medRxiv : the preprint server for health sciences最新文献

{"title":"Detecting short-interval longitudinal cortical atrophy in neurodegenerative dementias via cluster scanning: A proof of concept.","authors":"Yuta Katsumi, Michael Brickhouse, Lindsay C Hanford, Jared A Nielsen, Maxwell L Elliott, Ross W Mair, Alexandra Touroutoglou, Mark C Eldaief, Randy L Buckner, Bradford C Dickerson","doi":"10.1101/2025.03.14.25323769","DOIUrl":"https://doi.org/10.1101/2025.03.14.25323769","url":null,"abstract":"<p><p>Regional brain atrophy estimated from structural magnetic resonance imaging (MRI) is a widely used measure of neurodegeneration in Alzheimer's disease (AD), Frontotemporal Lobar Degeneration (FTLD), and other dementias. Yet, traditional MRI-derived morphometric estimates are susceptible to measurement errors, posing a challenge for reliably detecting longitudinal atrophy, particularly over short intervals. Here, we examined the utility of multiple MRI scans acquired in rapid succession (i.e., <i>cluster scanning</i> ) for detecting longitudinal cortical atrophy over 3- and 6-month intervals within individual patients. Four individuals with mild cognitive impairment or mild dementia likely due to AD or FTLD participated in this study. At baseline, 3 months, and 6 months, structural MRI data were collected on a 3 Tesla scanner using a fast 1.2-mm T1-weighted multi-echo magnetization-prepared rapid gradient echo (MEMPRAGE) sequence (acquisition time = 2'23''). At each timepoint, participants underwent up to 32 MEMPRAGE scans acquired in four separate sessions over two days. Using linear mixed-effects models, phenotypically vulnerable cortical (\"core atrophy\") regions exhibited statistically significant longitudinal atrophy in all participants (i.e., decreased cortical thickness) by 3 months and further demonstrated preferential vulnerability compared to control regions in three of the participants over at least one of the 3-month intervals. These findings provide proof-of-concept evidence that pooling multiple morphometric estimates derived from cluster scanning can detect longitudinal cortical atrophy over short intervals in individual patients with neurodegenerative dementias.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757128","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":"Performance of DeepSeek, Qwen 2.5 MAX, and ChatGPT Assisting in Diagnosis of Corneal Eye Diseases, Glaucoma, and Neuro-Ophthalmology Diseases Based on Clinical Case Reports.","authors":"Zain S Hussain, Mohammad Delsoz, Muhammad Elahi, Brian Jerkins, Elliot Kanner, Claire Wright, Wuqaas M Munir, Mohammad Soleimani, Ali Djalilian, Priscilla A Lao, Joseph W Fong, Malik Y Kahook, Siamak Yousefi","doi":"10.1101/2025.03.14.25323836","DOIUrl":"https://doi.org/10.1101/2025.03.14.25323836","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;This study evaluates the diagnostic performance of several AI models, including Deepseek, in diagnosing corneal diseases, glaucoma, and neuro□ophthalmologic disorders.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We retrospectively selected 53 case reports from the Department of Ophthalmology and Visual Sciences at the University of Iowa, comprising 20 corneal disease cases, 11 glaucoma cases, and 22 neuro□ophthalmology cases. The case descriptions were input into DeepSeek, ChatGPT□4.0, ChatGPT□01, and Qwens 2.5 Max. These responses were compared with diagnoses rendered by human experts (corneal specialists, glaucoma attendings, and neuro□ophthalmologists). Diagnostic accuracy and interobserver agreement, defined as the percentage difference between each AI model's performance and the average human expert performance, were determined.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;DeepSeek achieved an overall diagnostic accuracy of 79.2%, with specialty-specific accuracies of 90.0% in corneal diseases, 54.5% in glaucoma, and 81.8% in neuro□ophthalmology. ChatGPT□01 outperformed the other models with an overall accuracy of 84.9% (85.0% in corneal diseases, 63.6% in glaucoma, and 95.5% in neuro□ophthalmology), while Qwens exhibited a lower overall accuracy of 64.2% (55.0% in corneal diseases, 54.5% in glaucoma, and 77.3% in neuro□ophthalmology). Interobserver agreement analysis revealed that in corneal diseases, DeepSeek differed by -3.3% (90.0% vs 93.3%), ChatGPT□01 by -8.3%, and Qwens by -38.3%. In glaucoma, DeepSeek outperformed the human expert average by +3.0% (54.5% vs 51.5%), while ChatGPT□4.0 and ChatGPT□01 exceeded it by +12.1%, and Qwens was +3.0% above the human average. In neuro□ophthalmology, DeepSeek and ChatGPT□4.0 were 9.1% lower than the human average, ChatGPT□01 exceeded it by +4.6%, and Qwens was 13.6% lower.