Human Genomics最新文献

{"title":"Genetic signatures of exceptional longevity: a comprehensive analysis of coding region single nucleotide polymorphisms (SNPs) in centenarians and supercentenarians.","authors":"Audre Preena Maria Sundar Raj, Gayathri Selvakumar, James Clement, George M Church, Sudhakar Sivasubramaniam","doi":"10.1186/s40246-025-00772-3","DOIUrl":"10.1186/s40246-025-00772-3","url":null,"abstract":"<p><p>Aging, a complex biological process, entails sequential changes in organisms that elevate the risk of frailty, disease, and mortality, affecting individuals at the level of cellular, organ, and organism. This process is influenced by genetic diversity, socioeconomic status, healthcare infrastructure, lifestyle choices, and cultural practices. Gerontology delves into the factors shaping longevity, aging processes, and aging from both evolutionary and individual perspectives. Centenarians and supercentenarians serve as models for studying exceptional longevity, offering insights into the aging process and resistance to age-related diseases. This research investigates common genetic variations (SNPs) shared among 3 centenarians and 18 supercentenarians, individuals aged 110 years or older. 754,520 SNPs were found to be common among all the 21 samples. Utilizing SNPnexus, a genetic variant annotation tool, we annotated coding variants and assessed potential disease susceptibilities associated with these variants. Ensembl was used as an annotation system, we annotated 1,607,122 variants, and found 11,348 coding variants. Among them, 4980 had non-synonymous variants, and 110 variants were observed to have deleterious effects. These deleterious SNPs were linked with 79 genes among them 16 novel variants were identified in 9 genes. The population frequency comparison using the 1000 Genomes Project and gnomAD revealed that a subset of these common, non-synonymous SNPs and deleterious SNPs had minor allele frequencies (MAF) below 1% or were absent entirely, suggesting potential rare variants specific to this cohort. In addition, we also found statistically significant (p < 0.05) 148 enriched pathways, among them the top enriched pathways such as extracellular matrix (ECM) remodeling, signal transduction, disease-associated pathways, sensory processing and metabolism of proteins and RNA. These preliminary findings may help prioritize candidate variants and genes for future studies on larger cohorts with appropriate controls can help in understanding the genetic basis of exceptional longevity.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"115"},"PeriodicalIF":4.3,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel clinical and genetic insights into Gitelman syndrome from 95 Chinese patients.","authors":"Xiaomeng Shi, Lu Zhang, Xing Chen, Peijin Bai, Leping Shao","doi":"10.1186/s40246-025-00828-4","DOIUrl":"10.1186/s40246-025-00828-4","url":null,"abstract":"<p><strong>Background: </strong>Gitelman syndrome (GS) is a rare tubulopathy with clinical and genetic heterogeneity. This study aimed to investigate the characteristics of Chinese GS patients.</p><p><strong>Methods: </strong>The diagnosis of GS was established by combining clinical phenotypes with genetic testing, after which the clinical, biochemical, and genetic data were statistically analyzed.</p><p><strong>Results: </strong>We reported 95 Chinese GS patients aged 2-52 years. The younger group (≤ 16 years) had more frequent febrile episodes (20.4% vs. 4.3%, P = 0.028) and nausea/vomiting (12.2% vs. 0.0%, P = 0.027) but fewer paresthesia/numbness (20.4% vs. 43.5%, P = 0.026) and palpitations (8.2% vs. 37.0%, P = 0.001), along with higher serum potassium and magnesium levels (2.86 ± 0.45 mmol/L vs. 2.67 ± 0.38 mmol/L, P = 0.034; 0.65 ± 0.14 mmol/L vs. 0.58 ± 0.16 mmol/L, P = 0.031) than the older group (> 16 years). Moreover, serum potassium and magnesium levels were positively correlated and both were negatively correlated with age. Additionally, Among 170 detected SLC12A3 variants, 73 distinct variants were identified, including six novel ones. The compound heterozygous group exhibited higher serum magnesium levels compared to the heterozygous and homozygous groups (0.65 ± 0.17 mmol/L vs. 0.56 ± 0.09 mmol/L, P = 0.015; 0.65 ± 0.17 mmol/L vs. 0.51 ± 0.07 mmol/L, P < 0.001). Age at diagnosis was associated with variant types.