Pub Date : 2025-01-03DOI: 10.1038/s41380-024-02872-3
Jetro J. Tuulari, Matthieu Bourgery, Jo Iversen, Thomas Gade Koefoed, Annukka Ahonen, Ammar Ahmedani, Eeva-Leena Kataja, Linnea Karlsson, Romain Barrès, Hasse Karlsson, Noora Kotaja
Childhood maltreatment exposure (CME) increases the risk of adverse long-term health consequences for the exposed individual. Animal studies suggest that CME may also influence the health and behaviour in the next generation offspring through CME-driven epigenetic changes in the germ line. Here we investigated the associated between early life stress on the epigenome of sperm in humans with history of CME. We measured paternal CME using the Trauma and Distress Scale (TADS) questionnaire and mapped sperm-borne sncRNAs expression by small RNA sequencing (small RNA-seq) and DNA methylation (DNAme) in spermatozoa by reduced-representation bisulfite sequencing (RRBS-seq) in males from the FinnBrain Birth Cohort Study. The study design was a (nested) case-control study, high-TADS (TADS ≥ 39, n = 25 for DNAme and n = 14 for small RNA-seq) and low-TADS (TADS ≤ 10, n = 30 for DNAme and n = 16 for small RNA-seq). We identified 3 genomic regions with differential methylation between low and high-TADS and 68 tRNA-derived small RNAs (tsRNAs) and miRNAs with different levels in males with high CME (False discovery rate, FDR corrected p < 0.05). Of potential interest, we identified differential expression of miRNA hsa-mir-34c-5p and differential methylation levels near the CRTC1 and GBX2 genes, which are documented to control brain development. Our results provide further evidence that early life stress influences the paternal germline epigenome and supports a possible effect in modulating the development of the central nervous system of the next generation.
{"title":"Exposure to childhood maltreatment is associated with specific epigenetic patterns in sperm","authors":"Jetro J. Tuulari, Matthieu Bourgery, Jo Iversen, Thomas Gade Koefoed, Annukka Ahonen, Ammar Ahmedani, Eeva-Leena Kataja, Linnea Karlsson, Romain Barrès, Hasse Karlsson, Noora Kotaja","doi":"10.1038/s41380-024-02872-3","DOIUrl":"https://doi.org/10.1038/s41380-024-02872-3","url":null,"abstract":"<p>Childhood maltreatment exposure (CME) increases the risk of adverse long-term health consequences for the exposed individual. Animal studies suggest that CME may also influence the health and behaviour in the next generation offspring through CME-driven epigenetic changes in the germ line. Here we investigated the associated between early life stress on the epigenome of sperm in humans with history of CME. We measured paternal CME using the Trauma and Distress Scale (TADS) questionnaire and mapped sperm-borne sncRNAs expression by small RNA sequencing (small RNA-seq) and DNA methylation (DNAme) in spermatozoa by reduced-representation bisulfite sequencing (RRBS-seq) in males from the FinnBrain Birth Cohort Study. The study design was a (nested) case-control study, high-TADS (TADS ≥ 39, <i>n</i> = 25 for DNAme and <i>n</i> = 14 for small RNA-seq) and low-TADS (TADS ≤ 10, <i>n</i> = 30 for DNAme and <i>n</i> = 16 for small RNA-seq). We identified 3 genomic regions with differential methylation between low and high-TADS and 68 tRNA-derived small RNAs (tsRNAs) and miRNAs with different levels in males with high CME (False discovery rate, FDR corrected <i>p</i> < 0.05). Of potential interest, we identified differential expression of miRNA hsa-mir-34c-5p and differential methylation levels near the <i>CRTC1</i> and <i>GBX2</i> genes, which are documented to control brain development. Our results provide further evidence that early life stress influences the paternal germline epigenome and supports a possible effect in modulating the development of the central nervous system of the next generation.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"27 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917081","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 : 2025-01-03DOI: 10.1038/s41380-024-02885-y
Susanne Bejerot, Albert Max Hietala, Annika Söderbergh, Mats B Humble
{"title":"Circular reasoning concerning Red flags for predicting rituximab response in OCD.","authors":"Susanne Bejerot, Albert Max Hietala, Annika Söderbergh, Mats B Humble","doi":"10.1038/s41380-024-02885-y","DOIUrl":"https://doi.org/10.1038/s41380-024-02885-y","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927646","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 : 2024-12-31DOI: 10.1038/s41380-024-02877-y
Yazheng Di, Elior Rahmani, Joel Mefford, Jinhan Wang, Vijay Ravi, Aditya Gorla, Abeer Alwan, Kenneth S. Kendler, Tingshao Zhu, Jonathan Flint
Major depressive disorder (MDD) often goes undiagnosed due to the absence of clear biomarkers. We sought to identify voice biomarkers for MDD and separate biomarkers indicative of MDD predisposition from biomarkers reflecting current depressive symptoms. Using a two-stage meta-analytic design to remove confounds, we tested the association between features representing vocal pitch and MDD in a multisite case-control cohort study of Chinese women with recurrent depression. Sixteen features were replicated in an independent cohort, with absolute association coefficients (beta values) from the combined analysis ranging from 0.24 to 1.07, indicating moderate to large effects. The statistical significance of these associations remained robust, with P values ranging from 7.2 × 10–6 to 6.8 × 10–58. Eleven features were significantly associated with current depressive symptoms. Using genotype data, we found that this association was driven in part by a genetic correlation with MDD. Significant voice features, reflecting a slower pitch change and a lower pitch, achieved an AUC-ROC of 0.90 (sensitivity of 0.85 and specificity of 0.81) in MDD classification. Our results return vocal features to a more central position in clinical and research work on MDD.
