medRxiv : the preprint server for health sciences最新文献

{"title":"Immunogenomic landscape of T cell repertoire after human lung transplantation and its clinical significance.","authors":"Wenyu Jiao, Katherine D Long, Tyla Young, Constanza Bay Muntnich, Adriana Prada Rey, Morcel Khwajazadah, Joshua H Wang, Vineetha Mohan, Kortney Rogers, Arnold Valena, Joseph Costa, Luke Benvenuto, Joshua Sonett, Philippe Lemaitre, Frank D'Ovidio, Selim Arcasoy, Jianing Fu","doi":"10.1101/2025.06.03.25328904","DOIUrl":"https://doi.org/10.1101/2025.06.03.25328904","url":null,"abstract":"<p><p>Despite advances in surgical techniques and immunosuppression, long-term survival after lung transplantation (LuTx) remains suboptimal due to high rates of rejection, infection and graft dysfunction. To address this, we investigated post-LuTx T cell dynamics-tracking repopulation, clonal distribution, alloreactivity, and microbial reactivity-through flow cytometry and TCRβ sequencing of serial bronchoalveolar lavage (BAL) and peripheral blood samples. Pre- transplant mixed lymphocyte reactions coupled with TCRβ-seq identified alloreactive TCRs in both graft-versus-host (GvH) and host-versus-graft (HvG) directions, while pathogen-reactive clones were defined via cross-referencing with public databases. We observed progressive establishment of a recipient-derived tissue-resident memory T cell (TRM) repertoire in the BAL, stabilized predominantly by pre-existing, multi-tissue-shared TCRs. Clonal BAL-blood overlap was significantly driven by CD8⁺ non-alloreactive recipient TCRs originating from multiple tissues. A higher HvG:GvH TCR ratio correlated with faster recipient T cell repopulation in BAL, and HvG enrichment in BAL (but not peripheral blood) was associated with early rejection and reduced pulmonary function. Pathogen-reactive TCRs expanded in BAL during infection and were enriched within the non-alloreactive repertoire. This comprehensive TCR landscape analysis highlights the dual roles of T cells in maintaining mucosal homeostasis and contributing to rejection or infection pathogenesis. These findings support the development of precise, mechanism-informed diagnostics to better tailor immunosuppression and ultimately improve LuTx outcomes. Additionally, our work establishes LuTx as a powerful model for studying human tissue-adapted immunity, offering novel insights into the establishment, maintenance, and functional specialization of TRM repertoires.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532280","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":"Closed-loop Neuromotor Training System Pairing Transcutaneous Vagus Nerve Stimulation with Video-based Real-time Movement Classification.","authors":"Minoru Shinohara, Arya Mohan, Nathaniel Green, Joshua N Posen, Milka Trajkova, Woon-Hong Yeo, Hyeokhyen Kwon","doi":"10.1101/2025.05.23.25327218","DOIUrl":"https://doi.org/10.1101/2025.05.23.25327218","url":null,"abstract":"<p><p>As an emerging neurostimulation for improving motor rehabilitation, applying vagus nerve stimulation (VNS) after successful movement during training facilitates motor recovery in animals with neuromotor impairment. To translate this procedure to human rehabilitation in a non-invasive, objective, and automated manner, real-time classification of movement quality on a trial-by-trial basis in a minimally constrained state is required. In this work, we developed an integrated closed-loop system using video-based real-time movement classification that can automatically trigger transcutaneous VNS (tVNS) wirelessly as soon as successful movement is detected. We also created a film-like conformable tVNS electrode to be attached over the outer ear. For movement training, we focused on the use case of dance therapy (backward walking), which is widely used for people with Parkinson's disease and older adults. Our markerless video analysis model could detect steps with 0.91 precision and 0.72 recall and classify successful backward steps with a 0.93 F1 score. The classification triggers tVNS through Bluetooth Low Energy communications with a trigger relay device we created. The integrated system enabled real-time automated classification and stimulation, triggering tVNS with 71.3% of the successful movements and taking 2.24 s from video capture to tVNS. We consider our work to be an important step toward patient-driven rehabilitation at home showcasing non-invasive, low-cost, and automated closed-loop neurostimulation technologies.