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;ChatGPT□01 demonstrated the highest overall diagnostic accuracy, especially in neuro□ophthalmology, while DeepSeek and ChatGPT□4.0 showed comparable performance. Qwens underperformed relative to the other models, especially in corneal diseases. Although these AI models exhibit promising diagnostic capabilities, they currently lag behind human experts in certain areas, underscoring the need for a collaborative integration of clinical judgment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Plain language summary: &lt;/strong&gt;This study evaluated how well several artificial intelligence (AI) models diagnose eye diseases compared to human experts. We tested four AI systems across three types of eye conditions: diseases of the cornea, glaucoma, and neuro-ophthalmologic disorders. Overall, one AI model, ChatGPT-01, performed the best, correctly diagnosing about 85% of cases, and it excelled in neuro-ophthalmology by correctly diagnosing 95.5% of cases. Two other models, DeepSeek and ChatGPT-4.0, each achieved an overall accuracy of around 79%, while the Qwens model performed lower, with an overall accuracy of about 64%. When ","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756837","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":"Longitudinal changes in optoretinography provide an early and sensitive biomarker of outer retinal disease.","authors":"Teng Liu, Benjamin Wendel, Jennifer Huey, Vimal Prabhu Pandiyan, Debarshi Mustafi, Jennifer R Chao, Ramkumar Sabesan","doi":"10.1101/2025.03.12.25323718","DOIUrl":"10.1101/2025.03.12.25323718","url":null,"abstract":"<p><strong>Objective: </strong>To examine whether optoretinography (ORG) can provide greater sensitivity for assessing the time-course of disease progression in Retinitis Pigmentosa compared to standard clinical imaging in a longitudinal study.</p><p><strong>Design: </strong>Cohort, longitudinal study.</p><p><strong>Participants: </strong>Five non-syndromic RP patients and eight control subjects participated in the study.</p><p><strong>Methods: </strong>Clinical examination, imaging sessions and data analysis were all conducted at the University of Washington. Five eyes of 5 patients diagnosed with RP, comparing standard clinical imaging to ORG, were collected over a 21-month span between August 2022 and May 2024.</p><p><strong>Main outcome and measures: </strong>ORG response to visual stimuli, ellipsoid zone (EZ) width and outer segment length (OS length) were evaluated for longitudinal changes as markers of disease progression.</p><p><strong>Results: </strong>The reduction in cone function with ORG over time exceeds that observed in standard clinical markers of photoreceptor structure - EZ width and OS length. EZ width and OSL decreased by 4.5% ± 5.9% and 6.5% ± 1.4%, respectively, approximately 9.9 and 6.9 times less than the reduction noted in ORG, respectively. The most notable degradation was noted at the borders of the transition zone, where ORG showed progressive and sub-clinical losses in photoreceptor function whereas standard OCT showed healthy, unaffected outer retinal structure.</p><p><strong>Conclusions: </strong>Optoretinography detects sub-clinical disease and reliably identifies longitudinal markers of progression with greater sensitivity compared to standard clinical imaging. The ability to detect functional changes in the outer retina prior to standard clinical measures underscores its potential as a sensitive, accelerated and clinically-relevant outcome measure to guide patient selection and their therapeutic response in future clinical trials.