{"title":"Unraveling the associations between voice pitch and major depressive disorder: a multisite genetic study","authors":"Yazheng Di, Elior Rahmani, Joel Mefford, Jinhan Wang, Vijay Ravi, Aditya Gorla, Abeer Alwan, Kenneth S. Kendler, Tingshao Zhu, Jonathan Flint","doi":"10.1038/s41380-024-02877-y","DOIUrl":"https://doi.org/10.1038/s41380-024-02877-y","url":null,"abstract":"<p>Major depressive disorder (MDD) often goes undiagnosed due to the absence of clear biomarkers. We sought to identify voice biomarkers for MDD and separate biomarkers indicative of MDD predisposition from biomarkers reflecting current depressive symptoms. Using a two-stage meta-analytic design to remove confounds, we tested the association between features representing vocal pitch and MDD in a multisite case-control cohort study of Chinese women with recurrent depression. Sixteen features were replicated in an independent cohort, with absolute association coefficients (beta values) from the combined analysis ranging from 0.24 to 1.07, indicating moderate to large effects. The statistical significance of these associations remained robust, with P values ranging from 7.2 × 10<sup>–6</sup> to 6.8 × 10<sup>–58</sup>. Eleven features were significantly associated with current depressive symptoms. Using genotype data, we found that this association was driven in part by a genetic correlation with MDD. Significant voice features, reflecting a slower pitch change and a lower pitch, achieved an AUC-ROC of 0.90 (sensitivity of 0.85 and specificity of 0.81) in MDD classification. Our results return vocal features to a more central position in clinical and research work on MDD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"95 5 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904873","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 : 2024-12-27DOI: 10.1038/s41380-024-02878-x
Na Cai, Brad Verhulst, Ole A. Andreassen, Jan Buitelaar, Howard J. Edenberg, John M. Hettema, Michael Gandal, Andrew Grotzinger, Katherine Jonas, Phil Lee, Travis T. Mallard, Manuel Mattheisen, Michael C. Neale, John I. Nurnberger, Wouter Peyrout, Elliot M. Tucker-Drob, Jordan W. Smoller, Kenneth S. Kendler
Psychiatric disorders are highly comorbid, heritable, and genetically correlated [1,2,3,4]. The primary objective of cross-disorder psychiatric genetics research is to identify and characterize both the shared genetic factors that contribute to convergent disease etiologies and the unique genetic factors that distinguish between disorders [4, 5]. This information can illuminate the biological mechanisms underlying comorbid presentations of psychopathology, improve nosology and prediction of illness risk and trajectories, and aid the development of more effective and targeted interventions. In this review we discuss how estimates of comorbidity and identification of shared genetic loci between disorders can be influenced by how disorders are measured (phenotypic assessment) and the inclusion or exclusion criteria in individual genetic studies (sample ascertainment). Specifically, the depth of measurement, source of diagnosis, and time frame of disease trajectory have major implications for the clinical validity of the assessed phenotypes. Further, biases introduced in the ascertainment of both cases and controls can inflate or reduce estimates of genetic correlations. The impact of these design choices may have important implications for large meta-analyses of cohorts from diverse populations that use different forms of assessment and inclusion criteria, and subsequent cross-disorder analyses thereof. We review how assessment and ascertainment affect genetic findings in both univariate and multivariate analyses and conclude with recommendations for addressing them in future research.