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532290","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":"Focal Adhesion Kinase Variants May Contribute to Risk of Human Myelomeningocele.","authors":"Lydia Youmans, Charani Kamath, Sara Mansoorshahi, Myra Kurjee, Parkerson Laville, Ashabari Sprenger, Jeffrey Frost, Rachel Miller, Hope Northrup, Kit Sing Au","doi":"10.1101/2025.06.12.25329493","DOIUrl":"10.1101/2025.06.12.25329493","url":null,"abstract":"<p><p>Myelomeningocele (MMC) is the most severe form of an open neural tube defect (NTD) that is compatible with life. The prevalence of MMC in the United States is 1 in 2,500 live births, with the two ethnicities that have the highest occurrence of MMC being Mexican American (MA) and Caucasian American (EA). Research to date has shown that MMC results from a cumulative effect of environmental and genetic factors. Therefore, determining the underlying molecular etiology would be a step toward developing strategies for prevention and treatment. We examined variants in 568 nervous system development genes implicated in MMC by whole exome sequencing of 254 MA and 257 EA subjects born with MMC. Mutational burden analysis was used to compare the deleterious variant load between MMC subjects and the reference population in the Genome Aggregation Exome Database (gnomADe). Higher mutational burdens were found in 18 genes, with <i>PTK2</i> being the most significant (OR=3.49, <i>p</i>=5.3e-3) among genes known to be expressed in the human neural tube at the CS12/CS13 stages. Cell migration assay was performed using seven <i>PTK2 (aka FAK1)</i> deleterious variants in transfected Fak^-/- mouse embryonic cells. The effect of Ptk2 knockdown on neural tube development was examined using <i>Xenopus</i> embryos. Cell migration assay results showed the seven MMC-associated <i>PTK2</i> variants significantly affected migratory capacity compared to the wild-type <i>PTK2</i>. The Knockdown of Ptk2 significantly affected the normal neural tube closure of <i>Xenopus</i> embryos. Based on these findings, <i>PTK2</i> variants identified from MMC patients may play a role in the multifactorial causation of MMC.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532302","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":"Connectometry reveals differing associations of cortisol and PACAP with dorsal cingulum microstructure in posttraumatic stress.","authors":"Steven J Granger, Sydney A Jobson, Caitlin Ravichandran, Quentin Devignes, Eylül Akman, Jennifer U Blackford, Victor May, Sayamwong E Hammack, William A Carlezon, Kerry J Ressler, Scott L Rauch, Isabelle M Rosso","doi":"10.1101/2025.06.05.25329085","DOIUrl":"10.1101/2025.06.05.25329085","url":null,"abstract":"<p><p>Posttraumatic stress disorder (PTSD) has been associated with altered arousal regulation and dysfunction of the hypothalamic-pituitary-adrenal axis, including changes in circulating cortisol and pituitary adenylate cyclaseactivating polypeptide (PACAP). Both stress-related hormones affect extended amygdala to medial prefrontal cortex (mPFC) circuit functioning, but it is unclear whether they relate to white matter microstructure connecting these regions. We examined this question in 139 trauma-exposed adults (81 female; ages 19-54) who completed the Clinician-Administered PTSD Scale, a blood draw, and diffusion magnetic resonance imaging. White matter integrity was assessed in tracts connecting the extended amygdala to mPFC, including the uncinate fasciculus, frontal parahippocampal cingulum, and bed nucleus of the stria terminalis to mPFC projections. We used both tract-average fractional anisotropy (FA) to assess the global integrity of these white matter tracts and restricted connectometry to identify spatially localized associations along specific tract segments. Neither cortisol nor PACAP levels were associated with tract-average FA in any tract. However, connectometry, using a stringent statistical T-threshold revealed distinct, region-specific associations within the dorsal cingulum: higher cortisol levels were associated with lower FA (<i>FDR</i>=.002), whereas higher PACAP levels were associated with higher FA (<i>FDR</i>=.01). These localized FA alterations were not significantly associated with symptom severity. These findings suggest that cortisol and PACAP levels have differing associations with microstructural integrity of the dorsal cingulum, a region implicated in emotional regulation. These results highlight how distinct stress hormone pathways may differentially impact white matter organization in PTSD and demonstrate the utility of connectometry for detecting regionally specific brain-biomarker relationships.