medRxiv : the preprint server for health sciences最新文献

{"title":"Polygenic prediction of cardiorespiratory fitness: The HUNT Study.","authors":"Karsten Øvretveit, Marie Klevjer, Ben M Brumpton, Ulrik Wisløff, Kristian Hveem, Anja Bye","doi":"10.1101/2025.07.07.25330991","DOIUrl":"10.1101/2025.07.07.25330991","url":null,"abstract":"<p><strong>Background: </strong>Cardiorespiratory fitness (CRF) has a strong genetic component and low CRF is a major risk factor for cardiovascular morbidity and mortality. The purpose of this study was to develop and validate a polygenic score (PGS) for CRF (CRF_PGS) and assess its associations with cardiovascular disease (CVD) and all-cause mortality. We hypothesized that the CRF_PGS would demonstrate similar cardioprotective benefits as the CRF phenotype.</p><p><strong>Methods: </strong>Effect estimates from a genome-wide association study on directly measured CRF in the Trøndelag Health Study (HUNT; <i>n</i> = 4 525) were used in a Bayesian regression framework to develop multiple PGSs in an independent cohort from the UK Biobank (<i>n</i> = 65 165). The top performing score was applied in the HUNT target cohort, excluding the discovery sample (<i>n</i> = 82 109).</p><p><strong>Results: </strong>The PGS-CRF association varied considerably as a function of model fit and phenotypic accuracy. In the target population, we observed a difference in CRF of 1.55 [95% confidence interval: 1.26, 1.84] mL·kg^-1·min^-1 between the bottom and top decile of the CRF_PGS. Moreover, a high CRF_PGS demonstrated cardioprotective effects, with reduced risk for CVD, myocardial infarction, hypertension, and all-cause mortality. We also found that the CRF_PGS predisposed to lower risk of heart failure and hypertrophic cardiomyopathy in women.</p><p><strong>Conclusion: </strong>A PGS for CRF derived from gold-standard phenotypes captures small, but potentially clinical meaningful variations in CRF, and is associated with reduced risk of cardiovascular morbidity and mortality. Heterogeneity in CRF phenotyping in large populations remains a challenge to PGS development and refinement.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651732","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":"National burden and optimal vaccine policy for Japanese encephalitis virus in Bangladesh.","authors":"Mariana Perez Duque, Kishor K Paul, Rebeca Sultana, Gabriel Ribeiro Dos Santos, Megan O'Driscoll, Abu M Naser, Mahmudur Rahman, Mohammad Shafiul Alam, Hasan M Al-Amin, Mohammed Z Rahman, Mohammad E Hossain, Repon C Paul, Elias Krainski, Stephen P Luby, Simon Cauchemez, Jessica Vanhomwegen, Emily S Gurley, Henrik Salje","doi":"10.1101/2025.07.07.25330995","DOIUrl":"10.1101/2025.07.07.25330995","url":null,"abstract":"<p><strong>Background: </strong>Bangladesh first reported Japanese encephalitis virus (JEV) in 1977 and has seen regular cases since, however, no JEV vaccination program currently exists. A barrier to the use of JEV vaccines has been a limited understanding of the underlying burden.</p><p><strong>Methods: </strong>We conducted a nationally representative serological community study in 70 communities in individuals of all ages (N=2,938, October 2015-January 2016). Serum samples were tested for IgG antibodies against JEV. We developed spatially explicit serocatalytic models to estimate the underlying force of infection across the country. We then used mathematical models to estimate the annual JE disease burden currently and under different vaccination strategies.</p><p><strong>Findings: </strong>The overall JEV seroprevalence in Bangladesh was 3.4% (95%CI: 2.8-4.1, range 0-28% across communities). The annual probability of infection was 0.005 (95%CI: 0.003-0.009), with risk greatest near border regions. We estimated that annually there are 157 clinical cases (95%CI: 89-253) and 31 deaths (95%CI: 18-52). A vaccination strategy in the 10 most affected districts in 60% of 1-15 year olds would require 5 million doses and avert 1 case per 100,000 doses over five years compared to 35 million doses and 0.5 cases averted for a nationwide campaign. No vaccination scenario was cost-effective under a willingness-to-pay of three-times gross domestic product.</p><p><strong>Interpretation: </strong>A spatially targeted vaccine campaign would be most effective in reducing JEV burden, however, would still not meet standard cost effectiveness targets.</p><p><strong>Funding: </strong>CDC.