{"title":"Assessment and ascertainment in psychiatric molecular genetics: challenges and opportunities for cross-disorder research","authors":"Na Cai, Brad Verhulst, Ole A. Andreassen, Jan Buitelaar, Howard J. Edenberg, John M. Hettema, Michael Gandal, Andrew Grotzinger, Katherine Jonas, Phil Lee, Travis T. Mallard, Manuel Mattheisen, Michael C. Neale, John I. Nurnberger, Wouter Peyrout, Elliot M. Tucker-Drob, Jordan W. Smoller, Kenneth S. Kendler","doi":"10.1038/s41380-024-02878-x","DOIUrl":"https://doi.org/10.1038/s41380-024-02878-x","url":null,"abstract":"<p>Psychiatric disorders are highly comorbid, heritable, and genetically correlated [1,2,3,4]. The primary objective of cross-disorder psychiatric genetics research is to identify and characterize both the shared genetic factors that contribute to convergent disease etiologies and the unique genetic factors that distinguish between disorders [4, 5]. This information can illuminate the biological mechanisms underlying comorbid presentations of psychopathology, improve nosology and prediction of illness risk and trajectories, and aid the development of more effective and targeted interventions. In this review we discuss how estimates of comorbidity and identification of shared genetic loci between disorders can be influenced by how disorders are measured (phenotypic assessment) and the inclusion or exclusion criteria in individual genetic studies (sample ascertainment). Specifically, the depth of measurement, source of diagnosis, and time frame of disease trajectory have major implications for the clinical validity of the assessed phenotypes. Further, biases introduced in the ascertainment of both cases and controls can inflate or reduce estimates of genetic correlations. The impact of these design choices may have important implications for large meta-analyses of cohorts from diverse populations that use different forms of assessment and inclusion criteria, and subsequent cross-disorder analyses thereof. We review how assessment and ascertainment affect genetic findings in both univariate and multivariate analyses and conclude with recommendations for addressing them in future research.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"39 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887743","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 : 2024-12-27DOI: 10.1038/s41380-024-02873-2
Daniel Paul Eisenberg, Rachael Keir Blackman, Maria G. Tietcheu, Philip D. Kohn, Jasmin S. Bettina, Bhaskar Kolachana, Michael D. Gregory, Karen F. Berman
Dysfunction of dopamine systems has long been considered a hallmark of schizophrenia, and nearly all current first-line medication treatments block dopamine D2 receptors. However, approximately a quarter of patients will not adequately respond to these agents and are considered treatment-resistant. Whereas abnormally high striatal presynaptic dopamine synthesis capacity has been observed in people with schizophrenia, studies of treatment-resistant patients have not shown this pattern and have even found the opposite – i.e., reductions in striatal presynaptic dopamine synthesis capacity. Whether such reductions in fact represent clinical epiphenomena such as medication or other treatment effects or whether they rather represent neurobiological differences related to etiology has been unclear. To understand the dopaminergic implications of genetic liability for treatment-resistant schizophrenia without the confound of clinical epiphenomena, we studied a cohort of healthy individuals without neuropsychiatric illness using [18F]-FDOPA positron emission tomography (PET) and found that striatal presynaptic dopamine synthesis capacity showed an expected direct association with cumulative genetic risk burden for general schizophrenia but an inverse association with specific polygenic risk for treatment-resistant schizophrenia. Subsequent evaluation of D2/3 dopamine receptor availability in an overlapping cohort using [18F]-fallypride PET did not identify any effects of genetic risk in the striatum but found an association with treatment-resistant schizophrenia polygenic risk in the thalamus. Overall, these results align with prior PET studies in patients and implicate, at least with respect to the dopamine system, fundamentally distinct molecular mechanisms in the unique genetic liability for treatment-resistant schizophrenia.
