American Journal of Medical Genetics Part B: Neuropsychiatric Genetics最新文献

{"title":"Cover Image, Volume 198, Number 7, October 2025","authors":"Clio E. Franklin,&nbsp;Murat Altinay,&nbsp;Kala Bailey,&nbsp;Mahendra T. Bhati,&nbsp;Brent R. Carr,&nbsp;Susan K. Conroy,&nbsp;Khurshid Khurshid,&nbsp;William M. McDonald,&nbsp;Brian J. Mickey,&nbsp;James W. Murrough,&nbsp;Sean M. Nestor,&nbsp;Thomas Nickl-Jockschat,&nbsp;Irving M. Reti,&nbsp;Gerard Sanacora,&nbsp;Nicholas T. Trapp,&nbsp;Biju Viswanath,&nbsp;Jesse H. Wright,&nbsp;Peter P. Zandi,&nbsp;James B. Potash","doi":"10.1002/ajmg.b.33059","DOIUrl":"https://doi.org/10.1002/ajmg.b.33059","url":null,"abstract":"<p>The cover image is based on the article <i>Genetics of Response to ECT, TMS, Ketamine and Esketamine</i> by Clio E. Franklin et al., https://doi.org/10.1002/ajmg.b.33038.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"198 7","pages":""},"PeriodicalIF":1.5,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.33059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Systematic Review of the Application of Graph Neural Networks to Extract Candidate Genes and Biological Associations.","authors":"Ankita Saxena, Bridgette Nixon, Amelia Boyd, James Evans, Stephen V Faraone","doi":"10.1002/ajmg.b.33031","DOIUrl":"10.1002/ajmg.b.33031","url":null,"abstract":"<p><p>The development of high throughput technologies has resulted in the collection of large quantities of genomic and transcriptomic data. However, identifying disease-associated genes or networks from these data has remained an ongoing challenge. In recent years, graph neural networks (GNNs) have emerged as a promising analytical tool, but it is not well understood which characteristics of these models result in improved performance. We conducted a systematic search and review of publications that used GNNs to identify disease-associated biological interactions. Information was extracted about model characteristics and performance with the goal of examining the relationship between these factors and performance. Data leakage was found in 31% of these models. For node level tasks, univariate positive associations were identified between model accuracy and use of hyper parameter optimization, data leakage via hyperparameter optimization, test set size, and total dataset size. Among graph level tasks, an increase in AUC was identified in association with testing method and a decrease with optimization reporting. Data leakage may pose an issue for GNN-based approaches; the adoption of best practice guidelines and consistent reporting of model design would be beneficial for future studies.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":" ","pages":"3-18"},"PeriodicalIF":1.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Transcriptome-Wide Mendelian Randomization Study in Isolated Human Immune Cells Highlights Risk Genes Involved in Viral Infections and Potential Drug Repurposing Opportunities for Schizophrenia.","authors":"David Stacey, Liam Gaziano, Preethi Eldi, Catherine Toben, Beben Benyamin, S Hong Lee, Elina Hyppönen","doi":"10.1002/ajmg.b.33028","DOIUrl":"10.1002/ajmg.b.33028","url":null,"abstract":"<p><p>Schizophrenia is a neurodevelopmental psychiatric disorder characterized by symptoms of psychosis, thought disorder, and flattened affect. Immune mechanisms are associated with schizophrenia, though the precise nature of this relationship (causal, correlated, consequential) and the mechanisms involved are not fully understood. To elucidate these mechanisms, we conducted a transcriptome-wide Mendelian randomization study using gene expression exposures from 29 human cis-eQTL data sets encompassing 11 unique immune cell types, available from the eQTL catalog. These analyses highlighted 196 genes, including 67 located within the human leukocyte antigen (HLA) region. Enrichment analyses indicated an overrepresentation of immune genes, which was driven by the HLA genes. Stringent validation and replication steps retained 61 candidate genes, 27 of which were the sole causal signals at their respective loci, thereby representing strong candidate effector genes at known risk loci. We highlighted L3HYPDH as a potential novel schizophrenia risk gene and DPYD and MAPK3 as candidate drug repurposing targets. Furthermore, we performed follow-up analyses focused on one of the candidate effectors, interferon regulatory transcription factor 3 (IRF3), which coordinates interferon responses to viral infections. We found evidence of shared genetic etiology between schizophrenia and autoimmune diseases at the IRF3 locus, and a significant enrichment of IRF3 chromatin binding at known schizophrenia risk loci. Our findings highlight a novel schizophrenia risk gene, potential drug repurposing opportunities, and provide support for IRF3 as a schizophrenia hub gene, which may play critical roles in mediating schizophrenia-autoimmune comorbidities and the impact of infections on schizophrenia risk.