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651729","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":"GlaucoRAG: A Retrieval-Augmented Large Language Model for Expert-Level Glaucoma Assessment.","authors":"Mohammad Aminan, S Solomon Darnell, Mohammad Delsoz, Amin Nabavi, Claire Wright, Brian Jerkins, Siamak Yousefi","doi":"10.1101/2025.07.03.25330805","DOIUrl":"10.1101/2025.07.03.25330805","url":null,"abstract":"<p><strong>Purpose: </strong>Purpose: Accurate glaucoma assessment is challenging because of the complexity and chronic nature of the disease; therefore, there is a critical need for models that provide evidence-based, accurate assessment. The purpose of this study was to evaluate the capabilities of a glaucoma specialized Retrieval-Augmented Generation (RAG) framework (GlaucoRAG) that leverages a large language model (LLM) for diagnosing glaucoma and answering to glaucoma specific questions.</p><p><strong>Design: </strong>Evaluation of diagnostic capabilities and knowledge of emerging technologies in glaucoma assessment.</p><p><strong>Participants: </strong>Detailed case reports from 11 patients and 250 multiple choice questions from the Basic and Clinical Science Course (BCSC) Self-Assessment were used to test the LLM based GlaucoRAG. No human participants were involved.</p><p><strong>Methods: </strong>We developed GlaucoRAG, a RAG framework leveraging GPT-4.5-PREVIEW integrated with the R2R platform for automated question answering in glaucoma. We created a glaucoma knowledge base comprising more than 1,800 peer-reviewed glaucoma articles, 15 guidelines and three glaucoma textbooks. The diagnostic performance was tested on case reports and multiple-choice questions. Model outputs were compared with the independent answers of three glaucoma specialists, DeepSeek-R1, and GPT-4.5-PREVIEW (without RAG). Quantitative performance was further assessed with the RAG Assessment (RAGAS) framework, reporting faithfulness, context precision, context recall, and answer relevancy.</p><p><strong>Main outcome measures: </strong>The primary outcome measure was GlaucoRAG's diagnostic accuracy on patient case reports and percentage of correct responses to the BCSC Self-Assessment glaucoma items, compared with the performance of glaucoma specialists and two benchmark LLMs. Secondary outcomes included RAGAS sub scores.</p><p><strong>Results: </strong>GlaucoRAG achieved an accuracy of 81.8% on glaucoma case reports, compared with 72.7% for GPT-4.5-PREVIEW and 63.7% for DeepSeek-R1. On glaucoma BCSC Self-Assessment questions, GlaucoRAG achieved 91.2% accuracy (228 / 250), whereas GPT-4.5-PREVIEW and DeepSeek-R1 attained 84.4% (211 / 250) and 76.0% (190 / 250), respectively. The RAGAS evaluation returned an answer relevancy of 91%, with 80% context recall, 70% faithfulness, and 59% context precision.</p><p><strong>Conclusions: </strong>The glaucoma-specialized LLM, GlaucoRAG, showed encouraging performance in glaucoma assessment and may complement glaucoma research and clinical practice as well as question answering with glaucoma patients.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651682","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":"MEDICATION EXPOSURE AND NEURODEGENERATIVE DISEASE RISK ACROSS NATIONAL BIOBANKS.","authors":"Kristin S Levine, Lana Sargent, Emma N Somerville, Vanessa Pitz, Elvin T Price, Sara Bandres-Ciga, Emily Simmonds, Rodney Alan Long, Caroline Jonson, Lara M Lange, Alastair J Noyce, Valentina Escott-Price, Hirotaka Iwaki, Kendall Van Keuren-Jensen, Luigi Ferrucci, Mark R Cookson, Andrew Singleton, Mike Nalls, Hampton Leonard","doi":"10.1101/2025.07.07.25330740","DOIUrl":"10.1101/2025.07.07.25330740","url":null,"abstract":"<p><p>Advanced age, genetics, and environmental exposures are leading contributors to the development of neurodegenerative disorders (NDD). In this study, we used data from the UK Biobank (UKB) and the All of Us (AoU) initiative to determine if exposure to specific medications are associated with an increased or decreased risk of NDD, including Alzheimer's (AD), Parkinson's disease (PD), and all-cause dementia (DEM). We investigated the associations between these diseases and prescription drug exposures through an unbiased analysis, assessing both lifetime risk and risk from exposures occurring more than ten years before diagnosis, while also accounting for comorbid conditions.</p><p><strong>Methods: </strong>Cox proportional hazard models were used to evaluate both lifetime and ten-year lag-associated risks of developing a NDD following exposure to specific prescription medications. This analysis followed a two-stage design, incorporating separate discovery and replication cohorts sourced from national-scale biobanks.</p><p><strong>Findings: </strong>We pulled data from over 700,000 health records from individuals of European ancestry to survey a total of 480 prescription medication exposures. After multiple test corrections, we found 241 significant associations between medication exposure and risk of NDDs in our discovery cohort, with 157 of these replicated in an independent dataset. After adjusting for potential comorbidities, 15 medication-NDD associations remained significant, some of which were attenuated after accounting for <i>APOE</i>-ε4 status. Most of these significant pairings were associated with increased risk, however, two antibiotics, one proton pump inhibitor, and one statin had replicated effects inversely associated with disease risk.