Genomic psychiatry : advancing science from genes to society最新文献

{"title":"A PHD-zinc finger-mediated mechanism for PHF21B recognition of H3K36me3.","authors":"Q Ma, J Licinio, M L Wong","doi":"10.61373/gp026l.0042","DOIUrl":"10.61373/gp026l.0042","url":null,"abstract":"<p><p>HF21B is an epigenetic reader that modulates synaptic plasticity-related genes and social memory (1). Although PHF21B is known to bind H3K36me3, the domain responsible for this interaction has remained uncharacterized. Here, we used co-immunoprecipitation with PHF21B deletion mutants in HEK293T cells to show that the PHD-zinc finger domain is essential for H3K36me3 recognition, whereas the C-terminal coiled-coil region is dispensable. These findings identify the PHD-zinc finger domain as the critical H3K36me3-binding module of PHF21B, with implications for neurological disorders linked to chromosome 22q13.3 deletion, including Phelan-McDermid syndrome (2, 3).</p>","PeriodicalId":520875,"journal":{"name":"Genomic psychiatry : advancing science from genes to society","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13309230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148348573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tau protein: Physiological functions and multifaceted roles in neurodegenerative and psychiatric disorders.","authors":"Fei Tang, Junfen Wei, Ma-Li Wong, Peng Lei","doi":"10.61373/gp025i.0122","DOIUrl":"10.61373/gp025i.0122","url":null,"abstract":"<p><p>Tau, mainly expressed in neurons and less expressed in glial cells (astrocytes and oligodendrocytes) and peripheral tissues, is involved in the assembly and stabilization of microtubules, and other biological processes such as axonal transport, metal ion transport, etc. Dysfunction of tau, caused by mutations, hyperphosphorylation, aggregation, or reduced expression, is closely associated with tauopathies (e.g., Alzheimer disease) and psychiatric disorders. Tau-based biomarkers have emerged as predictive/diagnostic tools for these conditions. However, despite advancing to clinical trials, tau-targeted therapies have demonstrated limited efficacy in diseases. Therefore, this review aims to systematically summarize tau's physiological and pathological functions, the progress in tau-targeted therapies, and the development of tau as a disease biomarker, as well as to discuss critical gaps in understanding tau's pathophysiological roles and therapeutic translatability.</p>","PeriodicalId":520875,"journal":{"name":"Genomic psychiatry : advancing science from genes to society","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12758904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The deubiquitinase OTULIN regulates tau expression and RNA metabolism in neurons.","authors":"Karthikeyan Tangavelou, Virginie Bondu, Mingqi Li, Wei Li, Francesca-Fang Liao, Kiran Bhaskar","doi":"10.61373/gp025a.0116","DOIUrl":"10.61373/gp025a.0116","url":null,"abstract":"<p><p>The degradation of aggregation-prone tau is regulated by the ubiquitin-proteasome system (UPS) and autophagy, which are impaired in Alzheimer's disease (AD) and related dementias (ADRD), causing tau aggregation. Protein ubiquitination, with its linkage specificity determines the fate of proteins, which can be either protein degradative or stabilizing signals. While the linear M1-linked ubiquitination on protein aggregates serves as a signaling hub that recruits various ubiquitin-binding proteins for the coordinated actions of protein aggregate turnover and inflammatory NF-κB activation, the deubiquitinase OTULIN counteracts the M1-linked ubiquitin signaling. However, the exact role of OTULIN in neurons and tau aggregates clearance in AD are unknown. Based on our quantitative bulk RNA sequence analysis of human inducible pluripotent stem cell (iPSC)-derived neurons (iPSNs) from an individual with late-onset sporadic AD (sAD2.1), a downregulation of the ubiquitin ligase activating factors (MAGE-A2/A2B/H1) and OTULIN long non-coding RNA (OTULIN lncRNA) was observed compared to healthy control WTC11 iPSNs. The down-regulated OTULIN lncRNA is concurrently associated with increased levels of OTULIN protein and phosphorylated tau at p-S202/p-T205 (AT8), p-T231 (AT180), and p-S396/p-S404 (PHF-1) in sAD2.1 iPSNs. Inhibiting the deubiquitinase activity of OTULIN with a small molecule, UC495 reduced the phosphorylated tau in iPSNs and SH-SY5Y cells, whereas the CRISPR-Cas9-mediated <i>OTULIN</i> gene knockout in sAD2.1 iPSNs decreased both the total and phosphorylated tau levels. CRISPR-Cas9-mediated <i>OTULIN</i> knockout in SH-SY5Y resulted in a complete loss