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757132","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":"Trans-ancestry genome-wide association meta-analysis of gallstone disease.","authors":"Junghyun Lim, Marijana Vujkovic, Michael G Levin, Kim Lorenz, Benjamin F Voight, David Y Zhang, Max F Dudek, Matthew C Pahl, James A Pippin, Chun Su, Elisabetta Manduchi, Andrew D Wells, Struan F A Grant, Sarah Abramowitz, Scott M Damrauer, Samiran Mukherjee, Guoyi Yang, David E Kaplan, Daniel J Rader","doi":"10.1101/2025.03.16.25324077","DOIUrl":"https://doi.org/10.1101/2025.03.16.25324077","url":null,"abstract":"<p><p>Gallstone disease is a highly prevalent and costly gastrointestinal disease. Yet, genetic variation in susceptibility to gallstone disease and its implication in metabolic regulatory pathways remain to be explored. We report a trans-ancestry genome-wide association meta-analysis of gallstone disease including 88,063 cases and 1,490,087 controls in the UK Biobank, FinnGen, Biobank Japan, and Million Veteran Program. We identified 91 (37 novel) risk loci across the meta-analysis and found replication in statistically compelling signals in the All of Us Research Program. A polygenic risk score constructed from trans-ancestry lead variants was positively associated with liver chemistry and alpha-1-antitrypsin deficiency and negatively associated with total cholesterol and low-density lipoprotein levels among trans-ancestry and European ancestry groups in the Penn Medicine BioBank. Cross-trait colocalization analysis between risk loci and 44 liver, metabolic, renal, and inflammatory traits yielded 350 significant colocalizations as well as 97 significant colocalizations and 65 prioritized genes from expression quantitative trait loci from eight tissues. These findings broaden our understanding of the genetic architecture of gallstone disease.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757188","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":"Convergent Pathways Identified for Cannabis Use Disorder Across Diverse Ancestry Populations.","authors":"Qian Peng, Kirk C Wilhelmsen, Cindy L Ehlers","doi":"10.1101/2025.03.16.25324078","DOIUrl":"https://doi.org/10.1101/2025.03.16.25324078","url":null,"abstract":"<p><p>Large disparities in the prevalence of cannabis use disorder (CUD) exist across ethnic groups in the U.S. Despite large GWAS meta-analyses identifying numerous genome-wide significant loci for CUD in European descents, little is known about other ethnic groups. While most GWAS and SNP-heritability studies focus on common genomic variants, rare and low-frequency variants, particularly those altering proteins, are known to be enriched for the heritability of complex traits and may contribute to disease in different ways across populations, either through converging or alternative pathways. In this study, we examined three populations including European Americans (EA) and two understudied populations: American Indians (AI) and Mexican Americans (MA). We focused on rare and low frequency functional variants in genes and pathways, and performed association analysis with CUD severity. We identified 10 significant loci in AI, the <i>ARSA</i> gene in MA, three significant pathways in MA, and one in EA associated with CUD severity. Notably, pathways related to arylsulfatases activation and heparan sulfate degradation were supported by both EA and MA, with additional evidence from AI. The integrin beta-1 cell surface interaction pathway, involved in cell adhesion, was uniquely significant in MA. Several immune-related pathways were also found, including an autoimmune condition significant in MA with evidence from EA as well, and a p38-gamma/delta mediated signaling pathway supported across all three cohorts. Although each population displayed distinct pathways linked to CUD, overlapping genes in top pathways suggested shared genetic factors, further highlighting the importance of considering diverse populations in genetic research on cannabis use disorder.