</p><p><strong>Interpretation: </strong>While correlation does not imply causation and some associations may be driven by medications used to treat prodromal stages of disease, we have utilized large, unbiased datasets to identify and replicate associations between commonly prescribed medications and NDD risk. Additional longitudinal and mechanistic investigations are warranted.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651705","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":"Trigeminal Nerve Stimulation (TNS) for Children with Attention Deficit/Hyperactivity Disorder and Fetal Alcohol Spectrum Disorder: Feasibility Study Protocol.","authors":"Joseph O'Neill, Shantanu Joshi, Jeffry R Alger, Benjamin N Schneider, Mary J O'Connor","doi":"10.1101/2025.07.07.25331025","DOIUrl":"10.1101/2025.07.07.25331025","url":null,"abstract":"<p><p>Symptoms of attention deficit/hyperactivity disorder (ADHD) are common, severe and highly impairing in children with prenatal alcohol exposure (PAE), but often non-responsive to medication, leaving many with no beneficial treatment. External trigeminal nerve stimulation (TNS) is a minimal risk, non-invasive neuromodulatory intervention that is FDA-cleared for ADHD. No formal trial, however, has tested TNS in children with known PAE. We present here the protocol of the first clinical trial of TNS in children with ADHD associated with PAE. The study also uses multimodal MRI to explore possible brain mechanisms of TNS. An open-label pilot will be conducted of 4 weeks of TNS in 30 youth with ADHD associated with PAE, recruited in Southern California. Children will receive TNS nightly for 4 weeks. Safety, tolerability, and preliminary efficacy will be evaluated. Efficacy outcomes include change in the physician-administered parent-rated ADHD Rating Scale and the Clinical Global Impression Improvement (CGI-I) score for ADHD. Effects on executive function, mood, and sleep are also assessed. Maintenance of effects is evaluated at 4-week follow-up. TNS-related brain changes and predictors of response are measured using structural MRI, diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), and resting-state fMRI before and after treatment. This study will determine whether TNS is feasible in children with ADHD and PAE, whether it improves clinical and cognition symptoms, and whether efficacy persists 4 weeks. Trial registration: clinicaltrials.gov (NCT06847165) and protocol ID: IRB-24-0648-AM-007 June 16, 2025.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651760","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":"HEPATOCELLULAR CARCINOMA KINOME ATLAS AS AN EMPLOYABLE INSTRUMENTED PERSONALIZED MEDICINE.","authors":"Zachary A Kipp, Evelyn A Bates, Genesee J Martinez, Wang-Hsin Lee, Sally N Pauss, Terry D Hinds","doi":"10.1101/2025.07.04.25328828","DOIUrl":"https://doi.org/10.1101/2025.07.04.25328828","url":null,"abstract":"<p><p>Liver cancer ranks high among cancer death rates and is resistant to most therapies. Studies of protein functionality are limited in patients with hepatocellular carcinoma (HCC). Here, we constructed an HCC kinome activity atlas and used it to develop personalized medicine technology applicable to profiling protein functionality. We used PamGene PamStation kinome technology that quantified protein kinase activity across hundreds of pathways for HCC tumor and non-tumor regions from both sexes. According to our bioinformatic analyses of kinases, ABL was the most active for men and women with HCC. Next, we employed three ABL inhibitors while running the PamStation, which revealed discernible alterations in ABL and other pathways. We deconvoluted over 500 kinase pathways and generated a personalized medicine (PerMed) score delineating activity levels; results were substantiated in five human hepatocyte cancer cell lines. Our work establishes an HCC kinome atlas and demonstrates PamStations potential for precision medicine applications.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593369","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":"Exploring Heterogeneity in Treatment Effects: The Impact and Interaction of Asset-Based Wealth and Mass Azithromycin Distribution on Child Mortality.","authors":"Elisabeth A Gebreegziabher, Ali Sié, Mamadou Ouattara, Mamadou Bountogo, Boubacar Coulibaly, Valentin Boudo, Thierry Ouedraogo, Elodie Lebas, Huiyu Hu, Pearl Anne Ante-Testard, Steven E Gregorich, Kieran S O'Brien, Michelle S Hsiang, David V Glidden, Benjamin F Arnold, Thomas M Lietman, Catherine E Oldenburg","doi":"10.1101/2025.07.05.25329685","DOIUrl":"10.1101/2025.07.05.25329685","url":null,"abstract":"<p><strong>Objective: </strong>To examine how child mortality among children aged 1-59 months varies by asset-based wealth status in rural Burkina Faso and to assess the interaction between mass azithromycin distribution and wealth status on child mortality at both the household and community levels.