of tau at both mRNA and protein levels, and increased levels of polyubiquitinated proteins, which are being degraded by the proteasome as confirmed with an inhibitor, Lactacystin. In addition, SH-SY5Y <i>OTULIN</i> ^KO cells showed downregulation of various genes associated with inflammation, autophagy, ubiquitin-proteasome system, and the linear ubiquitin assembly complex (LUBAC) that consequently may prevent development of an autoinflammation in the absence of <i>OTULIN</i> gene in neurons. Together, our results suggest, for the first time, a non-canonical role for OTULIN in regulating the gene expression and RNA metabolism, which may have a significant pathogenic role in exacerbating tau aggregation in neurons. Thus, OTULIN could be a novel potential therapeutic target for AD and ADRD.</p>","PeriodicalId":520875,"journal":{"name":"Genomic psychiatry : advancing science from genes to society","volume":"1 6","pages":"48-58"},"PeriodicalIF":0.0,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12962826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147380404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Varying levels of interleukin 1 receptor antagonist (<i>Il1rn</i>) gene expression affect circulating leptin concentrations and fat distribution.","authors":"Ma-Li Wong, Claudio Mastronardi, Gilberto Paz-Filho, Charmaine Simeonovic, Julio Licinio","doi":"10.61373/gp025l.0056","DOIUrl":"10.61373/gp025l.0056","url":null,"abstract":"<p><p>The relationship between leptin and interleukin 1 receptor antagonist (IL1RA) is critical to the understanding of obesity's low-grade chronic inflammatory state. IL1RA antagonizes the proinflammatory effects of IL1, dampens systemic inflammation markers, and in clinical trials improved glycemic control in type 2 diabetes. We show that leptin levels decreased relative to the number of <i>Il1rn</i> copies in mice overexpressing IL1RA; these mice have altered white fat distribution with decreased epididymal and retroperitoneal fat tissue masses. They also have increased IL1RA plasma levels and insulin sensitivity. Recombinant IL1RA may be a novel treatment strategy for metabolic syndrome by improving resistance to leptin and insulin.</p>","PeriodicalId":520875,"journal":{"name":"Genomic psychiatry : advancing science from genes to society","volume":"1 4","pages":"74-75"},"PeriodicalIF":0.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13026026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147577612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translating stress systems: corticotropin releasing factor, its receptors, and the dopamine system in nonhuman primate models.","authors":"Julie L Fudge, Emily A Kelly, Iman Mahoui","doi":"10.61373/gp025i.0038","DOIUrl":"10.61373/gp025i.0038","url":null,"abstract":"<p><p>Stress is a fact of life, affecting organisms from the smallest invertebrates to humans. Mediating the stress system is the ancient neuropeptide, corticotropin releasing factor (CRF), which works as a neuromodulator to alter brain systems and homeostatic responses to stress. In humans, many stress-related psychiatric illnesses are linked to dysregulation of monoamine systems, which have cross-talk with CRF-enriched circuits. In this review, we focus on the CRF and the midbrain dopamine (DA) system, particularly as it relates to the nonhuman primate. While tremendous knowledge of CRF-DA mechanisms has been gleaned from rodent models, treatments for stress-related diseases have been elusive, raising the question of whether higher animal models might be required. Subtle shifts in CRF peptide or CRF receptor localization, and the expansion and complexity of DA neuron populations, may hold some of the keys to understanding long-standing stress effects on the DA system in humans. Our laboratory has especially been interested in laying out the neural architecture of the CRF-DA system interface in the nonhuman primate, as a close anatomic model for human. Using rodent models as a starting point, we describe aspects of this complex system that inform our understanding of CRF-DA interactions, and focus on results that have been, and those that still need to be, translated to nonhuman primate models.