Pub Date : 2024-07-18DOI: 10.1038/s41380-024-02645-y
Michele Fornaro, Claudio Caiazza, Martina Billeci, Michael Berk, Wolfgang Marx, Vicent Balanzá-Martinez, Michele De Prisco, Rosanna Pezone, Giuseppe De Simone, Niccolò Solini, Felice Iasevoli, Fabrice Berna, Guillaume Fond, Laurent Boyer, Andre Fèrrer Carvalho, Elena Dragioti, Jess G Fiedorowicz, Andrea de Bartolomeis, Christoph U Correll, Marco Solmi
Sub-optimal response in schizophrenia is frequent, warranting augmentation strategies over treatment-as-usual (TAU). We assessed nutraceuticals/phytoceutical augmentation strategies via network meta-analysis. Randomized controlled trials in schizophrenia/schizoaffective disorder were identified via the following databases: PubMed, MEDLINE, EMBASE, Scopus, PsycINFO, CENTRAL, and ClinicalTrials.gov. Change (Standardized Mean Difference = SMD) in total symptomatology and acceptability (Risk Ratio = RR) were co-primary outcomes. Secondary outcomes were positive, negative, cognitive, and depressive symptom changes, general psychopathology, tolerability, and response rates. We conducted subset analyses by disease phase and sensitivity analyses by risk of bias and assessed global/local inconsistency, publication bias, risk of bias, and confidence in the evidence. The systematic review included 49 records documenting 50 studies (n = 2384) documenting 22 interventions. Citicoline (SMD =-1.05,95%CI = -1.85; -0.24), L-lysine (SMD = -1.04,95%CI = -1.84; -0.25), N-acetylcysteine (SMD = -0.87, 95%CI = -1.27; -0.47) and sarcosine (SMD = -0.5,95%CI = -0.87-0.13) outperformed placebo for total symptomatology. High heterogeneity (tau2 = 0.10, I2 = 55.9%) and global inconsistency (Q = 40.79, df = 18, p = 0.002) emerged without publication bias (Egger's test, p = 0.42). Sarcosine improved negative symptoms (SMD = -0.65, 95%CI = -1.10; -0.19). N-acetylcysteine improved negative symptoms (SMD = -0.90, 95%CI = -1.42; -0.39)/general psychopathology (SMD = -0.76, 95%CI = -1.39; -0.13). No compound improved total symptomatology within acute phase studies (k = 7, n = 422). Sarcosine (SMD = -1.26,95%CI = -1.91; -0.60), citicoline (SMD = -1.05,95%CI = -1.65;-0.44), and N-acetylcysteine (SMD = -0.55,95%CI = -0.92,-0.19) outperformed placebo augmentation in clinically stable participants. Sensitivity analyses removing high-risk-of-bias studies confirmed overall findings in all phases and clinically stable samples. In contrast, the acute phase analysis restricted to low risk-of-bias studies showed a superior effect vs. placebo for N-acetylcysteine (SMD = -1.10, 95%CI = -1.75,-0.45), L-lysine (SMD = -1.05,95%CI = -1.55, -0.19), omega-3 fatty acids (SMD = -0.83,95%CI = -1.31, -0.34) and withania somnifera (SMD = -0.71,95%CI = -1.21,-0.22). Citicoline (SMD = -1.05,95%CI = -1.86,-0.23), L-lysine (SMD = -1.04,95%CI = -1.84,-0.24), N-acetylcysteine (SMD = -0.89,95%CI = -1.35,-0.43) and sarcosine (SMD = -0.61,95%CI = -1.02,-0.21) outperformed placebo augmentation of TAU ("any phase"). Drop-out due to any cause or adverse events did not differ between nutraceutical/phytoceutical vs. placebo+TAU. Sarcosine, citicoline, and N-acetylcysteine are promising augmentation interventions in stable patients with schizophrenia, yet the quality of evidence is low to very low. Further high-quality trials in acute phases/specific outcomes/difficult-to-treat schizophrenia
{"title":"Nutraceuticals and phytoceuticals in the treatment of schizophrenia: a systematic review and network meta-analysis \"Nutra NMA SCZ\".","authors":"Michele Fornaro, Claudio Caiazza, Martina Billeci, Michael Berk, Wolfgang Marx, Vicent Balanzá-Martinez, Michele De Prisco, Rosanna Pezone, Giuseppe De Simone, Niccolò Solini, Felice Iasevoli, Fabrice Berna, Guillaume Fond, Laurent Boyer, Andre Fèrrer Carvalho, Elena Dragioti, Jess G Fiedorowicz, Andrea de Bartolomeis, Christoph U Correll, Marco Solmi","doi":"10.1038/s41380-024-02645-y","DOIUrl":"10.1038/s41380-024-02645-y","url":null,"abstract":"<p><p>Sub-optimal response in schizophrenia is frequent, warranting augmentation strategies over treatment-as-usual (TAU). We assessed nutraceuticals/phytoceutical augmentation strategies via network meta-analysis. Randomized controlled trials in schizophrenia/schizoaffective disorder were identified via the following databases: PubMed, MEDLINE, EMBASE, Scopus, PsycINFO, CENTRAL, and ClinicalTrials.gov. Change (Standardized Mean Difference = SMD) in total symptomatology and acceptability (Risk Ratio = RR) were co-primary outcomes. Secondary outcomes were positive, negative, cognitive, and depressive symptom changes, general