{"title":"Genetic risk for treatment resistant schizophrenia and corresponding variation in dopamine synthesis capacity and D2/3 receptor availability in healthy individuals","authors":"Daniel Paul Eisenberg, Rachael Keir Blackman, Maria G. Tietcheu, Philip D. Kohn, Jasmin S. Bettina, Bhaskar Kolachana, Michael D. Gregory, Karen F. Berman","doi":"10.1038/s41380-024-02873-2","DOIUrl":"https://doi.org/10.1038/s41380-024-02873-2","url":null,"abstract":"<p>Dysfunction of dopamine systems has long been considered a hallmark of schizophrenia, and nearly all current first-line medication treatments block dopamine D<sub>2</sub> receptors. However, approximately a quarter of patients will not adequately respond to these agents and are considered treatment-resistant. Whereas abnormally high striatal presynaptic dopamine synthesis capacity has been observed in people with schizophrenia, studies of treatment-resistant patients have not shown this pattern and have even found the opposite – i.e., <i>reductions</i> in striatal presynaptic dopamine synthesis capacity. Whether such reductions in fact represent clinical epiphenomena such as medication or other treatment effects or whether they rather represent neurobiological differences related to etiology has been unclear. To understand the dopaminergic implications of genetic liability for treatment-resistant schizophrenia without the confound of clinical epiphenomena, we studied a cohort of healthy individuals without neuropsychiatric illness using [<sup>18</sup>F]-FDOPA positron emission tomography (PET) and found that striatal presynaptic dopamine synthesis capacity showed an expected direct association with cumulative genetic risk burden for general schizophrenia but an <i>inverse</i> association with specific polygenic risk for treatment-resistant schizophrenia. Subsequent evaluation of D<sub>2/3</sub> dopamine receptor availability in an overlapping cohort using [<sup>18</sup>F]-fallypride PET did not identify any effects of genetic risk in the striatum but found an association with treatment-resistant schizophrenia polygenic risk in the thalamus. Overall, these results align with prior PET studies in patients and implicate, at least with respect to the dopamine system, fundamentally distinct molecular mechanisms in the unique genetic liability for treatment-resistant schizophrenia.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"s3-2 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887815","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 : 2024-12-26DOI: 10.1038/s41380-024-02880-3
Masaya Misaki, Kymberly D. Young, Aki Tsuchiyagaito, Jonathan Savitz, Salvador M. Guinjoan
Major Depressive Disorder (MDD) poses a significant public health challenge due to its high prevalence and the substantial burden it places on individuals and healthcare systems. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF) shows promise as a treatment for this disorder, although its mechanisms of action remain unclear. This study investigated whole-brain response patterns during rtfMRI-NF training to explain interindividual variability in clinical efficacy in MDD. We analyzed data from 95 participants (67 active, 28 control) with MDD from previous rtfMRI-NF studies designed to increase left amygdala activation through positive autobiographical memory recall. Significant symptom reduction was observed in the active group (t = −4.404, d = −0.704, p < 0.001) but not in the control group (t = −1.609, d = −0.430, p = 0.111). However, left amygdala activation did not account for the variability in clinical efficacy. To elucidate the brain training process underlying the clinical effect, we examined whole-brain activation patterns during two critical phases of the neurofeedback procedure: activation during the self-regulation period, and transient responses to feedback signal presentations. Using a systematic process involving feature selection, manifold extraction, and clustering with cross-validation, we identified two subtypes of regulation activation and three subtypes of brain responses to feedback signals. These subtypes were significantly associated with the clinical effect (regulation subtype: F = 8.735, p = 0.005; feedback response subtype: F = 5.326, p = 0.008; subtypes’ interaction: F = 3.471, p = 0.039). Subtypes associated with significant symptom reduction were characterized by selective increases in control regions, including lateral prefrontal areas, and decreases in regions associated with self-referential thinking, such as default mode areas. These findings suggest that large-scale brain activity during training is more critical for clinical efficacy than the level of activation in the neurofeedback target region itself. Tailoring neurofeedback training to incorporate these patterns could significantly enhance its therapeutic efficacy.