</p><p><strong>Methods: </strong>We used data from a cluster-randomized trial and a population census data on household characteristics and assets. A wealth index score for each household, used to classify the population by wealth was generated using principal component analysis. We used the Relative Index of Inequality (RII), the Slope Index of Inequality (SII), and the concentration index to assess wealth-related inequalities in mortality, and the Gini Index to assess variability in child mortality across households and communities. Poisson regression models were used with person-time at risk included as an offset and robust standard error to estimate changes in mortality rates by wealth and treatment arm. We assessed interaction on both the multiplicative and additive scales.</p><p><strong>Results: </strong>Mortality declined with increasing wealth at both household and community levels, with a significant gradient at the community level (RII = 1.17, 95% CI: 1.05-1.29; SII = 2.3 per 1,000 person-years, 95% CI: 0.2-4.4), reflecting higher mortality among the poorest. The effect of AZ did not vary significantly by wealth index, and the change in mortality rates across wealth levels was similar between the two treatment arms. There was no statistically significant interaction between AZ and asset-based wealth on either a multiplicative or additive scale at the household or cluster level.</p><p><strong>Conclusion: </strong>Our findings show a wealth gradient in child mortality, with households and communities in the poorest quintiles experiencing the highest mortality rates. These disparities were consistent across both AZ-treated and placebo groups, suggesting that AZ's role in health disparities may primarily address gaps in treatment access rather than broader wealth-related disparities. AZ appears to offer similar benefits across economically diverse communities, with no evidence suggesting enhanced benefits for disadvantaged communities or for prioritizing treatment based on wealth status. Further work is needed to address the wealth-related disparities in child mortality in these communities.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT03676764.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593343","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 Subtypes and Progressions of Progressive Supranuclear Palsy: A Data-Driven Brain Bank Study.","authors":"Daisuke Ono, Hiroaki Sekiya, Nikhil B Ghayal, Alexia R Maier, Shanu F Roemer, Ryan J Uitti, Irene Litvan, Keith A Josephs, Zbigniew K Wszolek, Dennis W Dickson","doi":"10.1101/2025.07.04.25330863","DOIUrl":"10.1101/2025.07.04.25330863","url":null,"abstract":"<p><strong>Background: </strong>Progressive supranuclear palsy (PSP) is typically characterized by vertical supranuclear gaze palsy and early falls, referred to as Richardson's syndrome (PSP-RS). Other presentations include postural instability (PSP-PI), parkinsonism (PSP-P), speech/language impairment (PSP-SL), frontal presentation (PSP-F), ocular motor dysfunction (PSP-OM), and corticobasal syndrome (PSP-CBS). Differences across the early presentations and in their subsequent progression have yet to be elucidated.</p><p><strong>Objective: </strong>This study aimed to characterize early PSP subtypes and their subsequent progressions using a large postmortem dataset.</p><p><strong>Methods: </strong>An automated pipeline incorporating fine-tuned ChatGPT models was developed. The pipeline collected 195 clinical features with onset information from autopsy-confirmed PSP cases without significant neurodegenerative co-pathologies.</p><p><strong>Results: </strong>A structured clinicopathologic dataset from 588 patients was analyzed. After distilling results with unsupervised clustering, a decision tree model was developed. With five clinical manifestations: frontal presentation, PI, OM, SL, and parkinsonism, this mutually exclusive algorithm identified seven subtypes: PSP-PF (postural and frontal dysfunction), PSP-RS, PSP-PI, PSP-P, PSP-SL, PSP-F, and PSP-OM. PSP-PF, defined by PI and frontal presentation, showed rapid progression, the shortest median disease duration (six years), and high tau burden in cortical and subcortical regions. In PSP-F, frontal presentation preceded other symptoms by four years, and the disease duration was the second longest (nine years) after PSP-P (10 years). PSP-CBS was not identified as an independent subtype.