medRxiv : the preprint server for health sciences最新文献

{"title":"Genetic Architecture of Postpartum Psychosis: From Common to Rare Genetic Variation.","authors":"Seulgi Jung, Madison Caballero, Adrianna Kępińska, Shelby Smout, Trine Munk-Olsen, Thalia K Robakis, Veerle Bergink, Behrang Mahjani","doi":"10.1101/2024.12.09.24318732","DOIUrl":"https://doi.org/10.1101/2024.12.09.24318732","url":null,"abstract":"<p><p>Postpartum psychosis is a severe psychiatric condition marked by the abrupt onset of psychosis, mania, or psychotic depression following childbirth. Despite evidence for a strong genetic basis, the roles of common and rare genetic variation remain poorly understood. Leveraging data from Swedish national registers and genomic data from the All of Us Research Program, we estimated family-based heritability at 55% and WGS-based heritability at 37%, with an overrepresentation on the X chromosome. Rare coding variant analysis identified <i>DNMT1</i> and <i>HMGCR</i> as potential risk genes (q < 0.1). Analysis of 240,009 samples from All of Us demonstrated significant associations between these genes and multiple psychiatric disorders, supporting their biological relevance. Additionally, 17% of bipolar disorder, 21% of schizophrenia, and 16-25% of multiple autoimmune disorder risk genes overlapped with postpartum psychosis. These findings reveal unique genetic contributions and shared pathways, providing a foundation for understanding pathophysiology and advancing therapeutic strategies.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661424/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879311","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-life infectious disease exposure, the 'hygiene hypothesis', and lifespan: evidence from hookworm.","authors":"Ralph Lawton","doi":"10.1101/2024.12.09.24318730","DOIUrl":"https://doi.org/10.1101/2024.12.09.24318730","url":null,"abstract":"<p><p>Exposure to infectious disease in early life may have long-term ramifications for health and mortality. This study leverages quasi-experimental variation from the Rockefeller Sanitary Commission's de-worming campaign in the early 20th century, combined with pre-campaign hookworm prevalence, to rigorously examine the impacts of childhood hookworm exposure on later-life morbidity and lifespan. Pre-intervention surveys find widespread hookworm exposure among children in the American South, but minimal prevalence among adults. I show exposure to de-worming before age five leads to 2.5 additional months of life in a sample of older-age mortality. Further, decreasing hookworm exposure is related to later-life declines in biomarkers for inflammation and skin-tested allergies, in contrast with the predictions of the ``hygiene hypothesis''. Placebo tests using health outcomes that should not be affected by de-worming do not show similar patterns.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879258","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":"Linking multiple serological assays to infer dengue virus infections from paired samples using mixture models.","authors":"Marco Hamins-Puértolas, Darunee Buddhari, Henrik Salje, Angkana T Huang, Taweewun Hunsawong, Derek A T Cummings, Stefan Fernandez, Aaron Farmer, Surachai Kaewhiran, Direk Khampaen, Anon Srikiatkhachorn, Sopon Iamsirithaworn, Adam Waickman, Stephen J Thomas, Timothy Endy, Alan L Rothman, Kathryn B Anderson, Isabel Rodriguez-Barraquer","doi":"10.1101/2024.12.08.24318683","DOIUrl":"https://doi.org/10.1101/2024.12.08.24318683","url":null,"abstract":"<p><p>Dengue virus (DENV) is an increasingly important human pathogen, with already half of the globe's population living in environments with transmission potential. Since only a minority of cases are captured by direct detection methods (RT-PCR or antigen tests), serological assays play an important role in the diagnostic process. However, individual assays can suffer from low sensitivity and specificity and interpreting results from multiple assays remains challenging, particularly because interpretations from multiple assays may differ, creating uncertainty over how to generate finalized interpretations. We develop a Bayesian mixture model that can jointly model data from multiple paired serological assays, to infer infection events from paired serological data. We first test the performance of our