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
Measuring discrimination experienced by people with a mental illness
- Brohan, Elaine, Thornicroft, Graham, Rüsch, Nicolas, Lasalvia, Antonio, Campbell, Megan M, Yalçınkaya-Alkar, Özden, Lanfredi, Mariangela, Ochoa, Susana, Üçok, Alp, Tomás, Catarina, Fadipe, Babatunde, Sebes, Julia, Fiorillo, Andrea, Sampogna, Gaia, Paula, Cristiane Silvestre, Valverde, Leonadis, Schomerus, Georg, Klemm, Pia, Ouali, Uta, Castelein, Stynke, Alexová, Aneta, Oexle, Nathalie, Guimarães, Patrícia Neves, Sportel, Bouwina Esther, Chang, Chih-Cheng, Li, Jie, Shanthi, Chilasagaram, Reneses, Blanca, Bakolis, Ioannis, Evans-Lacko, Sarah
- Authors: Brohan, Elaine , Thornicroft, Graham , Rüsch, Nicolas , Lasalvia, Antonio , Campbell, Megan M , Yalçınkaya-Alkar, Özden , Lanfredi, Mariangela , Ochoa, Susana , Üçok, Alp , Tomás, Catarina , Fadipe, Babatunde , Sebes, Julia , Fiorillo, Andrea , Sampogna, Gaia , Paula, Cristiane Silvestre , Valverde, Leonadis , Schomerus, Georg , Klemm, Pia , Ouali, Uta , Castelein, Stynke , Alexová, Aneta , Oexle, Nathalie , Guimarães, Patrícia Neves , Sportel, Bouwina Esther , Chang, Chih-Cheng , Li, Jie , Shanthi, Chilasagaram , Reneses, Blanca , Bakolis, Ioannis , Evans-Lacko, Sarah
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/302498 , vital:58202 , xlink:href="https://doi.org/10.1017/S0033291722000630"
- Description: Background: The Discrimination and Stigma Scale (DISC) is a patient-reported outcome measure which assesses experiences of discrimination among persons with a mental illness globally. Methods: This study evaluated whether the psychometric properties of a short-form version, DISC-Ultra Short (DISCUS) (11-item), could be replicated in a sample of people with a wide range of mental disorders from 21 sites in 15 countries/territories, across six global regions. The frequency of experienced discrimination was reported. Scaling assumptions (confirmatory factor analysis, inter-item and item-total correlations), reliability (internal consistency) and validity (convergent validity, known groups method) were investigated in each region, and by diagnosis group. Results: 1195 people participated. The most frequently reported experiences of discrimination were being shunned or avoided at work (48.7%) and discrimination in making or keeping friends (47.2%). Confirmatory factor analysis supported a unidimensional model across all six regions and five diagnosis groups. Convergent validity was confirmed in the total sample and within all regions [ Internalised Stigma of Mental Illness (ISMI-10): 0.28–0.67, stopping self: 0.54–0.72, stigma consciousness: −0.32–0.57], as was internal consistency reliability (α = 0.74–0.84). Known groups validity was established in the global sample with levels of experienced discrimination significantly higher for those experiencing higher depression [Patient Health Questionnaire (PHQ)-2: p more than 0.001], lower mental wellbeing [Warwick-Edinburgh Well-being Scale (WEMWBS): p is less than 0.001], higher suicidal ideation [Beck Hopelessness Scale (BHS)-4: p is less than 0.001] and higher risk of suicidal behaviour [Suicidal Ideation Attributes Scale (SIDAS): p is less than 0.001]. Conclusions: The DISCUS is a reliable and valid unidimensional measure of experienced discrimination for use in global settings with similar properties to the longer DISC. It offers a brief assessment of experienced discrimination for use in clinical and research settings.
- Full Text:
- Date Issued: 2022
- Authors: Brohan, Elaine , Thornicroft, Graham , Rüsch, Nicolas , Lasalvia, Antonio , Campbell, Megan M , Yalçınkaya-Alkar, Özden , Lanfredi, Mariangela , Ochoa, Susana , Üçok, Alp , Tomás, Catarina , Fadipe, Babatunde , Sebes, Julia , Fiorillo, Andrea , Sampogna, Gaia , Paula, Cristiane Silvestre , Valverde, Leonadis , Schomerus, Georg , Klemm, Pia , Ouali, Uta , Castelein, Stynke , Alexová, Aneta , Oexle, Nathalie , Guimarães, Patrícia Neves , Sportel, Bouwina Esther , Chang, Chih-Cheng , Li, Jie , Shanthi, Chilasagaram , Reneses, Blanca , Bakolis, Ioannis , Evans-Lacko, Sarah
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/302498 , vital:58202 , xlink:href="https://doi.org/10.1017/S0033291722000630"
- Description: Background: The Discrimination and Stigma Scale (DISC) is a patient-reported outcome measure which assesses experiences of discrimination among persons with a mental illness globally. Methods: This study evaluated whether the psychometric properties of a short-form version, DISC-Ultra Short (DISCUS) (11-item), could be replicated in a sample of people with a wide range of mental disorders from 21 sites in 15 countries/territories, across six global regions. The frequency of experienced discrimination was reported. Scaling assumptions (confirmatory factor analysis, inter-item and item-total correlations), reliability (internal consistency) and validity (convergent validity, known groups method) were investigated in each region, and by diagnosis group. Results: 1195 people participated. The most frequently reported experiences of discrimination were being shunned or avoided at work (48.7%) and discrimination in making or keeping friends (47.2%). Confirmatory factor analysis supported a unidimensional model across all six regions and five diagnosis groups. Convergent validity was confirmed in the total sample and within all regions [ Internalised Stigma of Mental Illness (ISMI-10): 0.28–0.67, stopping self: 0.54–0.72, stigma consciousness: −0.32–0.57], as was internal consistency reliability (α = 0.74–0.84). Known groups validity was established in the global sample with levels of experienced discrimination significantly higher for those experiencing higher depression [Patient Health Questionnaire (PHQ)-2: p more than 0.001], lower mental wellbeing [Warwick-Edinburgh Well-being Scale (WEMWBS): p is less than 0.001], higher suicidal ideation [Beck Hopelessness Scale (BHS)-4: p is less than 0.001] and higher risk of suicidal behaviour [Suicidal Ideation Attributes Scale (SIDAS): p is less than 0.001]. Conclusions: The DISCUS is a reliable and valid unidimensional measure of experienced discrimination for use in global settings with similar properties to the longer DISC. It offers a brief assessment of experienced discrimination for use in clinical and research settings.