psychopathology, tolerability, and response rates. We conducted subset analyses by disease phase and sensitivity analyses by risk of bias and assessed global/local inconsistency, publication bias, risk of bias, and confidence in the evidence. The systematic review included 49 records documenting 50 studies (n = 2384) documenting 22 interventions. Citicoline (SMD =-1.05,95%CI = -1.85; -0.24), L-lysine (SMD = -1.04,95%CI = -1.84; -0.25), N-acetylcysteine (SMD = -0.87, 95%CI = -1.27; -0.47) and sarcosine (SMD = -0.5,95%CI = -0.87-0.13) outperformed placebo for total symptomatology. High heterogeneity (tau<sup>2</sup> = 0.10, I<sup>2</sup> = 55.9%) and global inconsistency (Q = 40.79, df = 18, p = 0.002) emerged without publication bias (Egger's test, p = 0.42). Sarcosine improved negative symptoms (SMD = -0.65, 95%CI = -1.10; -0.19). N-acetylcysteine improved negative symptoms (SMD = -0.90, 95%CI = -1.42; -0.39)/general psychopathology (SMD = -0.76, 95%CI = -1.39; -0.13). No compound improved total symptomatology within acute phase studies (k = 7, n = 422). Sarcosine (SMD = -1.26,95%CI = -1.91; -0.60), citicoline (SMD = -1.05,95%CI = -1.65;-0.44), and N-acetylcysteine (SMD = -0.55,95%CI = -0.92,-0.19) outperformed placebo augmentation in clinically stable participants. Sensitivity analyses removing high-risk-of-bias studies confirmed overall findings in all phases and clinically stable samples. In contrast, the acute phase analysis restricted to low risk-of-bias studies showed a superior effect vs. placebo for N-acetylcysteine (SMD = -1.10, 95%CI = -1.75,-0.45), L-lysine (SMD = -1.05,95%CI = -1.55, -0.19), omega-3 fatty acids (SMD = -0.83,95%CI = -1.31, -0.34) and withania somnifera (SMD = -0.71,95%CI = -1.21,-0.22). Citicoline (SMD = -1.05,95%CI = -1.86,-0.23), L-lysine (SMD = -1.04,95%CI = -1.84,-0.24), N-acetylcysteine (SMD = -0.89,95%CI = -1.35,-0.43) and sarcosine (SMD = -0.61,95%CI = -1.02,-0.21) outperformed placebo augmentation of TAU (\"any phase\"). Drop-out due to any cause or adverse events did not differ between nutraceutical/phytoceutical vs. placebo+TAU. Sarcosine, citicoline, and N-acetylcysteine are promising augmentation interventions in stable patients with schizophrenia, yet the quality of evidence is low to very low. Further high-quality trials in acute phases/specific outcomes/difficult-to-treat schizophrenia ","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-17DOI: 10.1038/s41380-024-02669-4
Jana Hagen, Shukti Ramkiran, Gereon J Schnellbächer, Ravichandran Rajkumar, Maria Collee, Nibal Khudeish, Tanja Veselinović, N Jon Shah, Irene Neuner
Major depressive disorder (MDD) typically manifests itself in depressed affect, anhedonia, low energy, and additional symptoms. Despite its high global prevalence, its pathophysiology still gives rise to questions. Current research places alterations in functional connectivity among MDD's most promising biomarkers. However, given the heterogeneity of previous findings, the use of higher-resolution imaging techniques, like ultra-high field (UHF) fMRI (≥7 Tesla, 7T), may offer greater specificity in delineating fundamental impairments. In this study, 7T UHF fMRI scans were conducted on 31 MDD patients and 27 age-gender matched healthy controls to exploratorily contrast cerebral resting-state functional connectivity patterns between both groups. The CONN toolbox was used to generate functional network connectivity (FNC) analysis based on the region of interest (ROI)-to-ROI correlations in order to enable the identification of clusters of significantly different connections. Correction for multiple comparisons was implemented at the cluster level using a false discovery rate (FDR). The analysis revealed three significant clusters differentiating MDD patients and healthy controls. In Clusters 1 and 2, MDD patients exhibited between-network hypoconnectivity in basal ganglia-cortical pathways as well as hyperconnectivity in thalamo-cortical pathways, including several individual ROI-to-ROI connections. In Cluster 3, they showed increased occipital interhemispheric within-network connectivity. These findings suggest that alterations in basal ganglia-thalamo-cortical circuits play a substantial role in the pathophysiology of MDD. Furthermore, they indicate potential MDD-related deficits relating to a combination of perception (vision, audition, and somatosensation) as well as more complex functions, especially social-emotional processing, modulation, and regulation. It is anticipated that these findings might further inform more accurate clinical procedures for addressing MDD.
