medRxiv : the preprint server for health sciences最新文献

{"title":"Oral Contraceptive Use Is Associated with Significant Differences in MicroRNA Cargo of L1CAM-Associated Extracellular Vesicles.","authors":"Dana M Lapato, Rebekah Frye, Vasily Yakovlev, Roxann Roberson-Nay","doi":"10.1101/2025.01.15.25320605","DOIUrl":"10.1101/2025.01.15.25320605","url":null,"abstract":"<p><p>Oral contraceptives (OCs) are approved for use after onset of menarche, which is well before brain maturation is complete. OC use may induce biochemical changes in the brain, especially during the neurobiologically dynamic adolescent/young adult years. MicroRNA cargo in L1CAM-associated extracellular vesicles was measured from serum samples collected from young women using the miRCURY LNA miRNA Focus PCR Panel (Qiagen) and validated using quantitative PCR. Linear regression and F-tests were applied to identify differentially expressed microRNAs by OC use (never versus current), and PANTHER pathway analysis was conducted on the gene targets of significantly differentially expressed microRNAs. Twelve microRNAs had significant differential expression variability by OC use (Bonferroni adjusted p < 0.002). Pathway analysis revealed that the 1254 unique genes targeted by the significant microRNAs were most enriched for the Gonadotropin-releasing hormone receptor pathway (FDR q = 5 × 10^-7), which is associated with the release of gonadotropins, pubertal development, and reproduction. The results are consistent with the hypothesis that microRNA cargo in circulating extracellular vesicles may reflect brain-related biological activity and that OC use may influence extracellular vesicle cargo composition. The significant difference in expression variability may have implications for designing future studies, including power calculations.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049261","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":"Rare variants in <i>PRKCI</i> cause Van der Woude syndrome and other features of peridermopathy.","authors":"Kelsey Robinson, Sunil K Singh, Rachel B Walkup, Dorelle V Fawwal, Wasiu Lanre Adeyemo, Terri H Beaty, Azeez Butali, Carmen J Buxó, Wendy K Chung, David J Cutler, Michael P Epstein, Azeez Fashina, Brooklynn Gasser, Lord Jj Gowans, Jacqueline T Hecht, Lina Moreno Uribe, Daryl A Scott, Gary M Shaw, Mary Ann Thomas, Seth M Weinberg, Harrison Brand, Mary L Marazita, Robert J Lipinski, Jeffrey C Murray, Robert A Cornell, Elizabeth J Leslie-Clarkson","doi":"10.1101/2025.01.17.25320742","DOIUrl":"10.1101/2025.01.17.25320742","url":null,"abstract":"<p><p>Van der Woude syndrome (VWS) is an autosomal dominant disorder characterized by lower lip pits and orofacial clefts (OFCs). With a prevalence of approximately 1 in 35,000 live births, it is the most common form of syndromic clefting and may account for ~2% of all OFCs. The majority of VWS is attributed to genetic variants in <i>IRF6</i> (~70%) or <i>GRHL3</i> (~5%), leaving up to 25% of individuals with VWS without a molecular diagnosis. Both IRF6 and GRHL3 function in a transcriptional regulatory network governing differentiation of periderm, a single layer of epithelial cells that prevents pathological adhesions during palatogenesis. Disruption of this layer results in a spectrum of phenotypes ranging from lip pits and OFCs to severe pterygia and other congenital anomalies that can be incompatible with life. Understanding the mechanisms of peridermopathies is vital in improving health outcomes for affected individuals. We reasoned that genes encoding additional members of the periderm gene regulatory network, including kinases acting upstream of IRF6 (i.e., atypical protein kinase C family members, RIPK4, and CHUK), are candidates to harbor variants resulting in VWS. Consistent with this prediction, we identified 6 <i>de novo</i> variants (DNs) and 11 rare variants in <i>PRKCI</i>, an atypical protein kinase C, in 17 individuals with clinical features consistent with syndromic OFCs and peridermopathies. Of the identified DNs, 4 were identical p.(Asn383Ser) variants in unrelated individuals with syndromic OFCs, indicating a likely hotspot mutation. We also performed functional validation of 12 variants using the enveloping layer in zebrafish embryos, a structure analogous to the periderm. Three patient-specific alleles (p.Arg130His, p.