</p><p><strong>Conclusion: </strong>The study characterized the phenotypic and genotypic features of Chinese GS patients, highlighting age and mutation genotype as key factors influencing phenotype, underscoring the importance of standardized potassium and magnesium supplementation, and expanding the known mutation spectrum with novel variants.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"114"},"PeriodicalIF":4.3,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recurrent acute liver failure and neutropenia caused by a novel homozygous RINT1 variant: a brief report of phenotypic expansion and population-specific findings.","authors":"Еkaterina Nuzhnaya, Andrey Marakhonov, Nikolai Prokhorov, Nelly Kan, Yulia Rodina, Anna Shcherbina, Polina Tsygankova, Anna Efremovа, Natalia Semenova","doi":"10.1186/s40246-025-00827-5","DOIUrl":"10.1186/s40246-025-00827-5","url":null,"abstract":"<p><strong>Background: </strong>Recurrent acute liver failure (RALF) is a rare and life-threatening disorder often triggered by infections or febrile episodes. Variants in genes regulating vesicular transport, including RINT1, NBAS have been implicated in RALF and are classified as infantile liver failure syndromes type 2 and 3 (ILFS2 and ILFS3), often associated with multisystemic manifestations.</p><p><strong>Methods: </strong>We conducted comprehensive clinical, laboratory and genetic evaluations of a proband presenting with RALF and neutropenia. Whole-exome sequencing (WES), whole-genome sequencing (WGS), Sanger analysis, autozygosity mapping and 3D protein structural modeling were conducted to identify and characterize the pathogenic variant.</p><p><strong>Results: </strong>A novel homozygous variant in the RINT1 gene (NM_021930.6:c.1435G > C, p.Ala479Pro) was identified in a proband from Chuvashia presenting with RALF and neutropenia, with both parents confirmed as heterozygous carriers. Structural modeling suggested a destabilizing effect on the RINT1/TIP20 domain. Two siblings with identical symptoms further supported the pathogenicity of this variant and its autosomal recessive inheritance. Runs of homozygosity (ROH) analysis indicated a possible founder effect in the Chuvash population. Our study expands the phenotypic spectrum of RINT1-related ILFS3, which in this case lacked the skeletal or neurological features previously described but included neutropenia.</p><p><strong>Conclusion: </strong>We report a novel RINT1 variant cause ILFS3 and neutropenia, supporting its classification as a potential population-specific disorder. These findings highlight the importance of early genetic screening and clinical monitoring in affected populations.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"116"},"PeriodicalIF":4.3,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of genetically-supported new drug targets for osteomyelitis based on druggable genomes.","authors":"Ruotong Yao, Yangguang Lu, Di Lu, Haiyong Ren, Xiang Wang, Bingyuan Lin, Siyao Chen, Yusheng Zhu, Feng Chen, Yukai Wang, Yi Gao, Jiawen Shen, Qiaofeng Guo, Kai Huang","doi":"10.1186/s40246-025-00826-6","DOIUrl":"10.1186/s40246-025-00826-6","url":null,"abstract":"<p><strong>Background: </strong>Limited drug treatment data are available for osteomyelitis (OM), an inflammatory bone condition secondary to infection. Given its genetic characteristics, it is necessary to integrate genetics into drug development for osteomyelitis. This study applied pharmacogenomics to identify new drug targets for osteomyelitis using Mendelian randomization (MR).</p><p><strong>Methods: </strong>Following the Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization guidelines, expression and protein quantitative trait loci (QTL) analysis was applied to simulate drug exposure. Single nucleotide polymorphisms were selected as instrumental variables for MR analysis using blood QTL data and independent osteomyelitis genome-wide association study datasets from UK Biobank and FinnGen R10. A random-effects model meta-analysis combining the results from two datasets was performed. Bayesian co-localization analysis was conducted to validate the targets. Sensitivity analyses were performed using various MR methods, with MR-Egger regression and Cochran's Q test being conducted to assess the horizontal pleiotropy and heterogeneity of the instrumental variables.