{"title":"Phenomena of hypo- and hyperconnectivity in basal ganglia-thalamo-cortical circuits linked to major depression: a 7T fMRI study.","authors":"Jana Hagen, Shukti Ramkiran, Gereon J Schnellbächer, Ravichandran Rajkumar, Maria Collee, Nibal Khudeish, Tanja Veselinović, N Jon Shah, Irene Neuner","doi":"10.1038/s41380-024-02669-4","DOIUrl":"https://doi.org/10.1038/s41380-024-02669-4","url":null,"abstract":"<p><p>Major depressive disorder (MDD) typically manifests itself in depressed affect, anhedonia, low energy, and additional symptoms. Despite its high global prevalence, its pathophysiology still gives rise to questions. Current research places alterations in functional connectivity among MDD's most promising biomarkers. However, given the heterogeneity of previous findings, the use of higher-resolution imaging techniques, like ultra-high field (UHF) fMRI (≥7 Tesla, 7T), may offer greater specificity in delineating fundamental impairments. In this study, 7T UHF fMRI scans were conducted on 31 MDD patients and 27 age-gender matched healthy controls to exploratorily contrast cerebral resting-state functional connectivity patterns between both groups. The CONN toolbox was used to generate functional network connectivity (FNC) analysis based on the region of interest (ROI)-to-ROI correlations in order to enable the identification of clusters of significantly different connections. Correction for multiple comparisons was implemented at the cluster level using a false discovery rate (FDR). The analysis revealed three significant clusters differentiating MDD patients and healthy controls. In Clusters 1 and 2, MDD patients exhibited between-network hypoconnectivity in basal ganglia-cortical pathways as well as hyperconnectivity in thalamo-cortical pathways, including several individual ROI-to-ROI connections. In Cluster 3, they showed increased occipital interhemispheric within-network connectivity. These findings suggest that alterations in basal ganglia-thalamo-cortical circuits play a substantial role in the pathophysiology of MDD. Furthermore, they indicate potential MDD-related deficits relating to a combination of perception (vision, audition, and somatosensation) as well as more complex functions, especially social-emotional processing, modulation, and regulation. It is anticipated that these findings might further inform more accurate clinical procedures for addressing MDD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141634005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-17DOI: 10.1038/s41380-024-02674-7
Kirsten Berding, Thomaz F S Bastiaanssen, Gerard M Moloney, Gerard Clarke, Timothy G Dinan, John F Cryan
{"title":"Adherence to a psychobiotic diet stabilizes the microbiome and reduces perceived stress: plenty of food for thought.","authors":"Kirsten Berding, Thomaz F S Bastiaanssen, Gerard M Moloney, Gerard Clarke, Timothy G Dinan, John F Cryan","doi":"10.1038/s41380-024-02674-7","DOIUrl":"https://doi.org/10.1038/s41380-024-02674-7","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-16DOI: 10.1038/s41380-024-02662-x
S. C. Kanjira, M. J. Adams, Y. Jiang, C. Tian, C. M. Lewis, K. Kuchenbaecker, A. M. McIntosh
Genome-Wide Association Studies (GWAS) over-represent European ancestries, neglecting all other ancestry groups and low-income nations. Consequently, polygenic risk scores (PRS) more accurately predict complex traits in Europeans than African Ancestries groups. Very few studies have looked at the transferability of European-derived PRS for behavioural and mental health phenotypes to Africans. We assessed the comparative accuracy of depression PRS trained on European and African Ancestries GWAS studies to predict major depressive disorder (MDD) and related traits in African ancestry participants from the UK Biobank. UK Biobank participants were selected based on Principal component analysis clustering with an African genetic similarity reference population, MDD was assessed with the Composite International Diagnostic Interview (CIDI). PRS were computed using PRSice2 software using either European or African Ancestries GWAS summary statistics. PRS trained on European ancestry samples (246,363 cases) predicted case control status in Africans of the UK Biobank with similar accuracies (R2 = 2%, β = 0.32, empirical p-value = 0.002) to PRS trained on far much smaller samples of African Ancestries participants from 23andMe, Inc. (5045 cases, R² = 1.8%, β = 0.28, empirical p-value = 0.008). This suggests that prediction of MDD status from Africans to Africans had greater efficiency relative to discovery sample size than prediction of MDD from Europeans to Africans. Prediction of MDD status in African UK Biobank participants using GWAS findings of likely causal risk factors from European ancestries was non-significant. GWAS of MDD in European ancestries are inefficient for improving polygenic prediction in African samples; urgent MDD studies in Africa are needed.
