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

{"title":"Genetic Underpinnings of Obsessive–Compulsive Disorder With and Without Tics: Implications of Genetic Heterogeneity on Clinical Management","authors":"Jade-Jocelyne Zouki,&nbsp;Weng Tong Wu,&nbsp;Anthea Stylianakis,&nbsp;Valsamma Eapen","doi":"10.1002/ajmg.b.33068","DOIUrl":"10.1002/ajmg.b.33068","url":null,"abstract":"<div>\u0000 \u0000 <p>The exact genetic mechanisms and link between obsessive–compulsive disorder (OCD) and tics/Tourette syndrome are not fully understood. This narrative review aims to summarize the literature examining whether the clinical phenotypes of OCD and OCD + tics (tic-related OCD) represent distinct entities and how this relates to their genetic underpinnings. Systematic searches were conducted in MEDLINE Complete and Embase databases to identify studies published since the Diagnostic and Statistical Manual 5th Edition introduced the category of OCD with and without tics in 2013. Articles reporting on family cohort studies, linkage and epigenetic analyses, and genome-wide association studies involving patients with OCD and/or tic-related OCD were included. While the studies have highlighted significant genetic heterogeneity, there is some evidence to suggest the role of serotonergic, glutamatergic, and dopaminergic systems, with the latter playing a significant role in the genesis of tic spectrum symptoms, which may have implications for choice of pharmacological management in those with OCD + tics. Given the significant genetic heterogeneity and consequent phenotypic variations, future research delineating homogeneous subgroups is needed, including longitudinal studies that examine whether the clinical phenotypes of the OCD/tic spectrum of conditions “breed true” in offspring, which may have implications for clinical assessment and management.</p>\u0000 </div>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"201 3","pages":"159-179"},"PeriodicalIF":1.5,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145566629","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":"Black EquaLity in OCD NeuroGenomics (BELONG): Study Protocol","authors":"Iasha J. Williams,&nbsp;Dalia Y. Marquez,&nbsp;Kara E. Lopez-lengowski,&nbsp;Malini Bommiasamy,&nbsp;Ogechi “Cynthia” Onyeka,&nbsp;Slayton J. Underwood,&nbsp;Juliana E. Avery,&nbsp;Jacob Gluckman,&nbsp;Thariana Pichardo,&nbsp;Rhea Chandler,&nbsp;Yulu Brown,&nbsp;Katie Mangen,&nbsp;Emma Grace Choplin,&nbsp;Black EquaLity in OCD NeuroGenomics (BELONG) Study Team,&nbsp;Sonyia C. Richardson,&nbsp;Joseph D. Buxbaum,&nbsp;Eric A. Storch,&nbsp;James J. Crowley,&nbsp;Sidney H. Hankerson,&nbsp;Dorothy E. Grice","doi":"10.1002/ajmgb.70002","DOIUrl":"10.1002/ajmgb.70002","url":null,"abstract":"<div>\u0000 \u0000 <p>Obsessive-compulsive disorder (OCD) is a chronic, serious psychiatric disorder that affects 2%–3% of the population and is associated with high personal and societal costs. Genetic factors are estimated to explain roughly half the risk of developing OCD, and genomic studies are just beginning to identify common and rare genetic variants mediating this risk. A major goal of genomic studies is to yield insights into the etiology of OCD and identify molecular targets for the development of novel therapeutics. However, the overwhelming majority of subjects in existing genetic studies are of European ancestry, limiting the generalizability of these findings. To address this gap in understanding, we established the Black EquaLity in OCD NeuroGenomics (BELONG) study (https://belongocd.com/). BELONG aims to collect DNA and clinical data from 1250 richly phenotyped OCD cases of African ancestry in a culturally sensitive manner. In addition, BELONG includes the collection of parental DNA samples for trio-based analyses and unrelated matched controls for case–control analysis. DNA samples will be sequenced using optimized approaches that will allow us to examine both rare and common genome-wide variation to identify OCD risk genes. We will also meta-analyze these data with other existing OCD genomic data. Overall, BELONG will increase the representation of Black Americans in OCD genetic research, which is necessary to generalize precision medicine discoveries in psychiatric genetics.