</p><p><strong>Results: </strong>At α = 1 × 10^-5, the meta-analysis identified 12 drug target mechanisms. Gene expression of QDPR, TGM1, NTSR1, CBR3, and NEK6 was positively correlated with osteomyelitis risk, whereas HLA-DRB1, LAMC1, LTB4R, MAPK3, FPR1, ABAT, and LTA4H were negatively correlated with this risk. Five potential drug repurposing opportunities and three drugs that may increase osteomyelitis risk were identified. Sensitivity analyses highlighted LTA4H, LAMC1, QDPR, and NEK6 as having the strongest genetic evidence based on MR-Egger regression and protein QTL tests.</p><p><strong>Conclusions: </strong>This study identified 12 new genetically supported drug targets for osteomyelitis, thereby providing a genetic foundation for new drug development, repurposing existing drugs, and personalized treatment.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"117"},"PeriodicalIF":4.3,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multicenter study reveals a novel pathogenic splice-site founder variant in OTOF.","authors":"Zippora Brownstein, Lara Kamal, Shir Mishan-Montefiori, Yael Hoffman, Dina Fine, Yoel Hirsch, Tzvi Weiden, Rivka Birnbaum, Hagar Mor-Shaked, Bella Davidov, Yuval Yaron, Karen B Avraham","doi":"10.1186/s40246-025-00819-5","DOIUrl":"10.1186/s40246-025-00819-5","url":null,"abstract":"","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"112"},"PeriodicalIF":4.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of C4BPA as a genetically informed drug target in NSCLC: an integrative single-cell and multi-omics study based on the druggable genes.","authors":"Zhihan Xiao, Xinji Liu, Wei Tang, Yan Lv, Tongyu Zhang, Xu Zhan, Qihang Sun, Willis Wasonga Omindo, Qi Wang, Ruijie Zhang, Wei Ping, Ni Zhang","doi":"10.1186/s40246-025-00829-3","DOIUrl":"10.1186/s40246-025-00829-3","url":null,"abstract":"<p><strong>Background: </strong>Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Despite advancements in treatment, drug resistance and limited therapeutic efficacy persist, underscoring the urgent need for novel and mechanistically informed therapeutic strategies. Identifying genetically supported drug targets may accelerate the development of precision therapies in NSCLC.</p><p><strong>Methods: </strong>We implemented an integrative multi-omics framework combining single-cell RNA sequencing (scRNA-seq), genome-wide association studies (GWAS), and molecular quantitative trait locus (QTL) datasets including expression (eQTL), protein (pQTL), and DNA methylation (mQTL) QTLs. Druggable candidates were systematically evaluated using a suite of Mendelian randomization (MR) approaches-including summary data-based MR (SMR), generalized SMR (GSMR), and genetic risk score (GRS) analysis. Epigenetic regulation and downstream signaling were further explored through mediation MR analysis.</p><p><strong>Results: </strong>C4BPA, a complement-regulatory macromolecule, emerged as a risk factor for NSCLC across multiple MR models, with consistent findings validated at both transcriptomic and proteomic levels. Epigenetic activation of C4BPA via DNA methylation was observed, and C4BPA expression was shown to promote NSCLC progression through the inflammatory chemokine CCL8 signaling axis. Sensitivity analyses confirmed the robustness of association inference.</p><p><strong>Conclusions: </strong>Our findings identify C4BPA as a genetically validated and biologically plausible therapeutic target for NSCLC. This study demonstrates the power of integrating single-cell transcriptomics with population-scale omics and association inference to uncover actionable targets, offering a scalable framework for advancing precision oncology in lung cancer.