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12155003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277233","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":"AI-based identification of patients who benefit from revascularization: a multicenter study.","authors":"Wenhao Zhang, Robert Jh Miller, Krishna Patel, Aakash D Shanbhag, Joanna X Liang, Mark Lemley, Giselle Ramirez, Valerie Builoff, Jirong Yi, Jianhang Zhou, Paul Kavanagh, Wanda Acampa, Timothy M Bateman, Marcelo Di Carli, Sharmila Dorbala, Andrew J Einstein, Mathews B Fish, M Timothy Hauser, Terrence D Ruddy, Philipp A Kaufmann, Edward J Miller, Tali Sharir, Monica Martins, Julian Halcox, Panithaya Chareonthaitawee, Damini Dey, Daniel S Berman, Piotr J Slomka","doi":"10.1101/2025.06.11.25329295","DOIUrl":"https://doi.org/10.1101/2025.06.11.25329295","url":null,"abstract":"<p><strong>Background and aims: </strong>Revascularization in stable coronary artery disease often relies on ischemia severity, but we introduce an AI-driven approach that uses clinical and imaging data to estimate individualized treatment effects and guide personalized decisions.</p><p><strong>Methods: </strong>Using a large, international registry from 13 centers, we developed an AI model to estimate individual treatment effects by simulating outcomes under alternative therapeutic strategies. The model was trained on an internal cohort constructed using 1:1 propensity score matching to emulate randomized controlled trials (RCTs), creating balanced patient pairs in which only the treatment strategy-early revascularization (defined as any procedure within 90 days of MPI) versus medical therapy-differed. This design allowed the model to estimate individualized treatment effects, forming the basis for counterfactual reasoning at the patient level. We then derived the AI-REVASC score, which quantifies the potential benefit, for each patient, of early revascularization. The score was validated in the held-out testing cohort using Cox regression.</p><p><strong>Results: </strong>Of 45,252 patients, 19,935 (44.1%) were female, median age 65 (IQR: 57-73). During a median follow-up of 3.6 years (IQR: 2.7-4.9), 4,323 (9.6%) experienced MI or death. The AI model identified a group (n=1,335, 5.9%) that benefits from early revascularization with a propensity-adjusted hazard ratio of 0.50 (95% CI: 0.25-1.00). Patients identified for early revascularization had higher prevalence of hypertension, diabetes, dyslipidemia, and lower LVEF.</p><p><strong>Conclusions: </strong>This study pioneers a scalable, data-driven approach that emulates randomized trials using retrospective data. The AI-REVASC score enables precision revascularization decisions where guidelines and RCTs fall short.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532238","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":"Epidemiological Profile of Road Traffic Injury Patients in Hospitals in Fako Division, Cameroon: A Foundation for Tailored Post-Traumatic Stress Disorder (PTSD) Management.","authors":"Claudia Ngeha Ngu, Priya Shete, Dickson Shey Nsagha, Elvis Asangbeng Tanue, Nicholas Tendongfor, Rasheedat Oke, Nahyeni Bassah, Chrisantus Eweh Ukah, Sandra I McCoy, Catherine Juillard, Alain Chichom Mefire, Edie Gregory Halle Ekane","doi":"10.1101/2025.06.10.25329319","DOIUrl":"https://doi.org/10.1101/2025.06.10.25329319","url":null,"abstract":"<p><strong>Background: </strong>Road traffic injuries (RTIs) are a major global public health concern, often leading to serious physical and psychological consequences, including post-traumatic stress disorder (PTSD). A limited understanding of specific RTI patient characteristics particularly regarding PTSD screening recommendation and uptake in Cameroon hinders, the development of effective PTSD management strategies. This study aimed to determine the epidemiological profile of RTI patients in Fako Division, Cameroon, to inform the development of tailored PTSD management interventions.