</p><p><strong>Conclusions: </strong>This data-driven study identified a novel, aggressive PSP phenotype characterized by early postural and frontal dysfunction. Early subtyping utilizing the decision tree would help clinicians estimate progression and facilitate early patient recruitment for clinical trials.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593340","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":"Unveiling genetic architecture of white matter microstructure through unsupervised deep representation learning of fractional anisotropy images.","authors":"Xingzhong Zhao, Ziqian Xie, Wei He, Myriam Fornage, Degui Zhi","doi":"10.1101/2025.07.04.25330856","DOIUrl":"https://doi.org/10.1101/2025.07.04.25330856","url":null,"abstract":"<p><p>Fractional anisotropy (FA) derived from diffusion MRI is a widely used marker of white matter (WM) integrity. However, conventional FA based genetic studies focus on phenotypes representing tract- or atlas-defined averages, which may oversimplify spatial patterns of WM integrity and thus limiting the genetic discovery. Here, we proposed a deep learning-based framework, termed unsupervised deep representation of white matter (UDR-WM), to extract brain-wide FA features-referred to as UDIP-FA, that capture distributed microstructural variation without prior anatomical assumptions. UDIP-FAs exhibit enhanced sensitivity to aging and substantially higher SNP-based heritability compared to traditional FA phenotypes ( <i>P</i> < 2.20e-16, Mann-Whitney U test, mean h ² = 50.81%). Through multivariate GWAS, we identified 939 significant lead SNPs in 586 loci, mapped to 3480 genes, dubbed UDIP-FA related genes (UFAGs). UFAGs are overexpressed in glial cells, particularly in astrocytes and oligodendrocytes (Bonferroni-corrected <i>P <</i> 2e-6, Wald Test), and show strong overlap with risk gene sets for schizophrenia and Parkinson disease (Bonferroni-corrected P < 7.06e-3, Fisher exact test). UDIP-FAs are genetically correlated with multiple brain disorders and cognitive traits, including fluid intelligence and reaction time, and are associated with polygenic risk for bone mineral density. Network analyses reveal that UFAGs form disease-enriched modules across protein-protein interaction and co-expression networks, implicating core pathways in myelination and axonal structure. Notably, several UFAGs, including <i>ACHE</i> and <i>ALDH2</i> , are targets of existing neuropsychiatric drugs. Together, our findings establish UDIP-FA as a biologically and clinically informative brain phenotype, enabling high-resolution dissection of white matter genetic architecture and its genetic links to complex brain traits.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593346","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":"Etiological basis for chronic pain genetic variation in brain and dorsal root ganglia cell types.","authors":"Sylvanus Toikumo, Marc Parisien, Michael J Leone, Chaitanya Srinivasan, Huasheng Yu, Asta Arendt-Tranholm, Úrzula Franco-Enzástiga, Christoph Hofstetter, Michele Curatolo, Wenqin Luo, Andreas R Pfenning, Rebecca P Seal, Rachel L Kember, Theodore J Price, Luda Diatchenko, Stephen G Waxman, Henry R Kranzler","doi":"10.1101/2025.07.03.25330832","DOIUrl":"10.1101/2025.07.03.25330832","url":null,"abstract":"<p><p>Chronic pain is a complex clinical problem comprising multiple conditions that may share a common genetic profile. Genome-wide association studies (GWAS) have identified many risk loci whose cell-type context remains unclear. Here, we integrated GWAS data on chronic pain (<i>N</i> = 1,235,695) with single-cell RNA sequencing (scRNA-seq) data from human brain and dorsal root ganglia (hDRG), and single-cell chromatin accessibility data from human brain and mouse dorsal horn. Pain-associated variants were enriched in glutamatergic neurons; mainly in prefrontal cortex, hippocampal CA1-3, and amygdala. In hDRG, the hPEP.TRPV1/A1.2 neuronal subtype showed robust enrichment. Chromatin accessibility analyses revealed variant enrichment in excitatory and inhibitory neocortical neurons in brain and in midventral neurons and oligodendrocyte precursor cells in the mouse dorsal horn. Gene-level heritability in the brain highlighted roles for kinase activity, GABAergic synapses, axon guidance, and neuron projection development. In hDRG, implicated genes related to glutamatergic signaling and neuronal projection. In cervical DRG of patients with acute or chronic pain (<i>N</i> = 12), scRNA-seq data from neuronal or non-neuronal cells were enriched for chronic pain-associated genes (e.g., <i>EFNB2</i>, <i>GABBR1</i>, <i>NCAM1</i>, <i>SCN11A</i>). This cell-type-specific genetic architecture of chronic pain across central and peripheral nervous system circuits provides a foundation for targeted translational research.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593341","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}