(Asn383Ser), and p.Leu385Phe) were confirmed to be loss-of-function variants. In summary, we identified <i>PRKCI</i> as a novel causal gene for VWS and syndromic OFC with other features of peridermopathies.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049247","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":"Pay-it-forward strategy reduced HPV vaccine delay and increased uptake among catch-up age girls: A randomized clinical trial.","authors":"Jing Li, Yifan Li, Chuanyu Qi, Yu He, Haidong Lu, Yewei Xie, Jason J Ong, Yajiao Lu, Ying Yang, Fan Yang, Heng Du, Wenfeng Gong, Fei Zou, Heidi J Larson, Mark Jit, Leesa Lin, Jennifer S Smith, Elvin H Geng, Dong Xu, Weiming Tang, Shenglan Tang, Joseph D Tucker, Dan Wu","doi":"10.1101/2025.01.16.25320655","DOIUrl":"10.1101/2025.01.16.25320655","url":null,"abstract":"<p><strong>Background: </strong>Catch-up HPV vaccination is challenging in many low and middle-income countries (LMICs). Pay-it-forward offers an individual a subsidized vaccine, then an opportunity to donate to help others access vaccinations. Our randomized control trial assessed the effectiveness of pay-it-forward in improving HPV vaccination among girls aged 15-18 years in China.</p><p><strong>Methods and findings: </strong>Eligible participants were randomly assigned to either the pay-it-forward arm or standard-of-care arm (self-paid vaccination). The primary outcome was the first-dose HPV vaccination rate, verified against clinical records. Among 321 participants enrolled, most caregivers were female (80.1%). In the pay-it-forward arm, 55 of 161 (34.2%) girls received the HPV vaccine, compared with 28 of 160 (17.5%) girls in the standard-of-care arm (adjusted proportion difference = 17.9%, 95% CI: 8.7, 27.0, P<0.001). Among 55 girls in the pay-it-forward arm who received the vaccination, 37 (67.3%) wrote a postcard message, and 39 (70.9%) of their caregivers donated to support future girls. The financial cost per person vaccinated was $294 in the standard-of-care arm and $230 in the pay-it-forward arm.</p><p><strong>Conclusions: </strong>The pro-social pay-it-forward strategy was effective to increase catch-up HPV vaccination among teenage girls with comparable costs.</p><p><strong>Trial registration: </strong>ChiCTR2200055542.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049268","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":"Standardized Measurement of Type 1 Diabetes Polygenic Risk Across Multi-Ancestry Population Cohorts.","authors":"Amber M Luckett, Richard A Oram, Aaron J Deutsch, Hector I Ortega, Diane P Fraser, Kaavya Ashok, Alisa K Manning, Josep M Mercader, Manuel Rivas, Miriam S Udler, Michael N Weedon, Anna L Gloyn, Seth A Sharp","doi":"10.1101/2025.01.16.25320691","DOIUrl":"10.1101/2025.01.16.25320691","url":null,"abstract":"<p><p>Type 1 diabetes (T1D) polygenic risk scores (PRS) are effective tools for discriminating T1D from other diabetes types and predicting T1D risk, with applications in screening and intervention trials. A previously published T1D Genetic Risk Score 2 (GRS2) is widely adopted, but challenges in standardization and accessibility have hindered broader clinical and research utility. To address this, we introduce GRS2x, a standardized and cross-compatible method for accurate T1D PRS calculation, demonstrating genotyping and reference panel independent performance across diverse datasets. GRS2x as a unified approach facilitates accessible and portable measurement of T1D polygenic risk.