model using simulated data. We then apply our model to 677 pairs of acute and convalescent serum collected as a part of illness and household investigations across two longitudinal cohort studies in Kamphaeng Phet, Thailand, including data from 232 RT-PCR confirmed infections (gold standard). We compare the classification of the new model to prior standard interpretations that independently utilize information from either the hemagglutination inhibition assay (HAI) or the enzyme-linked immunosorbent assay (EIA). We find that additional serological assays improve accuracy of infection detection for both simulated and real world data. Models incorporating paired IgG and IgM data as well as those incorporating IgG, IgM, and HAI data consistently have higher accuracy when using PCR confirmed infections as a gold standard (87-90% F1 scores, a combined metric of sensitivity and specificity) than currently implemented cut-point approaches (82-84% F1 scores). Our results provide a probabilistic framework through which multiple serological assays across different platforms can be leveraged across sequential serum samples to provide insight into whether individuals have recently experienced a DENV infection. These methods are applicable to other pathogen systems where multiple serological assays can be leveraged to quantify infection history.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879299","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":"Genomic Epidemiology of 2023-2024 Oropouche Outbreak in Iquitos, Peru reveals independent origin from a concurrent outbreak in Brazil.","authors":"Maribel Paredes Olortegui, Francesca Schiaffino, Pablo Peñataro Yori, Josh M Colston, Valentino Shapiama Lopez, Tackeshy Pinedo Vasquez, Paul F Garcia Bardales, Thomas G Flynn, Cesar Ramal-Asayag, Holley R Hughes, Emily Davis, Brandy J Russell, Aaron C Brault, Yuri Alfonso Alegre Palomino, Cesar Munayco, Jie Liu, Eric Houpt, Kerry K Cooper, Craig T Parker, Margaret N Kosek","doi":"10.1101/2024.12.08.24318674","DOIUrl":"https://doi.org/10.1101/2024.12.08.24318674","url":null,"abstract":"<p><p>Oropouche virus is an arbovirus endemic to the Americas. Periodic outbreaks have occurred since its description in 1955. In late 2023, an outbreak occurred in Peru, centered in and around Iquitos in the Eastern Peruvian Amazon. An existing acute febrile illness (AFI) surveillance program was able to document its emergence and characterize arthralgia and dysuria and the absence of diarrhea as distinctive clinical features of Oropouche virus-associated febrile illness relative to other causes of AFI. Sequencing of isolates from the outbreak demonstrated that strains from this region were distinct from those causing disease in Brazil, despite the large-scale movement of people along the Amazon corridor, but highly similar to strains from Colombia and Ecuador. Our findings suggest that the current outbreak in South America is fundamentally multifocal in origin and not the result of geographic spread from Brazil, which experienced an outbreak between 2022 and 2024.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879314","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":"Long-Term Carotid Plaque Progression and the Role of Intraplaque Hemorrhage: Analysis from Deep Learning-based Longitudinal Vessel Wall Imaging.","authors":"Yin Guo, Ebru Yaman Akcicek, Daniel S Hippe, SeyyedKazem HashemizadehKolowri, Xin Wang, Halit Akcicek, Gador Canton, Niranjan Balu, Duygu Baylam Geleri, Taewon Kim, Dean Shibata, Kaiyu Zhang, Xiaodong Ma, Marina S Ferguson, Mahmud Mossa-Basha, Thomas S Hatsukami, Chun Yuan","doi":"10.1101/2024.12.09.24318661","DOIUrl":"https://doi.org/10.1101/2024.12.09.24318661","url":null,"abstract":"<p><strong>Background: </strong>Carotid atherosclerosis is a major etiology of stroke. Although intraplaque hemorrhage (IPH) is known to increase stroke risk and plaque burden, its long-term effects on plaque dynamics remain unclear.</p><p><strong>Objectives: </strong>This study aimed to evaluate the long-term impact of IPH on carotid plaque burden progression using deep learning-based segmentation on multi-contrast vessel wall imaging (VWI).