{"title":"Polygenic prediction of major depressive disorder and related traits in African ancestries UK Biobank participants","authors":"S. C. Kanjira, M. J. Adams, Y. Jiang, C. Tian, C. M. Lewis, K. Kuchenbaecker, A. M. McIntosh","doi":"10.1038/s41380-024-02662-x","DOIUrl":"https://doi.org/10.1038/s41380-024-02662-x","url":null,"abstract":"<p>Genome-Wide Association Studies (GWAS) over-represent European ancestries, neglecting all other ancestry groups and low-income nations. Consequently, polygenic risk scores (PRS) more accurately predict complex traits in Europeans than African Ancestries groups. Very few studies have looked at the transferability of European-derived PRS for behavioural and mental health phenotypes to Africans. We assessed the comparative accuracy of depression PRS trained on European and African Ancestries GWAS studies to predict major depressive disorder (MDD) and related traits in African ancestry participants from the UK Biobank. UK Biobank participants were selected based on Principal component analysis clustering with an African genetic similarity reference population, MDD was assessed with the Composite International Diagnostic Interview (CIDI). PRS were computed using PRSice2 software using either European or African Ancestries GWAS summary statistics. PRS trained on European ancestry samples (246,363 cases) predicted case control status in Africans of the UK Biobank with similar accuracies (R2 = 2%, β = 0.32, empirical p-value = 0.002) to PRS trained on far much smaller samples of African Ancestries participants from 23andMe, Inc. (5045 cases, R² = 1.8%, β = 0.28, empirical p-value = 0.008). This suggests that prediction of MDD status from Africans to Africans had greater efficiency relative to discovery sample size than prediction of MDD from Europeans to Africans. Prediction of MDD status in African UK Biobank participants using GWAS findings of likely causal risk factors from European ancestries was non-significant. GWAS of MDD in European ancestries are inefficient for improving polygenic prediction in African samples; urgent MDD studies in Africa are needed.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141624878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-15DOI: 10.1038/s41380-024-02670-x
Hannah Stocker, Manuel Gentiluomo, Kira Trares, Léon Beyer, Joshua Stevenson-Hoare, Dan Rujescu, Bernd Holleczek, Konrad Beyreuther, Klaus Gerwert, Ben Schöttker, Daniele Campa, Federico Canzian, Hermann Brenner
The mitochondrial cascade hypothesis of Alzheimer’s disease (AD) has been portrayed through molecular, cellular, and animal studies; however large epidemiological studies are lacking. This study aimed to explore the association of mitochondrial DNA copy number (mtDNAcn), a marker representative of mtDNA abundance per cell, with risk of incident all-cause dementia, AD, and vascular dementia diagnosis within 17 years and dementia-related blood biomarkers (P-tau181, GFAP, and NfL). Additionally, sex-stratified analyses were completed. In this German population-based cohort study (ESTHER), 9940 participants aged 50–75 years were enrolled by general practitioners and followed for 17 years. Participants were included in this study if information on dementia status and blood-based mtDNAcn measured via real-time polymerase chain reaction were available. In a nested case-control approach, a subsample of participants additionally had measurements of P-tau181, GFAP, and NfL in blood samples taken at baseline. Of 4913 participants eligible for analyses, 386 were diagnosed with incident all-cause dementia, including 130 AD and 143 vascular dementia cases, while 4527 participants remained without dementia diagnosis within 17 years. Participants with low mtDNAcn (lowest 10%) experienced 45% and 65% percent increased risk of incident all-cause dementia and AD after adjusting for age and sex (all-cause dementia: HRadj, 95%CI:1.45, 1.08–1.94; AD: HRadj, 95%CI: 1.65, 1.01–2.68). MtDNAcn was not associated to vascular dementia diagnosis and was more strongly associated with all-cause dementia among women. In the nested case-control study (n = 790), mtDNAcn was not significantly associated with the dementia-related blood biomarkers (P-tau181, GFAP, and NfL) levels in blood from baseline before dementia diagnosis. This study provides novel epidemiological evidence connecting mtDNA abundance, measured via mtDNAcn, to incident dementia and AD at the population-based level. Reduced mitochondrial abundance may play a role in pathogenesis, especially among women.