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":" ","pages":"19-31"},"PeriodicalIF":1.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Do Influential Articles on the Genetics of Autism Show Evidence of Engagement With the Autistic Community?","authors":"Heidi Kristiina Kaljusto, Emma Wilson, Sue Fletcher-Watson","doi":"10.1002/ajmg.b.33030","DOIUrl":"10.1002/ajmg.b.33030","url":null,"abstract":"<p><p>Investigations into the etiology and genetic basis of autism continue to drive much autism research, yet reports are emerging of this research not aligning with priorities of autistic people. Engagement of autistic people in the research process is a key way to take their perspectives on board. We investigated whether influential genetic autism research shows evidence of engagement with the autistic community via indicators in published article texts. Through text mining of the abstracts of articles mentioning the words \"autism\" or \"autistic,\" we found minimal prevalence of progressive terminology associated with autism. We also devised a novel rating system to assess three hallmarks of autistic community engagement: presence of non-stigmatizing language, referencing community priorities, and the use of participatory methods. We reviewed 149 articles within leading autism and genetic journals. Minimal evidence of engagement with the autistic community was found within all three hallmarks. Genetics researchers focused on autism should embrace opportunities to engage with the autistic community to bring their work into closer alignment with their priorities, yielding scientific and moral benefits.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":" ","pages":"46-61"},"PeriodicalIF":1.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic Manifestations of a New Variant in HDAC4 Gene.","authors":"Monica Ianniello, Valentina De Angelis, Alessandro Ottaiano, Raffaella Ruggiero, Roberto Sirica, Nadia Petrillo, Antonio Fico, Tania Cerbone, Cecilia Rosania, Raffaella Mormile, Carmine Picone, Mariachiara Santorsola, Giovanni Savarese","doi":"10.1002/ajmg.b.33029","DOIUrl":"10.1002/ajmg.b.33029","url":null,"abstract":"<p><p>Psychomotor development delays affect 1%-3% of children and encompass a wide range of motor, cognitive, and social impairments. The histone deacetylase 4 (HDAC4) gene, critical for neurodevelopmental pathways, has been associated with developmental delays, autism spectrum disorders, and cognitive impairments. Here, we report a case of a female patient with global psychomotor developmental delay, hypotonia, and feeding difficulties since infancy. By the age of seven, she developed epilepsy, later diagnosed as Lennox-Gastaut syndrome. Brain magnetic resonance imaging revealed reduced white matter and polymicrogyria-like cortical malformations, primarily in the fronto-basal regions. Whole-exome sequencing identified a novel de novo HDAC4 mutation (p.Gln1046AspfsTer29; c.3136_3137delCA), resulting in a frameshift and a premature stop codon. Additional phenotypic features included distinct craniofacial abnormalities and hypertrichosis. This report highlights the critical role of HDAC4 in psychomotor development and cognitive function, expands the phenotypic spectrum associated with HDAC4 mutations, and suggests a potential link to epilepsy and cortical malformations.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":" ","pages":"32-37"},"PeriodicalIF":1.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LINC00665/miR-132-5p Reduces Inflammation in Epileptic Cells by Targeting MAPK3.","authors":"Qi-Ming Pang, Cui Wang, Bang-Tao Li, Su-Li Zhang, Jiao-Yang Li, Shuo Gu","doi":"10.1002/ajmg.b.33027","DOIUrl":"10.1002/ajmg.b.33027","url":null,"abstract":"<p><p>To investigate the role of miR-132-5p in the inflammatory response in epilepsy. Peripheral blood was collected from epileptic and healthy children, and the expression of LINC00665 and miR-132-5p was detected by q-PCR. Epilepsy cell models were constructed with microglia, transfected with miR-132-5p inhibitor and NC, and the expression of LINC00665 and miR-132-5p was detected by q-PCR, the expression of TNF-α, IL-1β, and IL-6 in the cell supernatant was detected by ELISA, and the protein levels of NLRP3 and MAPK3 were detected by WB. Finally, the targeting relationship between LINC00665 and miR-132-5p was verified by dual luciferase assay. The expression levels of both LINC00665 and miR-132-5p in the peripheral blood of children with epilepsy were significantly higher than those of healthy children. After transfection of epileptic cells with miR-132-5p inhibitor, the expression levels of LINC00665 and miR-132-5p were increased, and the expression levels of TNF-α, IL-1β, IL-6, NLRP3, and MAPK3 were decreased. Dual luciferase assay showed targeted binding of LINC00665 and miR-132-5p. LINC00665/miR-132-5p attenuates inflammatory responses in epileptic cells by targeting MAPK3.