</p><p><strong>Methods: </strong>Twenty-eight asymptomatic subjects with carotid atherosclerosis underwent an average of 4.7 ± 0.6 VWI scans over 5.8 ± 1.1 years. Deep learning pipelines segmented the carotid vessel walls and IPH. Bilateral plaque progression was analyzed using generalized estimating equations, and linear mixed-effects models evaluated long-term associations between IPH occurrence, IPH volume (%HV), and plaque burden (%WV) progression.</p><p><strong>Results: </strong>Two subjects with ipsilateral IPH developed new ischemic infarcts during follow- up. IPH was detected in 23/50 of arteries. Of arteries without IPH at baseline, 11/39 developed new IPH that persisted, while 5/11 arteries with baseline IPH exhibited it throughout the study. Bilateral plaque growth was significantly correlated (r = 0.54, p < 0.001), but this symmetry was weakened with IPH presence. The progression rate for arteries without IPH was -0.001 %/year (p = 0.895). However, IPH presence or development at any point was associated with a 2.34% absolute increase in %WV (p < 0.001), and %HV was associated with 0.73% per 2-fold increase over the mean of %HV (p = 0.005).</p><p><strong>Conclusions: </strong>IPH may persist asymptomatically for extended periods. While arteries without IPH demonstrated minimal progression under contemporary treatment, IPH significantly accelerated long-term plaque growth.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879322","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":"Cerebrospinal Fluid Flow within Ventricles and Subarachnoid Space Evaluated by Velocity Selective Spin Labeling MRI.","authors":"Yihan Wu, Feng Xu, Dan Zhu, Anna Li, Kexin Wang, Qin Qin, Jiadi Xu","doi":"10.1101/2024.12.09.24318672","DOIUrl":"https://doi.org/10.1101/2024.12.09.24318672","url":null,"abstract":"<p><p>This study aims to evaluate cerebrospinal fluid (CSF) flow dynamics within ventricles, and the subarachnoid space (SAS) using the velocity selective spin labeling (VSSL) MRI method with Fourier-transform-based velocity selective inversion preparation. The study included healthy volunteers who underwent MRI scanning with specific VSSL parameters optimized for CSF flow quantification. The VSSL sequence was calibrated against phase-contrast MRI (PC-MRI) to ensure accurate flow velocity measurements. The CSF flow patterns observed in the ventricles were consistent with those obtained using 3D amplified MRI and other advanced MRI techniques, verifying the reliability of the VSSL method. The VSSL method successfully measured CSF flow in the SAS along major arteries, including the middle cerebral artery (MCA), anterior cerebral artery (ACA), and posterior cerebral artery (PCA), with an average flow velocity of 0.339 ± 0.117 <i>cm</i> / <i>s</i> . The diffusion component was well suppressed by flow-compensated gradients, enabling comprehensive mapping of the rapid CSF flow pattern in the SAS system and ventricles. The flow pattern in the SAS system closely resembles the recently discovered perivascular subarachnoid space (PVSAS) system. CSF flow around the MCA, PCA, and ACA arteries in the SAS exhibited a weak orientation dependency. CSF flow in the ventricles was also measured, with an average flow velocity of 0.309 ± 0.116 <i>cm</i> / <i>s</i> , and the highest velocity observed along the superior-inferior direction. This study underscores the potential of VSSL MRI as a non-invasive tool for investigating CSF dynamics in both SAS and ventricles.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142878867","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":"Deep phenotyping obesity using EHR data: Promise, Challenges, and Future Directions.","authors":"Xiaoyang Ruan, Shuyu Lu, Liwei Wang, Andrew Wen, Murali Sameer, Hongfang Liu","doi":"10.1101/2024.12.06.24318608","DOIUrl":"10.1101/2024.12.06.24318608","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Obesity affects approximately 34% of adults and 15-20% of children and adolescents in the U.S, and poses significant economic and psychosocial burdens. Due to the multifaceted nature of obesity, currently patient responses to any single anti-obesity medication (AOM) vary significantly, highlighting the need for developing approaches to obesity deep phenotyping and associated precision medicine. While recent advancement in classical phenotyping-guided pharmacotherapies have shown clinical value, they are less embraced by healthcare providers within the precision medicine framework, primarily due to their operational complexity and lack