{"title":"Mitochondrial DNA abundance in blood is associated with Alzheimer’s disease- and dementia-risk","authors":"Hannah Stocker, Manuel Gentiluomo, Kira Trares, Léon Beyer, Joshua Stevenson-Hoare, Dan Rujescu, Bernd Holleczek, Konrad Beyreuther, Klaus Gerwert, Ben Schöttker, Daniele Campa, Federico Canzian, Hermann Brenner","doi":"10.1038/s41380-024-02670-x","DOIUrl":"https://doi.org/10.1038/s41380-024-02670-x","url":null,"abstract":"<p>The mitochondrial cascade hypothesis of Alzheimer’s disease (AD) has been portrayed through molecular, cellular, and animal studies; however large epidemiological studies are lacking. This study aimed to explore the association of mitochondrial DNA copy number (mtDNAcn), a marker representative of mtDNA abundance per cell, with risk of incident all-cause dementia, AD, and vascular dementia diagnosis within 17 years and dementia-related blood biomarkers (P-tau181, GFAP, and NfL). Additionally, sex-stratified analyses were completed. In this German population-based cohort study (ESTHER), 9940 participants aged 50–75 years were enrolled by general practitioners and followed for 17 years. Participants were included in this study if information on dementia status and blood-based mtDNAcn measured via real-time polymerase chain reaction were available. In a nested case-control approach, a subsample of participants additionally had measurements of P-tau181, GFAP, and NfL in blood samples taken at baseline. Of 4913 participants eligible for analyses, 386 were diagnosed with incident all-cause dementia, including 130 AD and 143 vascular dementia cases, while 4527 participants remained without dementia diagnosis within 17 years. Participants with low mtDNAcn (lowest 10%) experienced 45% and 65% percent increased risk of incident all-cause dementia and AD after adjusting for age and sex (all-cause dementia: HRadj, 95%CI:1.45, 1.08–1.94; AD: HRadj, 95%CI: 1.65, 1.01–2.68). MtDNAcn was not associated to vascular dementia diagnosis and was more strongly associated with all-cause dementia among women. In the nested case-control study (<i>n</i> = 790), mtDNAcn was not significantly associated with the dementia-related blood biomarkers (P-tau181, GFAP, and NfL) levels in blood from baseline before dementia diagnosis. This study provides novel epidemiological evidence connecting mtDNA abundance, measured via mtDNAcn, to incident dementia and AD at the population-based level. Reduced mitochondrial abundance may play a role in pathogenesis, especially among women.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-15DOI: 10.1038/s41380-024-02649-8
Austeja Ciulkinyte, Hayley S Mountford, Pierre Fontanillas, Timothy C Bates, Nicholas G Martin, Simon E Fisher, Michelle Luciano
Dyslexia is a learning difficulty with neurodevelopmental origins, manifesting as reduced accuracy and speed in reading and spelling. It is substantially heritable and frequently co-occurs with other neurodevelopmental conditions, particularly attention deficit-hyperactivity disorder (ADHD). Here, we investigate the genetic structure underlying dyslexia and a range of psychiatric traits using results from genome-wide association studies of dyslexia, ADHD, autism, anorexia nervosa, anxiety, bipolar disorder, major depressive disorder, obsessive compulsive disorder, schizophrenia, and Tourette syndrome. Genomic Structural Equation Modelling (GenomicSEM) showed heightened support for a model consisting of five correlated latent genomic factors described as: F1) compulsive disorders (including obsessive-compulsive disorder, anorexia nervosa, Tourette syndrome), F2) psychotic disorders (including bipolar disorder, schizophrenia), F3) internalising disorders (including anxiety disorder, major depressive disorder), F4) neurodevelopmental traits (including autism, ADHD), and F5) attention and learning difficulties (including ADHD, dyslexia). ADHD loaded more strongly on the attention and learning difficulties latent factor (F5) than on the neurodevelopmental traits latent factor (F4). The attention and learning difficulties latent factor (F5) was positively correlated with internalising disorders (.40), neurodevelopmental traits (.25) and psychotic disorders (.17) latent factors, and negatively correlated with the compulsive disorders (-.16) latent factor. These factor correlations are mirrored in genetic correlations observed between the attention and learning difficulties latent factor and other cognitive, psychological and wellbeing traits. We further investigated genetic variants underlying both dyslexia and ADHD, which implicated 49 loci (40 not previously found in GWAS of the individual traits) mapping to 174 genes (121 not found in GWAS of individual traits) as potential pleiotropic variants. Our study confirms the increased genetic relation between dyslexia and ADHD versus other psychiatric traits and uncovers novel pleiotropic variants affecting both traits. In future, analyses including additional co-occurring traits such as dyscalculia and dyspraxia will allow a clearer definition of the attention and learning difficulties latent factor, yielding further insights into factor structure and pleiotropic effects.