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":" ","pages":"38-45"},"PeriodicalIF":1.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Randomized Double-Blind Placebo-Controlled Trial of Guanfacine Extended Release for Aggression and Self-Injurious Behavior Associated With Prader-Willi Syndrome.","authors":"Deepan Singh, Michael Silver, Theresa Jacob","doi":"10.1002/ajmg.b.33032","DOIUrl":"10.1002/ajmg.b.33032","url":null,"abstract":"<p><p>Prader-Willi Syndrome (PWS), a rare genetic disorder, affects development and behavior, frequently resulting in self-injury, aggression, hyperphagia, oppositional behavior, impulsivity, and over-activity, causing significant morbidity. Currently, limited therapeutic options are available to manage these neuropsychiatric manifestations. A randomized, placebo-controlled trial was conducted to assess the efficacy of guanfacine-extended release (GXR) in reducing aggression and self-injury in individuals with PWS. Subjects with a diagnosis of PWS, aged 6-35 years with moderate to severe aggressive and/or self-injurious behavior, as determined by the clinical global impression (CGI)-Severity scale, were included in an 8-week double-blind, placebo-controlled, fixed-flexible dose clinical trial of GXR, that was followed by an 8-week open-label extension phase. Validated behavioral instruments and physician assessments measured the efficacy of GXR treatment, its safety, and tolerability. GXR was effective in reducing aggression/agitation and hyperactivity/noncompliance, as measured by the Aberrant Behavior Checklist (ABC) scales (p = 0.03). Overall aberrant behavior scores significantly reduced in the GXR arm. Aggression, as measured by the modified overt aggression scale (MOAS) also showed a significant reduction. Skin-picking lesions, as measured by the self injury trauma (SIT) scale, decreased in response to GXR. No serious adverse events were experienced by any of the study participants. Fatigue/sedation was the only adverse event significantly associated with GXR. The GXR group demonstrated significant overall clinical improvement, as measured by the CGI-Improvement (CGI-I) scale (p < 0.01). Findings of this pragmatic trial strongly support the use of GXR for the treatment of aggression, skin picking, and hyperactivity in children, adolescents, and adults with PWS.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":" ","pages":"62-70"},"PeriodicalIF":1.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Appraisal of Gene Expression-Based Classifiers for Neuropsychiatric Disorders: A Meta-Regression","authors":"Ali Razavi,&nbsp;Brittany Arensman,&nbsp;Eric J. Barnett,&nbsp;Leo A. Lee,&nbsp;Stephen V. Faraone,&nbsp;Stephen J. Glatt,&nbsp;Jonathan L. Hess","doi":"10.1002/ajmg.b.33055","DOIUrl":"10.1002/ajmg.b.33055","url":null,"abstract":"<p>A substantial body of research examines the potential of gene-expression-based biomarkers for diagnosing and selecting treatments for neuropsychiatric disorders, yet no clear consensus has been reached regarding the influence of controllable factors such as study design and model selection on the performance of gene-expression-based classifiers. To investigate study characteristics and methodologies that influence the accuracy of studies using transcriptomics to classify neuropsychiatric disorders, we conducted a literature review and meta-regression of relevant studies. We extracted several characteristics from each study, including the number of samples in a training dataset, approach for model validation, and classification model. Using univariate and multivariate mixed-effect meta-regression analyses, we estimated the association between these study characteristics and reported classification accuracies. Machine Learning (ML) models accounted for 55% of all models; Deep Learning (DL) models accounted for 20%, and variations of Logistic Regression models made up the remaining 25%. Support vector machine (SVM) was the most common model type (17%). The use of withheld test samples (56%) was the most frequent approach for validating the performance of classification models. We found significant associations between reported accuracies and study-rated bias risk, model type, class ratio, and validation approach. Overall, this review provides helpful insights into study characteristics that significantly influence classification accuracies and emphasizes the importance of prudent methodologies for training and evaluating classification models to mitigate biased accuracy estimates. In future research, these findings can direct study designs and support the development of clinically reliable, minimally invasive gene-expression biomarkers to improve diagnostic workflows and patient outcomes in neuropsychiatry.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"201 2","pages":"93-104"},"PeriodicalIF":1.