, Ola , Stein, Dan J , Rokicki, Jaroslav
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/302542 , vital:58206 , xlink:href="https://doi.org/10.1016/j.euroneuro.2022.07.263"
- Description: Background: Regional surface area and thickness of the cerebral cortex and volume of subcortical structures are highly heritable brain morphological features with complex genetic architectures, involving many common genetic variants with small effect sizes. However, the genetic architecture of the corpus callosum (CC) and its subregions remains largely unclear. We aim to determine the heritability and genetic architecture of CC volume and each subregion and the extent to which this overlaps with that of psychiatric disorders. Methods: Genetic and T1-weighted MRI data of 40,894 individuals from the UK-biobank was used to construct a multivariate GWAS. Here, we utilized a multivariate approach (Multivariate Omnibus Statistical Test, MOSTest) to assess the distributive effects of common variants across the five subregions of the CC (posterior, mid posterior, central, mid anterior and anterior) obtained by running the automatic subcortical segmentation algorithm in FreeSurfer 5.3. Gene-set enrichment analyses were performed using MAGMA. Linkage disequilibrium score regression was used to determine the SNP-based heritability of the CC and will be used to assess the genetic correlation between each subregion and a variety of psychiatric disorders. Results: Following MOSTest, 70 independent loci show pooled effects across the 5 subregions of the CC (p more than 5×10-8). Using LDSC, we found evidence to suggest that CC volume is heritable (h2SNP= 0.38, SE=0.03). Significant variants showed enrichment in pathways related to regulation of the nervous system and cell development, neurogenesis, and regulation of neuron differentiation. Gene-set analysis revealed 156 significant genes (p is less than 2.6x10-6). Many of the significant SNPs have been previously associated with white matter hyperintensity volume as well as a range of psychiatric disorders. Discussion: Here we provide the first preliminary evidence to suggest that volume of the CC is heritable. Gene set enrichment analyses identified pathways related to neuron development and neurogenesis, suggesting that CC alteration may have an independent developmental origin. Further investigation into the shared genetic architecture of CC subregions and psychiatric disorders may provide novel insight into disease manifestation.
- Full Text:
- Date Issued: 2022
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