{"title":"Genetic neurodevelopmental clustering and dyslexia.","authors":"Austeja Ciulkinyte, Hayley S Mountford, Pierre Fontanillas, Timothy C Bates, Nicholas G Martin, Simon E Fisher, Michelle Luciano","doi":"10.1038/s41380-024-02649-8","DOIUrl":"https://doi.org/10.1038/s41380-024-02649-8","url":null,"abstract":"<p><p>Dyslexia is a learning difficulty with neurodevelopmental origins, manifesting as reduced accuracy and speed in reading and spelling. It is substantially heritable and frequently co-occurs with other neurodevelopmental conditions, particularly attention deficit-hyperactivity disorder (ADHD). Here, we investigate the genetic structure underlying dyslexia and a range of psychiatric traits using results from genome-wide association studies of dyslexia, ADHD, autism, anorexia nervosa, anxiety, bipolar disorder, major depressive disorder, obsessive compulsive disorder, schizophrenia, and Tourette syndrome. Genomic Structural Equation Modelling (GenomicSEM) showed heightened support for a model consisting of five correlated latent genomic factors described as: F1) compulsive disorders (including obsessive-compulsive disorder, anorexia nervosa, Tourette syndrome), F2) psychotic disorders (including bipolar disorder, schizophrenia), F3) internalising disorders (including anxiety disorder, major depressive disorder), F4) neurodevelopmental traits (including autism, ADHD), and F5) attention and learning difficulties (including ADHD, dyslexia). ADHD loaded more strongly on the attention and learning difficulties latent factor (F5) than on the neurodevelopmental traits latent factor (F4). The attention and learning difficulties latent factor (F5) was positively correlated with internalising disorders (.40), neurodevelopmental traits (.25) and psychotic disorders (.17) latent factors, and negatively correlated with the compulsive disorders (-.16) latent factor. These factor correlations are mirrored in genetic correlations observed between the attention and learning difficulties latent factor and other cognitive, psychological and wellbeing traits. We further investigated genetic variants underlying both dyslexia and ADHD, which implicated 49 loci (40 not previously found in GWAS of the individual traits) mapping to 174 genes (121 not found in GWAS of individual traits) as potential pleiotropic variants. Our study confirms the increased genetic relation between dyslexia and ADHD versus other psychiatric traits and uncovers novel pleiotropic variants affecting both traits. In future, analyses including additional co-occurring traits such as dyscalculia and dyspraxia will allow a clearer definition of the attention and learning difficulties latent factor, yielding further insights into factor structure and pleiotropic effects.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-14DOI: 10.1038/s41380-024-02665-8
Allan Kalungi, Eugene Kinyanda, Dickens Howard Akena, Bizu Gelaye, Wilber Ssembajjwe, Richard Steven Mpango, Terry Ongaria, Joseph Mugisha, Ronald Makanga, Ayoub Kakande, Beatrice Kimono, Philip Amanyire, Fred Kirumira, Cathryn M Lewis, Andrew M McIntosh, Karoline Kuchenbaecker, Moffat Nyirenda, Pontiano Kaleebu, Segun Fatumo
Genetics research has potential to alleviate the burden of mental disorders in low- and middle-income-countries through identification of new mechanistic pathways which can lead to efficacious drugs or new drug targets. However, there is currently limited genetics data from Africa. The Uganda Genome Resource provides opportunity for psychiatric genetics research among underrepresented people from Africa. We aimed at determining the prevalence and correlates of major depressive disorder (MDD), suicidality, post-traumatic stress disorder (PTSD), alcohol abuse, generalised anxiety disorder (GAD) and probable attention-deficit hyperactivity disorder (ADHD) among participants of the Uganda Genome Resource. Standardised tools assessed for each mental disorder. Prevalence of each disorder was calculated with 95% confidence intervals. Multivariate logistic regression models evaluated the association between each mental disorder and associated demographic and clinical factors. Among 985 participants, prevalence of the disorders were: current MDD 19.3%, life-time MDD 23.3%, suicidality 10.6%, PTSD 3.1%, alcohol abuse 5.7%, GAD 12.9% and probable ADHD 9.2%. This is the first study to determine the prevalence of probable ADHD among adult Ugandans from a general population. We found significant association between sex and alcohol abuse (adjusted odds ratio [AOR] = 0.26 [0.14,0.45], p < 0.001) and GAD (AOR = 1.78 [1.09,2.49], p = 0.019) respectively. We also found significant association between body mass index and suicidality (AOR = 0.85 [0.73,0.99], p = 0.041), alcohol abuse (AOR = 0.86 [0.78,0.94], p = 0.003) and GAD (AOR = 0.93 [0.87,0.98], p = 0.008) respectively. We also found a significant association between high blood pressure and life-time MDD (AOR = 2.87 [1.08,7.66], p = 0.035) and probable ADHD (AOR = 1.99 [1.00,3.97], p = 0.050) respectively. We also found a statistically significant association between tobacco smoking and alcohol abuse (AOR = 3.2 [1.56,6.67], p = 0.002). We also found ever been married to be a risk factor for probable ADHD (AOR = 2.12 [0.88,5.14], p = 0.049). The Uganda Genome Resource presents opportunity for psychiatric genetics research among underrepresented people from Africa.