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049331","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":"Novel Risk Factors for Predicting Immune Effector Cell-Associated Neurotoxicity Syndrome.","authors":"Alec R Friedman, Ceren Tozlu, Christian A Gordillo, Hei Ton Chan, Ran Reshef, Sarah Flanagan Wesley","doi":"10.1101/2025.01.17.25320737","DOIUrl":"https://doi.org/10.1101/2025.01.17.25320737","url":null,"abstract":"<p><p>ICANS is a common form of neurological immunotoxicity from CAR T-cell therapy (CAR-T). While high tumor burden, product type and cell dose are established risk factors, there are many unknowns. Our objective was to characterize novel neurological and non-neurological risk factors for the development of ICANS in subjects who received CAR-T. We retrospectively identified 93 subjects (60% men, mean age 60) who had undergone CD19 or BCMA-targeting CAR-T for hematological malignancy from 2018 to 2023 at a large academic hospital. Incidence of ICANS was 31.2%, high-grade in 9.7%. A low baseline MOCA score (p=0.008) was associated with ICANS when controlled for baseline ferritin, KPS, and age; loss of points on specific cognitive sub-scores was also significant, with poor attention testing of particular concern. Presence of preexisting cerebrovascular disease, active autoimmune disease, and neurological tumor involvement were not associated with increased risk. ICANS was also associated with older age (p=0.024), elevated baseline ferritin (p=0.006), low KPS (p=0.004), and preceding or concurrent CRS of any grade (<0.001). Increasing ferritin between baseline and Day 5+ (p=0.002) was associated with development of high-grade ICANS, along with prior tocilizumab exposure (p=0.015). Subjects who developed any grade of ICANS had higher 90-day mortality than those who did not (p<0.001). Identification of these additional baseline risk factors for ICANS will help identify high-risk patients ahead of treatment and allow for improved preventative planning and early identification of ICANS.</p><p><strong>Key points: </strong>Low baseline MOCA score is an independent risk factor for ICANS. Impaired baseline attention testing is of particular concern.Baseline cerebrovascular disease, neurological exam focality, and active autoimmune disease are not associated with ICANS.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049259","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":"Community Threat, Positive Parenting, and Accelerated Epigenetic Aging: Longitudinal Links from Childhood to Adolescence.","authors":"Georgette Metrailer, Karina Tavares, Mikayla Ver Pault, Adamari Lopez, Shane Denherder, Everlyn Hernandez Valencia, Karissa DiMarzio, April Highlander, Sarah M Merrill, Darlynn M Rojo-Wissar, Justin Parent","doi":"10.1101/2024.12.23.24319484","DOIUrl":"10.1101/2024.12.23.24319484","url":null,"abstract":"<p><p>Early Life Adversity (ELA) has been linked to accelerated epigenetic aging. While positive parenting is hypothesized to buffer the detrimental effects of ELA on child development, its role in mitigating epigenetic age acceleration remains unclear. Data from 2,039 children (49.7% female) in the Future of Families and Child Wellbeing Study (FFCWS) were included in the current study (46.7% Black, 26.5% Hispanic, 19% White non-Hispanic). Home and community threat and observed parenting were measured from ages 3 to 9. Salivary epigenetic age acceleration was measured at ages 9 and 15. Positive parenting reduces the pace of epigenetic aging in low, but not high, community-threat environments. Interventions across home and community environments may be necessary to prevent ELA's biological embedding.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11703298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961007","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":"Functionally enriched human polymorphisms associate to species in the chronic wound microbiome.","authors":"Rebecca A Gabrilska, Khalid Omeir, Jacob Ancira, Clint Miller, Craig D Tipton, Kendra P Rumbaugh, Joseph Wolcott, Ashley Noe, Kumudu Subasinghe, Megan Rowe, Nicole Phillips, Caleb D Phillips","doi":"10.1101/2025.01.15.25320612","DOIUrl":"https://doi.org/10.1101/2025.01.15.25320612","url":null,"abstract":"<p><p>Chronic wounds are a burden to millions of patients and healthcare providers worldwide. With rising incidence and prevalence, there is an urgent need to address non-healing wounds with novel approaches. Impaired wound healing has been shown to be associated with wound microbiota, and multiple bacterial species are known to contribute to delays in closure. Recent evidence suggests human genetics may shape differences in composition of wound microbiomes, and unraveling this relationship has important implications for understanding wound bioburden and tailoring treatment. Here, a two-stage microbiome