</p>\u0000 </div>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"201 3","pages":"194-204"},"PeriodicalIF":1.5,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961093","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":"Longitudinal Behavior Phenotype Hallmarks in RNU4-2 Syndrome: Implications for Clinical Management","authors":"Paola Francesca Ajmone,&nbsp;Claudia Rigamonti,&nbsp;Francesca Brasca,&nbsp;Donatella Milani,&nbsp;Chiara Ranci Ortigosa,&nbsp;Maria Iascone,&nbsp;Lucrezia Goisis,&nbsp;Annalaura Torella,&nbsp;Maria Antonella Costantino","doi":"10.1002/ajmgb.70004","DOIUrl":"10.1002/ajmgb.70004","url":null,"abstract":"<p>Pathogenic variants in the non-coding spliceosomal gene RNU4-2 underlie ReNU syndrome, one of the most prevalent monogenic causes of neurodevelopmental disorders, accounting for ~0.4% of cases. Despite increasing recognition, little is known about the longitudinal behavioral and neuropsychiatric phenotype of affected individuals. We report two patients with RNU4-2 variants, providing a comprehensive description of their developmental trajectories from infancy to adolescence. Both exhibited global developmental delay, impaired adaptive functioning, and significant language deficits. Distinctive features included persistent attention deficits and Autistic Spectrum Disorder, which emerged as hallmarks of the Syndrome. Case-specific differences were notable: one patient developed self-injurious behavior and social anxiety during adolescence, while the other presented with epilepsy and structural brain anomalies. Neuroimaging revealed convergent features, including white matter reduction, corpus callosum thinning, and ventricular dysmorphisms. Our findings highlight the importance of early, individualized interventions, with particular emphasis on augmentative and alternative communication strategies and cognitive-behavioral approaches to mitigate communicative frustration, behavioral dysregulation, and social anxiety. This study provides the first longitudinal neuropsychiatric characterization of RNU4-2-related disorder, delineating clinical hallmarks, and therapeutic windows. A better understanding of developmental trajectories in this condition is essential to optimize patient management and improve long-term outcomes.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"201 3","pages":"205-211"},"PeriodicalIF":1.5,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmgb.70004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146183964","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":"Novel Variants Identified in Families With SNX27-Related Neurodevelopmental Disorder, Aiding in Characterizing Its Genotypic and Phenotypic Spectrum","authors":"Tayyaba Shan,&nbsp;Abrar Hussain,&nbsp;Anushree Acharya,&nbsp;Mulazim Hussain,&nbsp;Yumei Li,&nbsp;Hafiz Muhammad Jafar Hussain,&nbsp;Kiran Afshan,&nbsp;Suzanne M. Leal,&nbsp;Rui Chen,&nbsp;Asif Mir,&nbsp;Isabelle Schrauwen,&nbsp;Sabika Firasat","doi":"10.1002/ajmgb.70005","DOIUrl":"10.1002/ajmgb.70005","url":null,"abstract":"<div>\u0000 \u0000 <p>\u0000 <i>Sorting Nexin 27 (SNX27)</i>, a key regulator of synaptic receptor trafficking and endosomal recycling, has been implicated in maintaining synaptic homeostasis and cognitive function. To date, variants in <i>SNX27</i> have been reported in a small number of patients across three publications with severe neurodevelopmental phenotypes. However, the genetic and functional landscape of <i>SNX27</i>-related disorders remains poorly understood, and further evidence is needed to confirm its association with disease and to better delineate the associated phenotype. Two unrelated Pakistani families with a total of five affected individuals segregating a neurodevelopmental disorder were investigated via exome or genome sequencing. This revealed a novel homozygous frameshift variant in family I [NM_001330723.2: c.75dup; p. (Ser26Valfs*85)], predicted to be targeted by nonsense-mediated decay. In family II, a novel homozygous missense variant [NM_001330723.2: c.929 T&gt;C; p. (Met310Thr)] was found within the FERM-like region of the SNX27 protein, which is critical for retromer complex interaction. Comparison of five cases described in this study with previously reported six cases reinforces the presence of consistent “core” clinical features—global developmental delay, intellectual disability, speech delay, behavioral abnormalities, seizures, and motor dysfunction in all assessed cases. Other features such as dental anomalies, failure to thrive, and dysmorphisms occurred variably in few. Affected individuals with predicted loss-of-function variants typically presented with a more severe phenotype. Thus, core features of <i>SNX27</i>-related neurodevelopmental disorders (NDDs) are intellectual disability, developmental, and speech delays. This study, alongside prior reports, augments the genetic and phenotypic spectrum of <i>SNX27</i>-associated NDDs. The novel frameshift variant p.