{"title":"Prevalence and correlates of common mental disorders among participants of the Uganda Genome Resource: Opportunities for psychiatric genetics research.","authors":"Allan Kalungi, Eugene Kinyanda, Dickens Howard Akena, Bizu Gelaye, Wilber Ssembajjwe, Richard Steven Mpango, Terry Ongaria, Joseph Mugisha, Ronald Makanga, Ayoub Kakande, Beatrice Kimono, Philip Amanyire, Fred Kirumira, Cathryn M Lewis, Andrew M McIntosh, Karoline Kuchenbaecker, Moffat Nyirenda, Pontiano Kaleebu, Segun Fatumo","doi":"10.1038/s41380-024-02665-8","DOIUrl":"10.1038/s41380-024-02665-8","url":null,"abstract":"<p><p>Genetics research has potential to alleviate the burden of mental disorders in low- and middle-income-countries through identification of new mechanistic pathways which can lead to efficacious drugs or new drug targets. However, there is currently limited genetics data from Africa. The Uganda Genome Resource provides opportunity for psychiatric genetics research among underrepresented people from Africa. We aimed at determining the prevalence and correlates of major depressive disorder (MDD), suicidality, post-traumatic stress disorder (PTSD), alcohol abuse, generalised anxiety disorder (GAD) and probable attention-deficit hyperactivity disorder (ADHD) among participants of the Uganda Genome Resource. Standardised tools assessed for each mental disorder. Prevalence of each disorder was calculated with 95% confidence intervals. Multivariate logistic regression models evaluated the association between each mental disorder and associated demographic and clinical factors. Among 985 participants, prevalence of the disorders were: current MDD 19.3%, life-time MDD 23.3%, suicidality 10.6%, PTSD 3.1%, alcohol abuse 5.7%, GAD 12.9% and probable ADHD 9.2%. This is the first study to determine the prevalence of probable ADHD among adult Ugandans from a general population. We found significant association between sex and alcohol abuse (adjusted odds ratio [AOR] = 0.26 [0.14,0.45], p < 0.001) and GAD (AOR = 1.78 [1.09,2.49], p = 0.019) respectively. We also found significant association between body mass index and suicidality (AOR = 0.85 [0.73,0.99], p = 0.041), alcohol abuse (AOR = 0.86 [0.78,0.94], p = 0.003) and GAD (AOR = 0.93 [0.87,0.98], p = 0.008) respectively. We also found a significant association between high blood pressure and life-time MDD (AOR = 2.87 [1.08,7.66], p = 0.035) and probable ADHD (AOR = 1.99 [1.00,3.97], p = 0.050) respectively. We also found a statistically significant association between tobacco smoking and alcohol abuse (AOR = 3.2 [1.56,6.67], p = 0.002). We also found ever been married to be a risk factor for probable ADHD (AOR = 2.12 [0.88,5.14], p = 0.049). The Uganda Genome Resource presents opportunity for psychiatric genetics research among underrepresented people from Africa.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1038/s41380-024-02663-w
Paromita Sen, Oskar Ortiz, Elena Brivio, Danusa Menegaz, Laura Sotillos Elliott, Ying Du, Clemens Ries, Alon Chen, Wolfgang Wurst, Juan Pablo Lopez, Matthias Eder, Jan M. Deussing
The single nucleotide polymorphism rs13166360, causing a substitution of valine (Val) 147 to leucine (Leu) in the adenylyl cyclase 2 (ADCY2), has previously been associated with bipolar disorder (BD). Here we show that the disease-associated ADCY2 missense mutation diminishes the enzyme´s capacity to generate the second messenger 3’,5’-cylic adenosine monophosphate (cAMP) by altering its subcellular localization. We established mice specifically carrying the Val to Leu substitution using CRISPR/Cas9-based gene editing. Mice homozygous for the Leu variant display symptoms of a mania-like state accompanied by cognitive impairments. Mutant animals show additional characteristic signs of rodent mania models, i.e., they are hypersensitive to amphetamine, the observed mania-like behaviors are responsive to lithium treatment and the Val to Leu substitution results in a shifted excitatory/inhibitory synaptic balance towards more excitation. Exposure to chronic social defeat stress switches homozygous Leu variant carriers from a mania- to a depressive-like state, a transition which is reminiscent of the alternations characterizing the symptomatology in BD patients. Single-cell RNA-seq (scRNA-seq) revealed widespread Adcy2 mRNA expression in numerous hippocampal cell types. Differentially expressed genes particularly identified from glutamatergic CA1 neurons point towards ADCY2 variant-dependent alterations in multiple biological processes including cAMP-related signaling pathways. These results validate ADCY2 as a BD risk gene, provide insights into underlying disease mechanisms, and potentially open novel avenues for therapeutic intervention strategies.