</p>","PeriodicalId":520875,"journal":{"name":"Genomic psychiatry : advancing science from genes to society","volume":"1 3","pages":"28-43"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12191667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early infant white matter tract microstructure predictors of subsequent change in emotionality and emotional regulation.","authors":"Yicheng Zhang, Layla Banihashemi, Amelia Versace, Alyssa Samolyk, Mahmood Abdelkader, Megan Taylor, Gabrielle English, Vanessa J Schmithorst, Vincent K Lee, Richelle Stiffler, Haris Aslam, Alison E Hipwell, Mary L Phillips","doi":"10.61373/gp025a.0026","DOIUrl":"10.61373/gp025a.0026","url":null,"abstract":"<p><p>There are rapid changes in negative and positive emotionality (NE, PE) and emotional regulation (e.g., soothability) during the first year of life. Understanding the neural basis of these changes during maturation can enhance the understanding of the etiology of early psychopathology. Our goal was to determine how measures of white matter (WM) microstructure in tracts connecting key emotion-related neural networks, including the forceps minor (FM), cingulum bundle (CB), and uncinate fasciculus (UF) interconnecting the default mode network (DMN), salience network (SN), and central executive network (CEN), can predict developmental change in infant emotionality and emotional regulation. We used Neurite Orientation Dispersion and Density Imaging (NODDI) measures together with conventional diffusion tensor metrics to examine WM tract microstructure and fiber collinearity in the primary sample (n=95), and modeled each WM feature with caregiver-reported infant NE, PE, and soothability, with infant and caregiver sociodemographic factors as covariates. In 3-month infants, higher neurite dispersion and lower longitudinal fiber alignment in the FM were associated with a larger increase in NE from 3 to 9 months of age, suggesting that greater integration of the DMN, SN, and CEN leads to a larger subsequent increase in NE; while higher neurite density and dispersion as well as lower WM longitudinal alignment in the left CB were associated with a larger increase in PE, suggesting that greater integration within the CEN leads to increasing PE over time. In addition, higher neurite dispersion and lower WM longitudinal alignment in the left CB were associated with a larger increase in soothability. Associations among diffusion tensor measures and changes in infant emotionality and emotional regulation measures were replicated in an independent test sample (n=44). These findings suggest that early infant WM microstructural features support infant emotionality and emotional regulation development and could represent early biomarkers of future emotional and behavioral disorders.</p>","PeriodicalId":520875,"journal":{"name":"Genomic psychiatry : advancing science from genes to society","volume":"1 3","pages":"53-60"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144878027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent findings and future directions for the intersection of genetic and environmental contributions to schizophrenia.","authors":"Natassia Robinson, Sarah E Bergen","doi":"10.61373/gp024v.0055","DOIUrl":"https://doi.org/10.61373/gp024v.0055","url":null,"abstract":"<p><p>It is well established that both genetic and environmental factors contribute to risk for schizophrenia (SCZ), and much progress has been made in identifying the specific factors conferring risk. However, the nature and extent of interactions between them has long been a topic of debate. Both the data and methods available to address this have evolved rapidly, enabling new prospects for identifying gene-environment interactions in SCZ. To date, there is limited evidence of strong gene-environment interactions, with environmental factors, molecular genetic risk, and family history simultaneously contributing to risk of SCZ. Still, there are several enduring challenges, some of which can likely be addressed with new tools, methods, and approaches for investigating gene-environment interplay. Consequently, advancements in this field will enhance our capacity to identify individuals most vulnerable to specific environmental exposures, which is pivotal for targeted prevention and intervention.</p>","PeriodicalId":520875,"journal":{"name":"Genomic psychiatry : advancing science from genes to society","volume":"1 3","pages":"17-21"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12377634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating long noncoding RNA: New frontiers in biomarker research for mood disorders.","authors":"Bhaskar Roy, Anuj Kumar Verma, Ellie Marie Hulwi, Yogesh Dwivedi","doi":"10.61373/gp024i.0046","DOIUrl":"10.61373/gp024i.0046","url":null,"abstract":"<p><p>Unipolar and bipolar depression [major depressive disorder (MDD) and bipolar disorder (BD)] are complex psychiatric disorders characterized by disturbances in mood, affect, and cognition. Increasing evidence has confirmed epigenetic