(Ser26Valfs*85) is predicted to severely disrupt SNX27 function, causing profound neurodevelopmental impairment, whereas the missense p.(Met310Thr) in the FERM-like region is associated with a milder phenotype. Comparative analyses with previous reports reveal a spectrum from early lethality to long-term survival with intellectual disability in <i>SNX27</i>-linked families. These findings underscore the importance of <i>SNX27</i> in neurodevelopment and further validate its link to a neurodevelopmental disorder.</p>\u0000 </div>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"201 3","pages":"212-221"},"PeriodicalIF":1.5,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146088724","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":"Schizophrenia Genetics Modulates Clinical Depressive Features","authors":"Alessandro Serretti,&nbsp;Daniel Souery,&nbsp;Siegfried Kasper,&nbsp;Joseph Zohar,&nbsp;Stuart Montgomery,&nbsp;Panagiotis Ferentinos,&nbsp;Dan Rujescu,&nbsp;Raffaele Ferri,&nbsp;Giuseppe Fanelli,&nbsp;Chiara Fabbri,&nbsp;Raffaella Zanardi,&nbsp;Francesco Benedetti,&nbsp;Bernhard T. Baune,&nbsp;Julien Mendlewicz","doi":"10.1002/ajmg.b.33066","DOIUrl":"10.1002/ajmg.b.33066","url":null,"abstract":"<p>Schizophrenia (SCZ) genetic liability, quantified by polygenic scores (PGS), may influence clinical phenotypes in major depressive disorder (MDD). We investigated the effect of the SCZ-PGS derived from the latest SCZ genome-wide association study (GWAS) on MDD symptom severity, comorbidities, and treatment outcomes. The study included 1060 adults diagnosed with MDD from the GSRD sample, with replication in the STAR*D sample (<i>n</i> = 1503 MDD). Baseline and current depressive symptoms were assessed along with functional impairment and comorbid conditions. SCZ-PGS was calculated based on the latest SCZ GWAS summary statistics. Higher SCZ-PGS was associated with more severe baseline depressive symptoms, including apparent sadness, inner tension, lassitude, pessimistic thoughts, and suicidality. Functional impairment in social, familial, and work domains also increased with higher SCZ-PGS. Multivariable models suggested a small but significant independent association between elevated SCZ-PGS and poorer outcomes, confirmed in the STAR*D sample. Elevated SCZ-PGS correlated with a series of features suggesting more severe depression in both samples. Our findings confirm that the latest SCZ genetic liability scores contribute to MDD clinical heterogeneity, increasing depressive severity, functional impairment, and anxiety comorbidity. Although its influence on treatment response appears modest, SCZ-PGS may serve as a marker for more severe depressive presentations.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"201 3","pages":"180-193"},"PeriodicalIF":1.5,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.33066","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338479","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":"The Genetic Landscape of Kynurenine Predicts Neurovascular Pathology and Disrupted White Matter Integrity in Patients With Mood Disorders","authors":"Beatrice Bravi,&nbsp;Lidia Fortaner-Uyà,&nbsp;Marco Paolini,&nbsp;Stefano Comai,&nbsp;Sara Poletti,&nbsp;Cristina Lorenzi,&nbsp;Sara Spadini,&nbsp;Alessandro Serretti,&nbsp;Cristina Colombo,&nbsp;Raffaella Zanardi,&nbsp;Francesco Benedetti","doi":"10.1002/ajmg.b.33060","DOIUrl":"10.1002/ajmg.b.33060","url":null,"abstract":"<div>\u0000 \u0000 <p>Low-grade systemic inflammation is linked to cardiometabolic diseases and increased cardiovascular risk. Patients with mood disorders, such as Major Depressive Disorder (MDD) and Bipolar Disorder (BD), also show elevated cardiovascular risk and inflammatory markers, suggesting shared biological pathways between mood and cardiometabolic conditions. The kynurenine (KYN) pathway, activated by inflammatory cytokines and involved in neurotransmitter systems linked to mood, provides a promising area to explore inflammatory-related genetic overlaps in these disorders, with increasing interest in the SH2B3 rs3184504 SNP. Imaging markers like white matter hyperintensities (WMHs) and white matter (WM) microstructure alterations are associated with mood and cardiovascular disorders. This study aimed to investigate the genetic load linked to KYN levels, such as KYN polygenic risk score (PRS) and its effect