of granularity. From this perspective, several recent review articles highlighted the importance of obesity deep phenotyping for personalized precision medicine. In view of the established role of electronic health record (EHR) as an important data source for clinical phenotypings, we offer an in-depth analysis of the commonly available data elements from obesity patients prior to pharmacotherapy. We also experimented with a multi-modal longitudinal deep autoencoder to explore the feasibility, data requirements, clustering patterns, and challenges associated with EHR-based obesity deep phenotyping. Our analysis indicates at least nine clusters, among which five have distinct explainable clinical relevance. Further research within larger independent cohorts to validate the reproducibility, uncover more detailed substructures and corresponding treatment response is warranted.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Obesity affects approximately 40% of adults and 15-20% of children and adolescents in the U.S, and poses significant economic and psychosocial burdens. Currently, patient responses to any single anti-obesity medication (AOM) vary significantly, making obesity deep phenotyping and associated precision medicine important targets of investigation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;To evaluate the potential of EHR as a primary data source for obesity deep phenotyping, we conduct an in-depth analysis of the data elements and quality available from obesity patients prior to pharmacotherapy, and apply a multi-modal longitudinal deep autoencoder to investigate the feasibility, data requirements, clustering patterns, and challenges associated with EHR-based obesity deep phenotyping.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We analyzed 53,688 pre-AOM periods from 32,969 patients with obesity or overweight who underwent medium- to long-term AOM treatment. A total of 92 lab and vital measurements, along with 79 ICD-derived clinical classifications software (CCS) codes recorded within one year prior to AOM treatment, were used to train a gated recurrent unit with decay based longitudinal autoencoder (GRU-D-AE) to generate dense embeddings for each pre-AOM record. principal component analysis (PCA) and gaussian mixture modeling (GMM) were applied to identify clusters.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Our analysis identified at le","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831046","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":"MODELING EARLY-ONSET CANCER KINETICS TO STUDY CHANGES IN UNDERLYING RISK, DETECTION, AND IMPACT OF POPULATION SCREENING.","authors":"Navid Mohammad Mirzaei, Chin Hur, Mary Beth Terry, Piero Dalerba, Wan Yang","doi":"10.1101/2024.12.05.24318584","DOIUrl":"10.1101/2024.12.05.24318584","url":null,"abstract":"<p><p>Recent studies have reported increases in early-onset cancer cases (diagnosed under age 50) and call into question whether the increase is related to earlier diagnosis from other medical tests and reflected by decreasing tumor-size-at-diagnosis (apparent effects) or actual increases in underlying cancer risk (true effects), or both. The classic Multi-Stage Clonal Expansion (MSCE) model assumes cancer detection at the emergence of the first malignant cell, although later modifications have included lag-times or stochasticity in detection to more realistically represent tumor detection requiring a certain size threshold. Here, we introduce an approach to explicitly incorporate tumor-size-at-diagnosis in the MSCE framework and account for improvements in cancer detection over time to distinguish between apparent and true increases in early-onset cancer incidence. We demonstrate that our model is structurally identifiable and provides better parameter estimation than the classic model. Applying this model to colorectal, female breast, and thyroid cancers, we examine changes in cancer risk while accounting for detection improvements over time in three representative birth cohorts (1950-1954, 1965-1969, and 1980-1984). Our analyses suggest accelerated carcinogenic events and shorter mean sojourn times in more recent cohorts. We further use this model to examine the screening impact on the incidence of breast and colorectal cancers, both having established screening protocols. Our results align with well-documented differences in screening effects between these two cancers. These findings underscore the importance of accounting for tumor-size-at-diagnosis in cancer modeling and support true increases in early-onset cancer risk in recent years for breast, colorectal, and thyroid cancer.