genome wide association study (mbGWAS; n=509) was used to test effects of human genetics on the relative abundances of bacterial species detected in chronic wounds using bacterial 16S rRNA gene sequencing. Sixteen species were significantly associated to 193 genetic loci distributed across 25 non-overlapping genomic regions. No locus was associated with more than one species, with heritability estimates per species ranging up to 20%. Functional analyses on genomic regions and species resulted in overrepresentation pertaining to pathways relevant to microbial infection and wound healing, suggesting that genetic and species interactions jointly influence the wound microenvironment. Species associated to host genetics in turn exhibited significant co-occurrence relationships with common wound pathogens including <i>Staphylococcus aureus</i> and <i>Finegoldia magna</i> . Moreover, the overall genetic distance among patients was significantly related to differences in their overall wound microbiome composition. Identification of such genetic biomarkers reveals new mechanistic insight into patient-microbiome interactions and provides an avenue to identify predictive risk factors for diagnosis and management of chronic wounds.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049265","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 study meta-analysis of BMI in African Americans.","authors":"Kendra Ferrier, Mariaelisa Graff, Iain R Konigsberg, Maggie Stanislawski, Heather M Highland, Laura M Raffield, April P Carson, Eric Boerwinkle, Jill M Norris, Chris R Gignoux, Audrey E Hendricks, Sridharan Raghavan, Kari E North, Matthew A Allison, Mathew J Budoff, Silva Kasela, François Aguet, Joshua J Joseph, Charles Kooperberg, Stephen S Rich, Jerome I Rotter, Ethan M Lange, Leslie A Lange","doi":"10.1101/2025.01.15.25320607","DOIUrl":"https://doi.org/10.1101/2025.01.15.25320607","url":null,"abstract":"<p><p>Despite considerable advances in identifying risk factors for obesity development, there remains substantial gaps in our knowledge about its etiology. Variation in obesity (defined by BMI) is thought to be due in part to heritable factors; however, obesity-associated genetic variants only account for a small portion of heritability. Epigenetic regulation, defined by genetic and/or environmental factors with changes in gene expression, may account for some of this \"missing heritability\". Epigenetic studies of obesity have largely been conducted in populations of European ancestry, despite the disproportionate burden of obesity in African Americans (AAs). To address race/ethnic (RE)-differences in obesity, we conducted a BMI epigenome-wide association study (EWAS) meta-analysis using AA participants from the Jackson Heart Study (JHS, n=1604) and the Multi-Ethnic Study of Atherosclerosis (MESA, n=179). Analyses using a linear regression model with methylation as the outcome and continuous BMI as the predictor were stratified by study and sex, then meta-analyzed. There were 208 methylation sites (CpGs) that reached epigenome-wide significance (p< 8.72×10 ^-8 ); 151 of these were novel. Of the novel CpGs, 29 CpGs were available for replication testing in a separate sample of AA and 20 replicated. Differentially methylated region (DMR) analysis resulted in 54 DMRs significantly associated with BMI. Several regions are proximal to, or include, genes previously associated with obesity traits (e.g., <i>SOCS3, ABCG1</i> , and <i>TGFB1</i> ) in GWAS. Gene and trait enrichment and pathway analysis showed enrichment for genes in immune system and inflammation related pathways (e.g., the IL-6/JAK/STAT pathway). In conclusion, EWAS of BMI in AAs replicated previously known associations identified in European ancestry and multi-ethnic EWAS and identified novel obesity-associated CpGs.