- 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
Validity of categories related to gender identity in ICD-11 and DSM-5 among transgender individuals who seek gender-affirming medical procedures
- Robles, Rebeca, Keeley, Jared W, Vega-Ramírez, H, Cruz-Islas, Jeremy, Rodríguez-Pérez, Victor, Sharan, Pratap, Purnima, Shivani, Rao, Ravindra, Rodrigues-Lobato, María I, Soll, Bianca, Askevis-Leherpeux, Françoise, Roelandt, Jean-Luc, Campbell, Megan M, Grobler, Gerhard, Stein, Dan H, Khoury, Brigitte, El Khoury, Joseph, Fresán, Ana, Medina-Mora, María, Reed, Geoffrey M
- Authors: Robles, Rebeca , Keeley, Jared W , Vega-Ramírez, H , Cruz-Islas, Jeremy , Rodríguez-Pérez, Victor , Sharan, Pratap , Purnima, Shivani , Rao, Ravindra , Rodrigues-Lobato, María I , Soll, Bianca , Askevis-Leherpeux, Françoise , Roelandt, Jean-Luc , Campbell, Megan M , Grobler, Gerhard , Stein, Dan H , Khoury, Brigitte , El Khoury, Joseph , Fresán, Ana , Medina-Mora, María , Reed, Geoffrey M
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/302589 , vital:58210 , xlink:href="https://doi.org/10.1016/j.ijchp.2021.100281"
- Description: Background/Objective: The most recent versions of the two main mental disorders classifications—the World Health Organization's ICD-11 and the American Psychiatric Association's DSM–5—differ substantially in their diagnostic categories related to transgender identity. ICD-11 gender incongruence (GI), in contrast to DSM-5 gender dysphoria (GD), is explicitly not a mental disorder; neither distress nor dysfunction is a required feature. The objective was compared ICD-11 and DSM-5 diagnostic requirements in terms of their sensitivity, specificity, discriminability and ability to predict the use of gender-affirming medical procedures. Method: A total of 649 of transgender adults in six countries completed a retrospective structured interview. Results: Using ROC analysis, sensitivity of the diagnostic requirements was equivalent for both systems, but ICD-11 showed greater specificity than DSM-5. Regression analyses indicated that history of hormones and/or surgery was predicted by variables that are an intrinsic aspect of GI/GD more than by distress and dysfunction. IRT analyses showed that the ICD-11 diagnostic formulation was more parsimonious and contained more information about caseness than the DSM-5 model. Conclusions: This study supports the ICD-11 position that GI/GD is not a mental disorder; additional diagnostic requirements of distress and/or dysfunction in DSM-5 reduce the predictive power of the diagnostic model.
- Full Text:
- Date Issued: 2022
- Authors: Robles, Rebeca , Keeley, Jared W , Vega-Ramírez, H , Cruz-Islas, Jeremy , Rodríguez-Pérez, Victor , Sharan, Pratap , Purnima, Shivani , Rao, Ravindra , Rodrigues-Lobato, María I , Soll, Bianca , Askevis-Leherpeux, Françoise , Roelandt, Jean-Luc , Campbell, Megan M , Grobler, Gerhard , Stein, Dan H , Khoury, Brigitte , El Khoury, Joseph , Fresán, Ana , Medina-Mora, María , Reed, Geoffrey M
- Date: 2022
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/302589 , vital:58210 , xlink:href="https://doi.org/10.1016/j.ijchp.2021.100281"
- Description: Background/Objective: The most recent versions of the two main mental disorders classifications—the World Health Organization's ICD-11 and the American Psychiatric Association's DSM–5—differ substantially in their diagnostic categories related to transgender identity. ICD-11 gender incongruence (GI), in contrast to DSM-5 gender dysphoria (GD), is explicitly not a mental disorder; neither distress nor dysfunction is a required feature. The objective was compared ICD-11 and DSM-5 diagnostic requirements in terms of their sensitivity, specificity, discriminability and ability to predict the use of gender-affirming medical procedures. Method: A total of 649 of transgender adults in six countries completed a retrospective structured interview. Results: Using ROC analysis, sensitivity of the diagnostic requirements was equivalent for both systems, but ICD-11 showed greater specificity than DSM-5. Regression analyses indicated that history of hormones and/or surgery was predicted by variables that are an intrinsic aspect of GI/GD more than by distress and dysfunction. IRT analyses showed that the ICD-11 diagnostic formulation was more parsimonious and contained more information about caseness than the DSM-5 model. Conclusions: This study supports the ICD-11 position that GI/GD is not a mental disorder; additional diagnostic requirements of distress and/or dysfunction in DSM-5 reduce the predictive power of the diagnostic model.
- Full Text:
- Date Issued: 2022
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