{"title":"Clinical response to neurofeedback in major depression relates to subtypes of whole-brain activation patterns during training","authors":"Masaya Misaki, Kymberly D. Young, Aki Tsuchiyagaito, Jonathan Savitz, Salvador M. Guinjoan","doi":"10.1038/s41380-024-02880-3","DOIUrl":"https://doi.org/10.1038/s41380-024-02880-3","url":null,"abstract":"<p>Major Depressive Disorder (MDD) poses a significant public health challenge due to its high prevalence and the substantial burden it places on individuals and healthcare systems. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF) shows promise as a treatment for this disorder, although its mechanisms of action remain unclear. This study investigated whole-brain response patterns during rtfMRI-NF training to explain interindividual variability in clinical efficacy in MDD. We analyzed data from 95 participants (67 active, 28 control) with MDD from previous rtfMRI-NF studies designed to increase left amygdala activation through positive autobiographical memory recall. Significant symptom reduction was observed in the active group (<i>t</i> = −4.404, <i>d</i> = −0.704, <i>p</i> < 0.001) but not in the control group (<i>t</i> = −1.609, <i>d</i> = −0.430, <i>p</i> = 0.111). However, left amygdala activation did not account for the variability in clinical efficacy. To elucidate the brain training process underlying the clinical effect, we examined whole-brain activation patterns during two critical phases of the neurofeedback procedure: activation during the self-regulation period, and transient responses to feedback signal presentations. Using a systematic process involving feature selection, manifold extraction, and clustering with cross-validation, we identified two subtypes of regulation activation and three subtypes of brain responses to feedback signals. These subtypes were significantly associated with the clinical effect (regulation subtype: <i>F</i> = 8.735, <i>p</i> = 0.005; feedback response subtype: <i>F</i> = 5.326, <i>p</i> = 0.008; subtypes’ interaction: <i>F</i> = 3.471, <i>p</i> = 0.039). Subtypes associated with significant symptom reduction were characterized by selective increases in control regions, including lateral prefrontal areas, and decreases in regions associated with self-referential thinking, such as default mode areas. These findings suggest that large-scale brain activity during training is more critical for clinical efficacy than the level of activation in the neurofeedback target region itself. Tailoring neurofeedback training to incorporate these patterns could significantly enhance its therapeutic efficacy.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"25 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886955","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 : 2024-12-23DOI: 10.1038/s41380-024-02879-w
Guy Shapira, Gidon Karmon, Gal Hacohen-Kleiman, Maram Ganaiem, Shula Shazman, Paschalis Theotokis, Nikolaos Grigoriadis, Noam Shomron, Illana Gozes
Essential for brain formation and protective against tauopathy, activity-dependent neuroprotective protein (ADNP) is critical for neurogenesis and cognitive functions, while regulating steroid hormone biogenesis. As such, de novo mutations in ADNP lead to syndromic autism and somatic ADNP mutations parallel Alzheimer’s disease progression. Furthermore, clinical trials with the ADNP fragment NAP (the investigational drug davunetide) showed efficacy in women suffering from the tauopathy progressive supranuclear palsy and differentially boosted memory in men (spatial) and women (verbal), exhibiting prodromal Alzheimer’s disease. While autism is more prevalent in boys and Alzheimer’s disease in women, both involve impaired neurogenesis. Here, we asked whether ADNP sex-dependently regulates neurogenesis. Using bromodeoxyuridine (BrdU) as a marker of neurogenesis, we identified two-fold higher labeling in the hippocampal sub-ventricular zone of ADNP-intact male versus female mice. Adnp haplo-insufficient (Adnp+/−) mice or mice CRSIPR/Cas9-edited to present the most prevalent neurodevelopmental ADNP syndrome mutation, p.Tyr718* (Tyr) showed dramatic reductions in male BrdU incorporation, resulting in mutated females presenting higher labeling than males. Treatment with NAP compensated for the male reduction of BrdU labeling. Mechanistically, hippocampal RNAseq revealed male-specific Tyr down-regulation of endoplasmic reticulum unfolded protein response genes critical for sex-dependent organogenesis. Newly discovered mitochondrial accessibility of ADNP was inhibited by the Tyr718* mutation further revealing female-specific Tyr downregulation of mitochondrial ATP6. NAP moderated much of the differential expression caused by p.Tyr718*, accompanied by the down-regulation of neurotoxic, pro-inflammatory and pro-apoptotic genes. Thus, ADNP is a key regulator of sex-dependent neurogenesis that acts by controlling canonical pathways, with NAP compensating for fundamental ADNP deficiencies, striding toward clinical development targeting the ADNP syndrome and related neurodevelopmental/neurodegenerative diseases.
{"title":"ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation","authors":"Guy Shapira, Gidon Karmon, Gal Hacohen-Kleiman, Maram Ganaiem, Shula Shazman, Paschalis Theotokis, Nikolaos Grigoriadis, Noam Shomron, Illana Gozes","doi":"10.1038/s41380-024-02879-w","DOIUrl":"https://doi.org/10.1038/s41380-024-02879-w","url":null,"abstract":"<p>Essential for brain formation and protective against tauopathy, activity-dependent neuroprotective protein (ADNP) is critical for neurogenesis and cognitive functions, while regulating steroid hormone biogenesis. As such, de novo mutations in ADNP lead to syndromic autism and somatic ADNP mutations parallel Alzheimer’s disease progression. Furthermore, clinical trials with the ADNP fragment NAP (the investigational drug davunetide) showed efficacy in women suffering from the tauopathy progressive supranuclear palsy and differentially boosted memory in men (spatial) and women (verbal), exhibiting prodromal Alzheimer’s disease. While autism is more prevalent in boys and Alzheimer’s disease in women, both involve impaired neurogenesis. Here, we asked whether ADNP sex-dependently regulates neurogenesis. Using bromodeoxyuridine (BrdU) as a marker of neurogenesis, we