</p><p><strong>Material and methods: </strong>A chart review of medical records of RTI patients received between 2019 and 2023 was conducted from July 30 ^th 2024 to August 30 ^th 2024 at three hospitals in Fako Division, Cameroon: Buea Regional Hospital, Saint Luke Hospital Buea, and Limbe Regional Hospital. A data extraction form was used to collect demographic information, injury characteristics, and PTSD screening recommendations and uptake. Descriptive statistics and Chi square test were used for data analysis. The data was analysed in SPSS version 25.</p><p><strong>Results: </strong>A total of 4218 RTI patients were received and managed at the three hospitals during the study period. Patients were predominantly male, 2937(69.6%). The age group of 26-35 years recorded the highest proportion, 1339(31.7%). The median age of patients was 28 years (interquartile range: 22-37). Students, 820(19.4%) were among the most involved in RTIs. Only 59(11.0%) out of the 534(12.7%) hospitalized patients after RTIs were recommended for PTSD screening, and only 26(44.1%) underwent PTSD screening. Lower limbs, 2136(50.6%), and upper limbs, 1639(38.9%) were the most affected location for the traumatic injury. In-hospital mortality was recorded in 27(5.1%) of the patients. Means of transportation of patient to the hospital, ( <i>p</i> =0.050), pain medication given ( <i>p</i> =0.024), sedative given ( <i>p</i> = <b><</b> 0.001), surgery performed ( <i>p</i> =0.005), psychotherapy recommended ( <i>p</i> = <b><</b> 0.001) and transfusion performed ( <i>p</i> =<0.001) were significantly associated with recommendation for PTSD screening. A statistically significant association was found between PTSD screening uptake and recommendation for psychotherapy ( <i>p</i> =0.010).</p><p><strong>Conclusion: </strong>Few patients were recommended for PTSD screening and uptake was low. This indicates a significant gap in access to PTSD and mental health services for RTI patients in Fako. PTSD screening uptake was significantly associated with recommendation for psychotherapy. Findings provide information for developing tailored PTSD management strategies and improving patients' outcomes in this region.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532296","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":"Neural signatures and personalized neuromodulation in a subject experiencing context-dependent inhibitory control deficits.","authors":"Layth S Mattar, Shraddha Shah, Lily S Chamakura, Denise Oswalt, Yue Zhang, Davin Devara, Jung Uk Kang, Zahra Jourahmad, Ryan Jafri, Geoffrey Liu, Joshua Adkinson, Isabel A Danstrom, Xiaoxu Fan, Yvonne Y Reed, Kelly R Bijanki, Alica Goldman, Lu Lin, Vaishnav Krishnan, Nicole R Provenza, Andrew J Watrous, Sarah R Heilbronner, Sameer A Sheth, Garrett P Banks, Eleonora Bartoli","doi":"10.1101/2025.06.06.25328536","DOIUrl":"https://doi.org/10.1101/2025.06.06.25328536","url":null,"abstract":"<p><p>The ability to override prepotent actions is critical to control impulses and adjust behavior depending on goals and contextual needs. In this study, we investigate the inhibitory control abilities of a patient diagnosed with Klüver-Bucy Syndrome following a left temporal resection. The patient presented with disruptive hypersexuality symptoms akin to compulsions, leading to the inability to control and suppress inappropriate actions. The patient was recruited for the current research study while undergoing intracranial monitoring for epilepsy, to investigate the cognitive and neural processes underlying the patient's inhibitory control symptoms. We formulated the hypothesis that an inhibitory control deficit emerges in response to provocative triggers, and we designed a personalized paradigm pairing arousing images with a classic inhibitory control task. We not only confirmed disrupted performance following exposure to triggering, provocative material, but we also leveraged the simultaneously recorded neural data to identify a biomarker