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831637","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":"Intraoperative superb microvascular ultrasound imaging in glioma: novel quantitative analysis correlates with tumour grade.","authors":"Luke Dixon, Alistair Weld, Dolin Bhagawati, Neekhil Patel, Stamatia Giannarou, Matthew Grech-Sollars, Adrian Lim, Sophie Camp","doi":"10.1101/2024.12.07.24318636","DOIUrl":"10.1101/2024.12.07.24318636","url":null,"abstract":"<p><p>Accurate grading of gliomas is critical to guide therapy and predict prognosis. The presence of microvascular proliferation is a hallmark feature of high grade gliomas which traditionally requires targeted surgical biopsy of representative tissue. Superb microvascular imaging (SMI) is a novel high resolution Doppler ultrasound technique which can uniquely define the microvascular architecture of whole tumours. We examined both qualitative and quantitative vascular features of gliomas captured with SMI, analysing flow signal density, vessel number, branching points, curvature, vessel angle deviation, fractal dimension, and entropy. Results indicate that high-grade gliomas exhibit significantly greater vascular complexity and disorganisation, with increased fractal dimension and entropy, correlating with known histopathological markers of aggressive angiogenesis. The integrated ROC model achieved high accuracy (AUC = 0.95), highlighting SMI's potential as a non-invasive diagnostic and prognostic tool. While further validation with larger datasets is required, this study opens avenues for SMI in glioma management, supporting intraoperative decision-making and informing future prognosis.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831601","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":"Epigenome-wide Association Analysis of Mitochondrial Heteroplasmy Provides Insight into Molecular Mechanisms of Disease.","authors":"Meng Lai, Kyeezu Kim, Yinan Zheng, Christina A Castellani, Scott M Ratliff, Mengyao Wang, Xue Liu, Jeffrey Haessler, Tianxiao Huan, Lawrence F Bielak, Wei Zhao, Roby Joehanes, Jiantao Ma, Xiuqing Guo, JoAnn E Manson, Megan L Grove, Jan Bressler, Kent D Taylor, Tuuli Lappalainen, Silva Kasela, Thomas W Blackwell, Nicole J Lake, Jessica D Faul, Kendra R Ferrier, Lifang Hou, Charles Kooperberg, Alexander P Reiner, Kai Zhang, Patricia A Peyser, Myriam Fornage, Eric Boerwinkle, Laura M Raffield, April P Carson, Stephen S Rich, Yongmei Liu, Daniel Levy, Jerome I Rotter, Jennifer A Smith, Dan E Arking, Chunyu Liu","doi":"10.1101/2024.12.05.24318557","DOIUrl":"10.1101/2024.12.05.24318557","url":null,"abstract":"<p><p>The relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA (nDNA) methylation (CpGs) remains to be studied. We conducted an epigenome-wide association analysis of heteroplasmy burden scores across 10,986 participants (mean age 77, 63% women, and 54% non-White races/ethnicities) from seven population-based observational cohorts. We identified 412 CpGs (FDR p < 0.05) associated with mtDNA heteroplasmy. Higher levels of heteroplasmy burden were associated with lower nDNA methylation levels at most significant CpGs. Functional inference analyses of genes annotated to heteroplasmy-associated CpGs emphasized mitochondrial functions and showed enrichment in cardiometabolic conditions and traits. We developed CpG-scores based on heteroplasmy-count associated CpGs (MHC-CpG scores) using elastic net Cox regression in a training cohort. A one-unit higher level of the standardized MHC-CpG scores were associated with 1.26-fold higher hazard of all-cause mortality (95% CI: 1.14, 1.39) and 1.09-fold higher hazard of CVD (95% CI: 1.01-1.17) in the meta-analysis of testing cohorts, adjusting for age, sex, and smoking. These findings shed light on the relationship between mtDNA heteroplasmy and DNA methylation, and the role of heteroplasmy-associated CpGs as biomarkers in predicting all-cause mortality and cardiovascular disease.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831551","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}