identified two-fold higher labeling in the hippocampal sub-ventricular zone of ADNP-intact male versus female mice. <i>Adnp</i> haplo-insufficient (<i>Adnp</i><sup><i>+/−</i></sup>) mice or mice CRSIPR/Cas9-edited to present the most prevalent neurodevelopmental ADNP syndrome mutation, p.Tyr718* (Tyr) showed dramatic reductions in male BrdU incorporation, resulting in mutated females presenting higher labeling than males. Treatment with NAP compensated for the male reduction of BrdU labeling. Mechanistically, hippocampal RNAseq revealed male-specific Tyr down-regulation of endoplasmic reticulum unfolded protein response genes critical for sex-dependent organogenesis. Newly discovered mitochondrial accessibility of ADNP was inhibited by the Tyr718* mutation further revealing female-specific Tyr downregulation of mitochondrial <i>ATP6</i>. NAP moderated much of the differential expression caused by p.Tyr718*, accompanied by the down-regulation of neurotoxic, pro-inflammatory and pro-apoptotic genes. Thus, ADNP is a key regulator of sex-dependent neurogenesis that acts by controlling canonical pathways, with NAP compensating for fundamental ADNP deficiencies, striding toward clinical development targeting the ADNP syndrome and related neurodevelopmental/neurodegenerative diseases.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"2 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879684","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 : 2024-12-21DOI: 10.1038/s41380-024-02876-z
Cuihua Xia, Ney Alliey-Rodriguez, Carol A. Tamminga, Matcheri S. Keshavan, Godfrey D. Pearlson, Sarah K. Keedy, Brett Clementz, Jennifer E. McDowell, David Parker, Rebekka Lencer, S. Kristian Hill, Jeffrey R. Bishop, Elena I. Ivleva, Cindy Wen, Rujia Dai, Chao Chen, Chunyu Liu, Elliot S. Gershon
The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) created psychosis Biotypes based on neurobiological measurements in a multi-ancestry sample. These Biotypes cut across DSM diagnoses of schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis. Two recently developed post hoc ancestry adjustment methods of Polygenic Risk Scores (PRSs) generate Ancestry-Adjusted PRSs (AAPRSs), which allow for PRS analysis of multi-ancestry samples. Applied to schizophrenia PRS, we found the Khera AAPRS method to show superior portability and comparable prediction accuracy as compared with the Ge method. The three Biotypes of psychosis disorders had similar AAPRSs across ancestries. In genomic analysis of Biotypes, 12 genes, and isoforms showed significant genomic associations with specific Biotypes in a Transcriptome-Wide Association Study (TWAS) of genetically regulated expression (GReX) in the adult brain and fetal brain. TWAS inflation was addressed by the inclusion of genotype principal components in the association analyses. Seven of these 12 genes/isoforms satisfied Mendelian Randomization (MR) criteria for putative causality, including four genes TMEM140, ARTN, C1orf115, CYREN, and three transcripts ENSG00000272941, ENSG00000257176, ENSG00000287733. These genes are enriched in the biological pathways of Rearranged during Transfection (RET) signaling, Neural Cell Adhesion Molecule 1 (NCAM1) interactions, and NCAM signaling for neurite out-growth. The specific associations with Biotypes suggest that pharmacological clinical trials and biological investigations might benefit from analyzing Biotypes separately.
{"title":"Genetic analysis of psychosis Biotypes: shared Ancestry-adjusted polygenic risk and unique genomic associations","authors":"Cuihua Xia, Ney Alliey-Rodriguez, Carol A. Tamminga, Matcheri S. Keshavan, Godfrey D. Pearlson, Sarah K. Keedy, Brett Clementz, Jennifer E. McDowell, David Parker, Rebekka Lencer, S. Kristian Hill, Jeffrey R. Bishop, Elena I. Ivleva, Cindy Wen, Rujia Dai, Chao Chen, Chunyu Liu, Elliot S. Gershon","doi":"10.1038/s41380-024-02876-z","DOIUrl":"https://doi.org/10.1038/s41380-024-02876-z","url":null,"abstract":"<p>The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) created psychosis Biotypes based on neurobiological measurements in a multi-ancestry sample. These Biotypes cut across DSM diagnoses of schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis. Two recently developed <i>post hoc</i> ancestry adjustment methods of Polygenic Risk Scores (PRSs) generate Ancestry-Adjusted PRSs (AAPRSs), which allow for PRS analysis of multi-ancestry samples. Applied to schizophrenia PRS, we found the Khera AAPRS method to show superior portability and comparable prediction accuracy as compared with the Ge method. The three Biotypes of psychosis disorders had similar AAPRSs across ancestries. In genomic analysis of Biotypes, 12 genes, and isoforms showed significant genomic associations with specific Biotypes in a Transcriptome-Wide Association Study (TWAS) of genetically regulated expression (GReX) in the adult brain and fetal brain. TWAS inflation was addressed by the inclusion of genotype principal components in the association analyses. Seven of these 12 genes/isoforms satisfied Mendelian Randomization (MR) criteria for putative causality, including four genes <i>TMEM140</i>, <i>ARTN</i>, <i>C1orf115</i>, <i>CYREN</i>, and three transcripts ENSG00000272941, ENSG00000257176, ENSG00000287733. These genes are enriched in the biological pathways of Rearranged during Transfection (RET) signaling, Neural Cell Adhesion Molecule 1 (NCAM1) interactions, and NCAM signaling for neurite out-growth. The specific associations with Biotypes suggest that pharmacological clinical trials and biological investigations might benefit from analyzing Biotypes separately.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"24 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869943","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 : 2024-12-19DOI: 10.1038/s41380-024-02870-5