单核苷酸多态性 rs13166360 导致腺苷酸环化酶 2(ADCY2)中的缬氨酸(Val)147 被亮氨酸(Leu)取代,该多态性以前曾与双相情感障碍(BD)有关。在这里,我们发现与疾病相关的 ADCY2 错义突变通过改变其亚细胞定位,削弱了该酶生成第二信使 3',5'-胞嘧啶单磷酸(cAMP)的能力。我们利用基于 CRISPR/Cas9 的基因编辑技术建立了特异性携带 Val 到 Leu 替换的小鼠。同源携带Leu变体的小鼠表现出类似躁狂症的症状,并伴有认知障碍。突变体动物表现出啮齿类动物躁狂症模型的其他特征,即它们对苯丙胺过敏,观察到的躁狂症样行为对锂治疗有反应,Val 到 Leu 的置换导致兴奋/抑制突触平衡向更兴奋的方向移动。暴露于慢性社会失败压力下会使同源的Leu变异携带者从躁狂状态转为抑郁状态,这种转变让人联想到BD患者症状的交替特征。单细胞RNA-seq(scRNA-seq)研究发现,Adcy2 mRNA在许多海马细胞类型中广泛表达。特别是从谷氨酸能 CA1 神经元中发现的差异表达基因表明,ADCY2 变异依赖于多种生物过程的改变,包括 cAMP 相关信号通路。这些结果验证了 ADCY2 是一种 BD 风险基因,提供了对潜在疾病机制的见解,并可能为治疗干预策略开辟新的途径。
{"title":"A bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior","authors":"Paromita Sen, Oskar Ortiz, Elena Brivio, Danusa Menegaz, Laura Sotillos Elliott, Ying Du, Clemens Ries, Alon Chen, Wolfgang Wurst, Juan Pablo Lopez, Matthias Eder, Jan M. Deussing","doi":"10.1038/s41380-024-02663-w","DOIUrl":"https://doi.org/10.1038/s41380-024-02663-w","url":null,"abstract":"<p>The single nucleotide polymorphism rs13166360, causing a substitution of valine (Val) 147 to leucine (Leu) in the adenylyl cyclase 2 (ADCY2), has previously been associated with bipolar disorder (BD). Here we show that the disease-associated ADCY2 missense mutation diminishes the enzyme´s capacity to generate the second messenger 3’,5’-cylic adenosine monophosphate (cAMP) by altering its subcellular localization. We established mice specifically carrying the Val to Leu substitution using CRISPR/Cas9-based gene editing. Mice homozygous for the Leu variant display symptoms of a mania-like state accompanied by cognitive impairments. Mutant animals show additional characteristic signs of rodent mania models, i.e., they are hypersensitive to amphetamine, the observed mania-like behaviors are responsive to lithium treatment and the Val to Leu substitution results in a shifted excitatory/inhibitory synaptic balance towards more excitation. Exposure to chronic social defeat stress switches homozygous Leu variant carriers from a mania- to a depressive-like state, a transition which is reminiscent of the alternations characterizing the symptomatology in BD patients. Single-cell RNA-seq (scRNA-seq) revealed widespread <i>Adcy2</i> mRNA expression in numerous hippocampal cell types. Differentially expressed genes particularly identified from glutamatergic CA1 neurons point towards ADCY2 variant-dependent alterations in multiple biological processes including cAMP-related signaling pathways. These results validate <i>ADCY2</i> as a BD risk gene, provide insights into underlying disease mechanisms, and potentially open novel avenues for therapeutic intervention strategies.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Common psychiatric disorders constitute one of the most substantial healthcare burdens worldwide. However, drug development in psychiatry remains hampered partially due to the lack of approaches to estimating drugs that can simultaneously modulate the expression of a nontrivial fraction of disease susceptibility genes. We proposed a new drug prioritization strategy under the framework of our previously proposed phenotype-associated tissues estimation approach (DESE) by investigating the drugs' selective perturbation effect on disease susceptibility genes. Based on the genome-wide association study summary data and drug-induced gene expression profiles of neural progenitor cells, we applied this strategy to prioritize candidate drugs for schizophrenia, depression and bipolar I disorder and identified several known therapeutic drugs among the top-ranked drug candidates. Also, our results revealed that the disease susceptibility genes involved in the selective gene perturbation analysis were enriched with many biologically sensible function terms and interacted with known therapeutic drugs. Our results suggested that selective gene perturbation analysis could be a promising starting point to prioritize biologically sensible drug candidates under the "one drug, multiple targets" paradigm for the drug development of common psychiatric disorders.
{"title":"Application of GWAS summary data and drug-induced gene expression profiles of neural progenitor cells in psychiatric drug prioritization analysis.","authors":"Xiangyi Li, Chao Xue, Zheng Zhu, Xuegao Yu, Qi Yang, Liqian Cui, Miaoxin Li","doi":"10.1038/s41380-024-02660-z","DOIUrl":"https://doi.org/10.1038/s41380-024-02660-z","url":null,"abstract":"<p><p>Common psychiatric disorders constitute one of the most substantial healthcare burdens worldwide. However, drug development in psychiatry remains hampered partially due to the lack of approaches to estimating drugs that can simultaneously modulate the expression of a nontrivial fraction of disease susceptibility genes. We proposed a new drug prioritization strategy under the framework of our previously proposed phenotype-associated tissues estimation approach (DESE) by investigating the drugs' selective perturbation effect on disease susceptibility genes. Based on the genome-wide association study summary data and drug-induced gene expression profiles of neural progenitor cells, we applied this strategy to prioritize candidate drugs for schizophrenia, depression and bipolar I disorder and identified several known therapeutic drugs among the top-ranked drug candidates. Also, our results revealed that the disease susceptibility genes involved in the selective gene perturbation analysis were enriched with many biologically sensible function terms and interacted with known therapeutic drugs. Our results suggested that selective gene perturbation analysis could be a promising starting point to prioritize biologically sensible drug candidates under the \"one drug, multiple targets\" paradigm for the drug development of common psychiatric disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}