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049096","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":"Global DNA methylomes reveal oncogenic-associated 5-hydroxylmethylated cytosine (5hmC) signatures in the cell-free DNA of cancer patients.","authors":"Gabriel E Rech, Alyssa C Lau, Rachel L Goldfeder, Rahul Maurya, Alexey V Danilov, Chia-Lin Wei","doi":"10.1101/2025.01.09.25320283","DOIUrl":"10.1101/2025.01.09.25320283","url":null,"abstract":"<p><p>Characterization of tumor epigenetic aberrations is integral to understanding the mechanisms of tumorigenesis and provide diagnostic, prognostic, and predictive information of high clinical relevance. Among the different tumor-associated epigenetic signatures, 5 methyl-cytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are the two most well-characterized DNA methylation alterations linked to cancer pathogenesis. 5hmC has a tissue-specific distribution and its abundance is subjected to changes in tumor DNA, making it a promising biomarker. Detecting tumor-related DNA methylation alterations in tissues is highly invasive, while the analysis of the cell-free DNA (cfDNA) is poised to supplement, if not replace, surgical biopsies. Despite many studies attempted to identify new epigenetic targets for liquid biopsy assays, little is known about the regulatory roles of 5hmC, its impacts on the molecular phenotypes in tumors. Most importantly, whether the oncogenic-associated 5hmC signatures found in tumor tissues can be recapitulated in patients' cfDNA. In this study, we performed the unbiased and simultaneous detection of 5mC and 5hmC whole-genome DNA modifications at base-resolution from two distinct cancer cohorts, from patients with bladder cancer or B-Cell lymphoma, their corresponding normal tissues, and cfDNAs from plasma. We analyzed tissue-specific methylation patters and searched for signatures in gene coding and regulatory regions linked to cancerous states. We then looked for methylation signatures in patients' cfDNA to determine if they were consistent with the tumor-specific patterns. We determined the functional significance of 5hmC in tissue specific transcription and uncovered hundreds of tumor-associated 5hmC signatures. These tumor-associated 5hmC changes, particularly in genes and enhancers, were functionally significant in tumorigenesis pathways and correlated with tumor specific gene expression. To investigate if cfDNA is a faithful surrogate for tumor-associated 5hmC, we devised a targeted capture strategy to examine the alterations of 5hmC in cfDNA from patients with bladder cancer and lymphoma with sufficient sensitivity and specificity and confirmed that they recapitulated the patterns we observed in tumor tissues. Our results provide analytic validation of 5hmC as a cancer-specific biomarker. The methods described here for systematic characterization of 5hmC at functional elements open new avenues to discover epigenetic markers for non-invasive diagnosis, monitoring, and stratifying cancer.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049270","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":"Large-scale audiometric phenotyping identifies distinct genes and pathways involved in hearing loss subtypes.","authors":"Samah Ahmed, Kenneth I Vaden, Darren Leitao, Judy R Dubno, Britt I Drögemöller","doi":"10.1101/2025.01.14.24318673","DOIUrl":"https://doi.org/10.1101/2025.01.14.24318673","url":null,"abstract":"<p><p>Age-related hearing loss affects one-third of the population over 65 years. However, the diverse pathologies underlying these heterogenous phenotypes complicate genetic studies. To overcome challenges associated with accurate phenotyping for older adults with hearing loss, we applied computational phenotyping approaches based on audiometrically measured hearing loss. This novel phenotyping strategy uncovered distinct genetic variants associated with sensory and metabolic hearing loss. Sex-stratified analyses of these sexually dimorphic hearing loss phenotypes revealed a novel locus of relevance to sensory hearing loss in males, but not females. Enrichment analyses revealed that genes involved in frontotemporal dementia were implicated in metabolic hearing loss, while genes relating to sensory processing of sound by hair cells were implicated in sensory hearing loss. Our study has enhanced our understanding of these two distinct hearing loss phenotypes, representing the first step in the development of more precise treatments for these pathologically distinct hearing loss phenotypes.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143048507","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}