Carl-Philipp Meinung, Laura Boi, Sareh Pandamooz, David Mazaud, Grégory Ghézali, Nathalie Rouach, Inga D. Neumann
Astrocytes are an indispensable part of signal processing within the mammalian brain. Thus, the mode of action of a neuropeptide such as oxytocin (OXT) can only be fully understood considering this integral part of the CNS. Here, we show that OXT regulates astrocytic gene expression, intracellular signaling and specific proteins both in vitro and in vivo. This translates into rapid regulation of astroglial structural and functional properties including cytoskeletal plasticity, coverage of synapses and gap-junction coupling. At the molecular level, we identify the previously undescribed Sp1-Gem signaling cascade as the key driver for these cell type-specific OXT effects. Finally at the behavioral level, we found in vivo that OXT requires astrocytes to exert its well described anxiolytic properties within the hypothalamic paraventricular nucleus. Thus, our study points to OXT receptor-expressing astrocytes as a critical component of the brain OXT system.
{"title":"OXTR-mediated signaling in astrocytes contributes to anxiolysis","authors":"Carl-Philipp Meinung, Laura Boi, Sareh Pandamooz, David Mazaud, Grégory Ghézali, Nathalie Rouach, Inga D. Neumann","doi":"10.1038/s41380-024-02870-5","DOIUrl":"https://doi.org/10.1038/s41380-024-02870-5","url":null,"abstract":"<p>Astrocytes are an indispensable part of signal processing within the mammalian brain. Thus, the mode of action of a neuropeptide such as oxytocin (OXT) can only be fully understood considering this integral part of the CNS. Here, we show that OXT regulates astrocytic gene expression, intracellular signaling and specific proteins both in vitro and in vivo. This translates into rapid regulation of astroglial structural and functional properties including cytoskeletal plasticity, coverage of synapses and gap-junction coupling. At the molecular level, we identify the previously undescribed Sp1-Gem signaling cascade as the key driver for these cell type-specific OXT effects. Finally at the behavioral level, we found in vivo that OXT requires astrocytes to exert its well described anxiolytic properties within the hypothalamic paraventricular nucleus. Thus, our study points to OXT receptor-expressing astrocytes as a critical component of the brain OXT system.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"24 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849178","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 : 2024-12-18DOI: 10.1038/s41380-024-02733-z
Marco Solmi, Michele Fornaro, Stefano Caiolo, Marialaura Lussignoli, Claudio Caiazza, Michele De Prisco, Niccolo Solini, Andrea de Bartolomeis, Felice Iasevoli, Giorgio Pigato, Cinzia Del Giovane, Andrea Cipriani, Christoph U. Correll
Tardive Dyskinesia (TD) can occur in people exposed to dopamine receptor antagonists (DRAs). Its clinical management remains challenging. We conducted a systematic review/random-effects network meta-analysis (NMA) searching PubMed/MEDLINE/PsycINFO/ClinicalTrials.gov/Cochrane Central Register (22/05/2023, pre-defined protocol https://osf.io/b52ae/ ), for randomized controlled trials (RCTs) of pharmacological/brain stimulation interventions for DRA-induced TD in adults with schizophrenia or mood disorders. Primary outcomes were TD symptom change (standardized mean difference/SMD) and all-cause discontinuation (acceptability-risk ratio/RR). Sensitivity analyses were conducted. Global, local inconsistencies, risk of bias (RoB-2 tool), and confidence in evidence (CINeMA) were measured. We included 46 trials (n = 2844, age = 52.89 ± 9.94 years, males = 59.8%, schizophrenia = 84.6%, mood disorders = 15.4%), all testing pharmacological interventions versus placebo. We identified three subnetworks. In network 1, several treatments outperformed placebo on TD symptoms with large effect sizes (k = 34, n = 2269), encompassing 22 interventions versus placebo, but 18 had 1 RCTs only, and 15 had n ≤ 20. High heterogeneity (I2 = 57.1%; tau2 = 0.0797), and global inconsistency (Q = 32.64; df = 14; p = 0.0032) emerged. No significant differences emerged in acceptability. When restricting analyses to treatments with trials with n > 20 and >1 RCT, only valbenazine (k = 5, SMD = −0.69; 95% CI = −1.00, −0.37) and vitamin E (k = 7, SMD = −0.49; 95% CI = −0.87, −0.11) were superior to placebo. Deutetrabenazine outperformed placebo considering AIMS score and in low risk of bias trials only and with a moderate effect size for 24/36 mg (k = 2, SMD = −0.57/−0.60). Confidence in findings was low for deutetrabenazine and valbenazine, very low for all others. In network 2 (k = 2, n = 63), switch to molindone (k = 1, n = 9) versus switch to haloperidol worsened TD (SMD = 1.68; 95% CI = 0.61,2.76). In network 3 (k = 3, n = 194), antipsychotic wash-out+placebo (k = 1, n = 25) versus TAU+placebo (k = 1, n = 27) worsened TD (SMD = 1.30; 95% CI = 0.36,2.23). Despite large effect sizes for some treatments with very low quality/confidence, when considering higher quality evidence only valbenazine or deutetrabenazine are evidence-based first-line treatments for TD, and potentially vitamin E as second-line. Switching to molindone and antipsychotic washout should be avoided. More treatment options and higher-quality trials are needed.