malfunctioning at the core of these two mental conditions; however, the exact molecular nature of that epigenetic maladaptivity is less known. Lately, long noncoding RNAs (lncRNAs) have emerged as essential epigenetic regulators of gene expression and cellular processes, offering new avenues for exploring the pathophysiology of mood disorders. In this report, we present a comprehensive review of recent clinical studies investigating the involvement of lncRNA in MDD and BD, and emphasizing their disease-specific contribution as potential biomarkers. We explore the dysregulation of specific lncRNAs detected in peripheral blood samples of individuals with mood disorders, while underscoring their significance for clinical diagnosis, prognosis, and predicting treatment response. Additionally, we provide future directions for lncRNA research in the context of mood disorders.</p>","PeriodicalId":520875,"journal":{"name":"Genomic psychiatry : advancing science from genes to society","volume":"1 2","pages":"21-33"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prepartum bumetanide treatment reverses altered neonatal social communication but nonspecifically reduces postpubertal social behavior in a mouse model of fragile X syndrome.","authors":"Yui Sakamoto, Takeshi Takano, Shuji Shimoyama, Takeshi Hiramoto, Noboru Hiroi, Kazuhiko Nakamura","doi":"10.61373/gp024h.0094","DOIUrl":"10.61373/gp024h.0094","url":null,"abstract":"<p><p>Fragile X syndrome is caused by monogenic silencing of the <i>FMR1</i> gene and is characterized by high rates of autism spectrum disorder. A previous study demonstrated that prepartum administration of bumetanide, a chloride transporter blocker, normalized neonatal vocalization in non-congenic <i>Fmr1</i> knockout (KO) pups. However, the genuine contribution of <i>Fmr1</i> deletion to this phenotype in a congenic <i>Fmr1</i> KO mouse model and the long-lasting effect of prepartum bumetanide administration on postpubertal social interaction remains unclear. The current study aimed to determine the impact of prepartum bumetanide administration on vocalization at postnatal day 7 and social interaction at 6 and 8 weeks of age in a congenic <i>Fmr1</i> KO mouse model in which the genetic backgrounds were homogeneous between KO and wild-type (WT) littermates. Moreover, we applied a computational analytical algorithm and determined predictive variables of neonatal vocalization for postpubertal social interaction. Our data showed that (1) KO mice exhibited altered numbers and sequences of distinct call types during neonatal vocalization and reduced social interaction at 6 weeks, (2) select sets of neonatal vocalization variables predicted postpubertal social interaction levels, and (3) bumetanide restored neonatal vocalization in KO pups but nonspecifically reduced social interaction in WT and KO mice at 6 weeks. These data indicate that <i>Fmr1</i> deletion selectively impacts distinct elements of neonatal vocalization and postpubertal social interaction. Additionally, bumetanide selectively restores neonatal vocalization but has a transient nonspecific negative impact on subsequent postpubertal social interaction.</p>","PeriodicalId":520875,"journal":{"name":"Genomic psychiatry : advancing science from genes to society","volume":"1 1","pages":"61-72"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lessons we learned from the Lothian Birth Cohorts of 1921 and 1936.","authors":"Ian J Deary, Simon R Cox","doi":"10.61373/gp024i.0076","DOIUrl":"10.61373/gp024i.0076","url":null,"abstract":"<p><p>The authors are, respectively, the founding and current Directors of the Lothian Birth Cohorts of 1921 and 1936. In this invited and, admittedly, self-regarding and necessarily self-citing piece, we enumerate and explicate some things we learned from working with the cohorts and their data. Some of the lessons are scientific results, some are to do with scientific practice, and some are more general reflections. We hope the paper provides a useful summary of some of the main findings from these too-many-papers-to-read cohorts and an enjoyable account of our building a research team and a network of collaborators. The original aim of assembling the cohorts was to fashion a tool to discover why some people's thinking skills aged better than others'. That tool, we discovered, had many additional uses.</p>","PeriodicalId":520875,"journal":{"name":"Genomic psychiatry : advancing science from genes to society","volume":"1 1","pages":"47-60"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144228437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}