reflecting inhibitory control failures. Next, we repeated the experimental paradigm during and after personalized neuromodulation via direct high-frequency stimulation of the right inferior frontal cortex. The patient displayed a marked improvement in his behavior during neuromodulation, mirrored by changes in neural activity, spanning spectral features, event-related potentials and functional connectivity. Altogether, our study revealed that the patient's symptoms were not due to a global inhibition deficit, but to a specific control issue triggered by exposure to provocative material. Overall, our work showcases a feasible, effective approach towards data-driven personalized neuromodulation, which could be leveraged to mitigate specific inhibitory control deficits and potentially other symptoms of executive dysfunction.</p><p><strong>Abstract figure: </strong></p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532311","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":"Regulatory risk loci link disrupted androgen response to pathophysiology of Polycystic Ovary Syndrome.","authors":"Jaya Srivastava, Ivan Ovcharenko","doi":"10.1101/2025.03.26.25324630","DOIUrl":"10.1101/2025.03.26.25324630","url":null,"abstract":"<p><p>A major challenge in deciphering the complex genetic landscape of Polycystic Ovary Syndrome (PCOS) lies in the limited understanding of how susceptibility loci drive molecular mechanisms across diverse phenotypes. To address this, we integrated molecular and epigenomic annotations from proposed causal cell-types and employed a deep learning (DL) framework to predict cell-type-specific regulatory effects of PCOS risk variants. Our analysis revealed that these variants affect key transcription factor (TF) binding sites, including NR4A1/2, NHLH2, FOXA1, and WT1, which regulate gonadotropin signaling, folliculogenesis, and steroidogenesis across brain and endocrine cell-types. The DL model, which showed strong concordance with reporter assay data, identified enhancer-disrupting activity in approximately 20% of risk variants. Notably, many of these variants disrupt TFs involved in androgen-mediated signaling, providing molecular insights into hyperandrogenemia in PCOS. Variants prioritized by the model were more pleiotropic and exerted stronger downregulatory effects on gene expression compared to other risk variants. Using the IRX3-FTO locus as a case study, we demonstrate how regulatory disruptions in tissues such as the fetal brain, pancreas, adipocytes, and endothelial cells may link obesity-associated mechanisms to PCOS pathogenesis via neuronal development, metabolic dysfunction, and impaired folliculogenesis. Collectively, our findings highlight the utility of integrating DL models with epigenomic data to uncover disease-relevant variants, reveal cross-tissue regulatory effects, and refine mechanistic understanding of PCOS.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805274","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 Multiethnic Cohort: A Resource for the study of Genetic and non-Genetic Cancer Risk Across Populations.","authors":"David Bogumil, Xin Sheng, Peggy Wan, Lucy Xia, Loreall Pooler, Iona Cheng, Samantha Streicher, Brian Z Huang, Fei Chen, Daniel Stram, Sylvia Shen, Gillian King, Charleston W K Chiang, Chrissie Ongaco, Marcia Adams, Ivy McMullen, Peng Zhang, Hua Ling, Michelle Mawhinney, Kimberly F Doheny, Loïc Le Marchand, Lynne R Wilkens, Christopher A Haiman, David V Conti","doi":"10.1101/2025.06.09.25328993","DOIUrl":"https://doi.org/10.1101/2025.06.09.25328993","url":null,"abstract":"<p><strong>Introduction: </strong>The Multiethnic Cohort Study (MEC) is a U.S. prospective cohort of over 215,000 participants, designed to investigate variation in risk factors and disease across diverse racial and ethnic groups. Over 74,000 participants contributed biospecimens for genetic studies. We describe this sub-cohort and demonstrate the types of analyses it enables.</p><p><strong>Methods: </strong>The MEC recruited adults aged 45-75 in California and Hawaii between 1993 and 1996. Cancer diagnoses were identified via state tumor registries. The MEC Genetics Database includes 73,139 participants with germline genotype data. We evaluated genetic similarity, its relationship with self-reported race/ethnicity, and baseline characteristics, including neighborhood socioeconomic status. Using breast, colorectal, and prostate cancer as examples, the database supports multi-ancestry genome-wide association studies (GWAS), evaluation of non-genetic factors, and time-to-event analyses.