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757124","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":"Humoral Immunity Against Orthopoxvirus in Vaccinated and Unvaccinated Individuals during 2022 Mpox Outbreak.","authors":"Yijia Li, Michael B Townsend, Shanshan Li, Quinn E Testa, Tom Medvec, Elizabeth A Thompson, Frank J Palella, Matthew J Mimiaga, James B Brock, Maria L Alcaide, Anandi N Sheth, Michelle Floris-Moore, Aruna Chandran, Audrey L French, Phyllis C Tien, Daniel J Merenstein, Michael Augenbraun, Anjali Sharma, Caitlin A Moran, Charles R Rinaldo, Bernard Jc Macatangay, Panayampalli S Satheshkumar, Ken S Ho","doi":"10.1101/2025.03.16.25324075","DOIUrl":"https://doi.org/10.1101/2025.03.16.25324075","url":null,"abstract":"<p><p>Little is known about serological responses to MVA-BN (JYNNEOS) against mpox in elderly individuals with or without HIV. In this study, MVA-BN induced sustained IgG levels regardless of HIV status even up to one year. Birth before 1973 correlated with higher IgG. MVA-BN unvaccinated individuals with HIV had lower IgG than vaccinated.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756918","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":"Bayesian estimation of shared polygenicity identifies drug targets and repurposable medicines for human complex diseases.","authors":"Noah Lorincz-Comi, Feixiong Cheng","doi":"10.1101/2025.03.17.25324106","DOIUrl":"https://doi.org/10.1101/2025.03.17.25324106","url":null,"abstract":"<p><strong>Background: </strong>Complex diseases may share portions of their polygenic architectures which can be leveraged to identify drug targets with low off-target potential or repurposable candidates. However, the literature lacks methods which can make these inferences at scale using publicly available data.</p><p><strong>Methods: </strong>We introduce a Bayesian model to estimate the polygenic structure of a trait using only gene-based association test statistics from GWAS summary data and returns gene-level posterior risk probabilities (PRPs). PRPs were used to infer shared polygenicity between 496 trait pairs and we introduce measures that can prioritize drug targets with low off-target effects or drug repurposing potential.</p><p><strong>Results: </strong>Across 32 traits, we estimated that 69.5 to 97.5% of disease-associated genes are shared between multiple traits, and the estimated number of druggable genes that were only associated with a single disease ranged from 1 (multiple sclerosis) to 59 (schizophrenia). Estimating the shared genetic architecture of ALS with all other traits identified the <i>KIT</i> gene as a potentially harmful drug target because of its deleterious association with triglycerides, but also identified <i>TBK1</i> and <i>SCN11B</i> as putatively safer because of their non-association with any of the other 31 traits. We additionally found 21 genes which are candidate repourposable targets for Alzheimer's disease (AD) (e.g., <i>PLEKHA1, PPIB</i> ) and 5 for ALS (e.g., <i>GAK, DGKQ</i> ).</p><p><strong>Conclusions: </strong>The sets of candidate drug targets which have limited off-target potential are generally smaller compared to the sets of pleiotropic and putatively repurposable drug targets, but both represent promising directions for future experimental studies.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756915","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":"Invasive Brain Mapping Identifies Personalized Therapeutic Neuromodulation Targets for Obsessive-Compulsive Disorder.","authors":"A Moses Lee, Audrey Kist, John Alvarez, Kristin K Sellers, Ankit N Khambhati, Leo P Sugrue, Lee B Reid, Kelly Kadlec, Joline M Fan, Anusha B Allawala, Caroline A Racine, Tenzin Norbu, Dani Astudillo, Alexandra G Tremblay-McGaw, Natalie Becker, Ahmad Alhourani, Philip A Starr, Edward F Chang, Andrew D Krystal","doi":"10.1101/2025.03.14.25323348","DOIUrl":"https://doi.org/10.1101/2025.03.14.25323348","url":null,"abstract":"<p><p>Deep brain stimulation has been used to treat severe, refractory obsessive-compulsive disorder (OCD) with variable outcomes across multiple anatomical targets. To overcome these limitations, we developed an invasive brain mapping paradigm in which electrodes were implanted across the OCD cortico-striato-thalamo-cortical circuit in a single individual. We then performed extensive stimulation mapping during a multi-day inpatient stay to identify personalized therapeutic targets and characterize their downstream circuit effects. We found two targets within the right ventral capsule (VC) that acutely reduced OCD symptoms. Prolonged VC stimulation suppressed high frequency activity within the structurally and functionally connected orbitofrontal cortex, which encoded the severity of OCD symptoms. These VC sites were implanted for DBS and combined stimulation of these targets led to a rapid therapeutic response. This case provides the first proof-of-concept that invasive brain mapping can be used to guide a novel personalized, multi-site neuromodulation approach to treat refractory OCD.