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.33055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144985836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and Environmental Factors of Nicotine Addiction: Examination of Multiple Substance Addictions","authors":"Muammer Albayrak,&nbsp;Kemal Turhan","doi":"10.1002/ajmg.b.33057","DOIUrl":"10.1002/ajmg.b.33057","url":null,"abstract":"<div>\u0000 \u0000 <p>Nicotine addiction, like many other forms of addiction, is a multifaceted behavior influenced by both genetic and environmental factors. Despite the well-established role of these influences, relatively few studies have simultaneously examined the interaction between genetic predispositions and environmental variables in the context of substance addiction. This study investigated the role of specific genetic variants within nicotinic acetylcholine receptor (nAChR) and cytochrome P450 genes in relation to nicotine and other substance addictions, as well as environmental factors. From a total of 66,936 genetic variants, a Polygenic Risk Score (PRS) was computed using selected SNPs within the nAChR and cytochrome gene families. Structural Equation Modeling (SEM) was employed to examine the relationships between PRS, the Wisconsin Index of Smoking Dependence Motives (WISDM), socioeconomic status (SES), and various forms of substance addiction, using a dataset comprising 2969 individuals (1786 females, 1168 males). The results demonstrate that substance addiction is shaped by a complex interplay of genetic, environmental, and psychological factors. The PRS significantly predicted the Fagerström Test for Nicotine Dependence (FTND) and DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) based nicotine dependence. PRS had smaller, yet significant, effects on alcohol and marijuana dependence and WISDM. However, it showed no meaningful relationship with SES or other addictions. In contrast, SES strongly influenced smoking motives (WISDM), which in turn significantly predicted multiple types of substance addiction, positioning WISDM as a key mediator. Additionally, alcohol dependence emerged as a central factor, showing cascading effects on nicotine, marijuana, and cocaine addiction. Overall, while genetic predisposition plays a notable role, especially in nicotine-related outcomes, social context and motivational factors exert broader and more substantial effects across various addiction pathways, underscoring the need for multifaceted intervention strategies.</p>\u0000 </div>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"201 2","pages":"116-126"},"PeriodicalIF":1.5,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144985825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep Phenotyping at Scale: Study Protocol for the Korean Mood Disorder Genetic Study-Depression (KOMOGEN-D)","authors":"Sooyeon Min,&nbsp;Sang Jin Rhee,&nbsp;Yoojin Song,&nbsp;Kyooseob Ha,&nbsp;Yong Min Ahn,&nbsp;Kenneth S. Kendler,&nbsp;Jonathan Flint,&nbsp;KOMOGEN-D Group","doi":"10.1002/ajmg.b.33056","DOIUrl":"10.1002/ajmg.b.33056","url":null,"abstract":"<div>\u0000 \u0000 <p>A core challenge in the genetic analysis of major depressive disorder (MDD) is how to recruit large numbers of stringently diagnosed cases with sufficient information to explore the interplay between genetic and environmental risk factors and evaluate genetic influences on putative MD subtypes and key clinical features. Currently, most genome-wide association studies of MDD rely on self-administered questionnaires or electronic health records, both of which are limited in diagnostic accuracy and introduce systematic, heritable biases that confound the interpretation of genetic analyses. Here, we describe how to address this problem through a combination of targeted ascertainment and in-depth phenotyping by clinical interview. We increase the homogeneity of the sample, reducing the number of cases needed to detect genetic signals, by recruiting only women with recurrent depressive episodes, ascertained through hospitals. Structured interviews capture detailed information on the known and putative risk factors for the disorder. We trained 347 interviewers working at 47 participating hospitals across South Korea and recruited 5704 cases and 4995 screened controls over 4 years toward a total target sample of 10,000 cases and 10,000 controls. We met and overcame a series of logistic challenges, including restrictions due to COVID-19 and an ongoing medical crisis. We confirmed that our cases have recurrent, severe MDD and are suitable to explore the causes of recurrent episodes of disturbances of sleep and appetite, suicidality, guilty ruminations, anhedonia, and low mood. Our study design provides deeply phenotyped cases and screened controls at scale and can be adapted for deployment in other countries to yield cohorts for the genetic analysis of MDD.</p>\u0000 </div>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"201 2","pages":"105-115"},"PeriodicalIF":1.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144985867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}