</p><p><strong>Results: </strong>Participants included 10,962 African Americans, 24,234 Japanese Americans, 17,242 Latinos, 5,488 Native Hawaiians, 14,649 Whites, and 564 other. Principal component analysis revealed substantial diversity in ancestry. Multiethnic GWAS demonstrated effective control of population stratification while replicating many previously discovered variants. Polygenic risk score (PRS) effects varied by racial and ethnic group. Time-to-event analysis showed associations between cancer incidence and neighborhood socioeconomic status, population descriptors, and genetic similarity.</p><p><strong>Discussion: </strong>The MEC Genetics Database enables comprehensive assessment of genetic and non-genetic cancer risk, revealing differences in absolute risk by race and ethnicity. Studying both types of risk factors in diverse and admixed populations is critical for improving risk characterization and reducing disparities. This resource supports future research in polygenic traits, gene-environment interactions, and integrated risk prediction.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532282","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":"Pleiotropic heritability quantifies the shared genetic variance of common diseases.","authors":"Yujie Zhao, Benjamin Strober, Kangcheng Hou, Gaspard Kerner, John Danesh, Steven Gazal, Wei Cheng, Michael Inouye, Alkes L Price, Xilin Jiang","doi":"10.1101/2025.06.10.25329261","DOIUrl":"https://doi.org/10.1101/2025.06.10.25329261","url":null,"abstract":"<p><p>Common diseases are highly pleiotropic, but the overall contribution of pleiotropy to a target disease's architecture is unknown, as most studies focus on genetic correlations with each auxiliary disease in turn. Here we propose a new method, pleiotropic heritability with bias correction (PHBC), to estimate pleiotropic heritability ( <i>h</i> ² _<i>pleio</i> ), defined as the liability-scale genetic variance of a target disease that is shared with a specific set of auxiliary diseases. We estimate <i>h</i> ² _<i>pleio</i> from GWAS summary statistics by estimating the proportion of variance explained from an estimated genetic correlation matrix and employing a Monte-Carlo bias correction procedure to account for sampling noise in genetic correlation estimates. Simulations showed that PHBC produces approximately unbiased estimates of pleiotropic heritability. The average ratio of pleiotropic heritability vs. total SNP-heritability ( <i>h</i> ² _<i>pleio</i> / <i>h</i> ² ) across 15 diseases from the UK Biobank (spanning 7 disease categories) was 34% (s.e. 7%). Several diseases were dominated by pleiotropic heritability, including depression (71%) and type 2 diabetes (65%). Pleiotropic heritability was broadly distributed across disease categories, with <i>h</i> ² _<i>pleio</i> / <i>h</i> ² decreasing only slightly when removing all auxiliary diseases in the target disease category (avg = 31% (s.e. 7%)) and only moderately when further removing one other (most informative) category whose removal had the greatest impact (avg = 20% (s.e. 3%)). Average ² _<i>pleio</i> ² increased to 44% (s.e. 9%) when adding 16 auxiliary quantitative traits in UK Biobank, and 50% (s.e. 5%) when further adding 30 auxiliary diseases from large GWAS meta-analyses. On average, <i>h</i> ² _<i>pleio</i> / <i>h</i> ² was 2.4x larger than the proportion of liability-scale total phenotypic variance explained by the same set of auxiliary diseases, implying higher pleiotropy for genetic effects than the effects of non-genetic exposures. In conclusion, we have uncovered pervasive sharing of genetic aetiologies, with roughly half of common disease heritability being pleiotropic with diseases from a broad range of disease categories, which strongly motivates the importance of multi-disease approaches to risk prediction and therapeutic development.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532315","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}