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756995","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":"Partner military deployment and war conditions increase perinatal depression and decrease postpartum mother-infant bonding.","authors":"Hadas Allouche-Kam, Sabrina J Chan, Isha Hemant Arora, Christina T Pham, Inbal Reuveni, Eyal Sheiner, Sharon Dekel","doi":"10.1101/2025.01.20.25320861","DOIUrl":"10.1101/2025.01.20.25320861","url":null,"abstract":"<p><p>The pregnancy and postpartum period represents a time of potentially heightened psychological vulnerability with implications for the offspring. Knowledge of the mental health of perinatal women exposed to armed conflict when their partner is in military deployment is scarce. This matched-control, survey-based study included a sample of 429 women recruited during the first months of the Israel-Hamas War who were pregnant or within six months postpartum. Women reporting partner in military deployment (n=250) were matched on background factors to women whose partner was no longer deployed (n=179). We found that nearly 44% of pregnant women with partner deployed endorsed depression symptoms at a clinical level. This group was more than two times as likely to endorse depression symptoms than matched controls. Postpartum women with partner deployed had significantly lower levels of mother-infant bonding than the matched group of partners not deployed. Mediation models revealed that social support mediated the relationship between study group and these maternal outcomes. Our findings suggest that war-exposed spouses of partners who are deployed are at increased risk for psychiatric morbidity and problems with attachment to the infant. Attention to optimizing social support in perinatal population is warranted during times of war and other large-scale traumas.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11838974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143461320","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":"Genetic Regulation of the Metabolome Differs by Sex, Alzheimer's Disease Stage, and Plasma Biomarker Status.","authors":"Jaclyn M Eissman, Min Qiao, Vrinda Kalia, Marielba Zerlin-Esteves, Dolly Reyes-Dumeyer, Angel Piriz, Saurabh Dubey, Renu Nandakumar, Annie J Lee, Rafael A Lantigua, Martin Medrano, Diones Rivera Mejia, Lawrence S Honig, Clifton L Dalgard, Gary W Miller, Richard Mayeux, Badri N Vardarajan","doi":"10.1101/2025.02.26.25322932","DOIUrl":"10.1101/2025.02.26.25322932","url":null,"abstract":"<p><p>We investigated genetic regulators of circulating plasma metabolites to identify pathways underlying biochemical changes in clinical and biomarker-assisted diagnosis of Alzheimer's disease (AD). We computed metabolite quantitative trait loci by using whole genome sequencing and small molecule plasma metabolites from 229 older adults with clinical AD and 322 age-matched healthy controls. Unbiased associations between 6,881 metabolites and 332,772 common genetic variants were tested, adjusted for age, sex, and both metabolomic and genomic principal components. We identified 72 novel and known SNP-metabolite associations spanning 66 genes and 12 metabolite classes, including <i>PYROXD2</i> and N6-methyllysine, <i>FAAH</i> and myristoylglycine, as well as <i>FADS2</i> and arachidonic acid. In addition, we found differences in genetic regulation of metabolites among individuals with clinically defined AD compared to AD defined by a published plasma P-tau181 level cut-off. We also found more SNP-metabolite associations among males compared to females. In summary, we identified sex- and disease-specific genetic regulators of plasma metabolites and unique biological mechanisms of genetic perturbations in AD.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589125","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}