{"title":"Efficacy and acceptability of pharmacological interventions for tardive dyskinesia in people with schizophrenia or mood disorders: a systematic review and network meta-analysis","authors":"Marco Solmi, Michele Fornaro, Stefano Caiolo, Marialaura Lussignoli, Claudio Caiazza, Michele De Prisco, Niccolo Solini, Andrea de Bartolomeis, Felice Iasevoli, Giorgio Pigato, Cinzia Del Giovane, Andrea Cipriani, Christoph U. Correll","doi":"10.1038/s41380-024-02733-z","DOIUrl":"10.1038/s41380-024-02733-z","url":null,"abstract":"Tardive Dyskinesia (TD) can occur in people exposed to dopamine receptor antagonists (DRAs). Its clinical management remains challenging. We conducted a systematic review/random-effects network meta-analysis (NMA) searching PubMed/MEDLINE/PsycINFO/ClinicalTrials.gov/Cochrane Central Register (22/05/2023, pre-defined protocol https://osf.io/b52ae/ ), for randomized controlled trials (RCTs) of pharmacological/brain stimulation interventions for DRA-induced TD in adults with schizophrenia or mood disorders. Primary outcomes were TD symptom change (standardized mean difference/SMD) and all-cause discontinuation (acceptability-risk ratio/RR). Sensitivity analyses were conducted. Global, local inconsistencies, risk of bias (RoB-2 tool), and confidence in evidence (CINeMA) were measured. We included 46 trials (n = 2844, age = 52.89 ± 9.94 years, males = 59.8%, schizophrenia = 84.6%, mood disorders = 15.4%), all testing pharmacological interventions versus placebo. We identified three subnetworks. In network 1, several treatments outperformed placebo on TD symptoms with large effect sizes (k = 34, n = 2269), encompassing 22 interventions versus placebo, but 18 had 1 RCTs only, and 15 had n ≤ 20. High heterogeneity (I2 = 57.1%; tau2 = 0.0797), and global inconsistency (Q = 32.64; df = 14; p = 0.0032) emerged. No significant differences emerged in acceptability. When restricting analyses to treatments with trials with n > 20 and >1 RCT, only valbenazine (k = 5, SMD = −0.69; 95% CI = −1.00, −0.37) and vitamin E (k = 7, SMD = −0.49; 95% CI = −0.87, −0.11) were superior to placebo. Deutetrabenazine outperformed placebo considering AIMS score and in low risk of bias trials only and with a moderate effect size for 24/36 mg (k = 2, SMD = −0.57/−0.60). Confidence in findings was low for deutetrabenazine and valbenazine, very low for all others. In network 2 (k = 2, n = 63), switch to molindone (k = 1, n = 9) versus switch to haloperidol worsened TD (SMD = 1.68; 95% CI = 0.61,2.76). In network 3 (k = 3, n = 194), antipsychotic wash-out+placebo (k = 1, n = 25) versus TAU+placebo (k = 1, n = 27) worsened TD (SMD = 1.30; 95% CI = 0.36,2.23). Despite large effect sizes for some treatments with very low quality/confidence, when considering higher quality evidence only valbenazine or deutetrabenazine are evidence-based first-line treatments for TD, and potentially vitamin E as second-line. Switching to molindone and antipsychotic washout should be avoided. More treatment options and higher-quality trials are needed.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"30 3","pages":"1207-1222"},"PeriodicalIF":9.6,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841166","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}