on white matter hyperintensities (WMHs), outcomes of presumed vascular suffering, and WM microstructure in a sample of 95 MDD and 80 BD patients. Higher PRS for KYN was associated with increased circulating KYN levels and KYN/TRP ratio. KYN PRS predicted the presence of WMHs. The SH2B3 rs3184504 T variant was associated with increased PRS for KYN and a higher number of WMHs. KYN levels and KYN/TRP ratio were not associated with WMHs, while KYN PRS positively correlated with higher axial (AD) and mean diffusivity (MD), with a nominal significance for radial diffusivity (RD). The findings support a genetic contribution to elevated KYN and WM integrity alterations in mood disorders. PRS for KYN indicates a potential predisposition to inflammatory and vascular dysregulation, and SH2B3 rs3184504 may modulate this risk.</p>\u0000 </div>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"201 2","pages":"144-155"},"PeriodicalIF":1.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116059","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":"Treg Cells Modulate Neuroinflammation and Behavioral Deficits in Autism: Evidence From MR-Based Genetic Analyses and Experimental Models","authors":"Zuqing Nie,&nbsp;Xinyi Xu,&nbsp;Junhao Chen,&nbsp;Huiling Chen,&nbsp;Meng Li,&nbsp;Yang Zhang,&nbsp;Zhiwei Li,&nbsp;Chen Shen,&nbsp;Jie Wen,&nbsp;Xia Cao","doi":"10.1002/ajmg.b.33061","DOIUrl":"10.1002/ajmg.b.33061","url":null,"abstract":"<p>Autism spectrum disorder (ASD) is a neurodevelopmental condition that is increasingly linked to immune dysfunction and neuroinflammation. Regulatory T cells (Tregs), which are crucial in maintaining immune homeostasis, have been implicated in the pathogenesis of ASD. However, their role in neuroimmune interactions and behavioral outcomes remains poorly understood. We employed Mendelian Randomization (MR) to assess the causal relationship between Tregs and ASD risk, using genetic data to infer causality. To further confirm the reliability of the MR results, we incorporated data from an independent genome-wide association study (GWAS) and conducted a meta-analysis to strengthen causal inference. Additionally, we validated our findings in an ASD-like mouse model (BTBR mice) treated with the IL-2/JES6.1 complex to enhance Tregs' function. Neuroinflammation and behavioral outcomes were assessed in treated and control mice. MR analysis revealed significant associations between several Tregs subsets and ASD risk. The proportion of CD127^‒ CD8⁺ T cells among total T cells showed a consistent protective effect (OR = 0.84, <i>p</i> = 0.01166), which was validated across multiple analytical methods. The absolute count of resting CD4⁺ regulatory T cells was also inversely associated with ASD risk and demonstrated an independent protective effect in multivariable MR analysis. Sensitivity analyses revealed no evidence of horizontal pleiotropy or heterogeneity. Experimental treatment with IL-2/JES6.1 in BTBR mice significantly increased CD4⁺ Tregs populations, enhanced CD4⁺ Tregs activation, and improved social interactions and repetitive behavior. Furthermore, IL-2/JES6.1 treatment reduced neuroinflammatory markers, including microglial activation. Transcriptomic analysis revealed that IL-2/JES6.1 treatment induced neuroendocrine and synaptic plasticity pathways in the hippocampus and cortex while suppressing inflammatory signaling. This study demonstrates that Tregs modulation can influence ASD pathogenesis through immune regulation and behavioral improvement. Our findings highlight the potential of Treg-targeted therapies for ASD. Future studies should focus on the mechanistic pathways involved and explore the clinical applicability of these therapies.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"201 2","pages":"127-143"},"PeriodicalIF":1.5,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.33061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031568","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":"Pseudo-Schizophrenia Should Always Be Considered in Genetic Studies Regarding Psychosis","authors":"João Gama-Marques,&nbsp;Josef Finsterer","doi":"10.1002/ajmg.b.33062","DOIUrl":"10.1002/ajmg.b.33062","url":null,"abstract":"","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"201 2","pages":"91-92"},"PeriodicalIF":1.5,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025031","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":"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":1.5,"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}