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"113"},"PeriodicalIF":4.3,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the demographic history of Sindhi population inhabited in West Coast India.","authors":"Lomous Kumar, Suraj Nongmaithem, Sachin Kumar, Kumarasamy Thangaraj","doi":"10.1186/s40246-025-00822-w","DOIUrl":"10.1186/s40246-025-00822-w","url":null,"abstract":"<p><strong>Background: </strong>South Asian populations are genetically well stratified due to multiple waves of migration, admixture events, and endogamy. India remains a rich resource for population genomics studies with many small and socio-culturally homogeneous communities whose origins and demographic histories are largely unknown.</p><p><strong>Methods: </strong>In this study, we analysed such a small Sindhi settlement in the Thane district in Maharashtra of West coast India using genome-wide autosomal SNP data from 13 healthy Sindhi individuals using both frequency- and haplotype-based approaches.</p><p><strong>Results: </strong>Our analyses suggest that the West coast Indian Sindhi community is very unique and has significant population affinity with a group more closely related to the Pakistani Burusho than to the Pakistani Sindhi, as it has an additional East/Southeast Asian component. Furthermore, the sharing of haplotypes and Identity by Descent (IBD) suggests recent gene flow from the local Konkani population on the west coast of India into Indian Sindhi. Admixture modelling suggested that Indian Sindhi admixture with the East/Southeast Asian source group could be 40-50 generations before present (GBP), explaining their current unique demographics. However, apart from this additional admixture, they share the basic genetic composition of the Pakistan/Northwest Indian groups, as reflected in Principal Component Analysis (PCA), outgroup F3 and IBD sharing.</p><p><strong>Conclusion: </strong>Our new findings suggest that Indian Sindhi settlement from the Thane in Maharashtra in West coast of India derive their genetic ancestry not directly from Pakistani Sindhis but from other groups related to Burusho in Pakistan. The study therefore encourages further research to identify the heterogeneous nature of migrations to the Indian subcontinent and thus further decipher its unique demographics.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"111"},"PeriodicalIF":4.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Significance of GNAS mutations for morbid obesity in children.","authors":"Ramil R Salakhov, Rita I Khusainova, Olga V Vasyukova, Daria A Kopytina, Bulat I Yalaev, Yulia S Karpova, Pavel L Okorokov, Valentina A Peterkova, Ildar R Minniakhmetov, Natalia G Mokrysheva","doi":"10.1186/s40246-025-00781-2","DOIUrl":"10.1186/s40246-025-00781-2","url":null,"abstract":"<p><strong>Background: </strong>Hereditary forms of obesity are characterized by early severe heterogeneous manifestations of the phenotype along with a rapid progression to morbid obesity, primary due to pathogenic variants of certain genes. Most forms are characterized by moderate to severe neuropsychic developmental delays, dysmorphic features and organ-specific developmental anomalies.</p><p><strong>Result: </strong>We searched for hereditary causes of morbid obesity in children by exome sequencing. As a result, we have identified 5 variants in the GNAS locus, two of which were identified for the first time: NM_000516.7(GNAS):c.201del, (p.Phe68Leufs*32) and NM_000516.7(GNAS):c.586 - 18_591del. Children showed tolerance to parathyroid hormone and thyroid-stimulating hormone. It has been observed that almost all the children with frameshift variants or nonsense mutations presented with subcutaneous ossifications.</p><p><strong>Conclusions: </strong>The search for variants in a group of patients with morbid obesity, as conducted in our research, reaffirms the need for use molecular genetic testing to determine the main diagnosis and facilitate early detection of the disease. This is particularly relevant given the wide clinical variability of monogenic forms of obesity.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"108"},"PeriodicalIF":4.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-order single-nucleotide polymorphism interactions between selected anti-oxidant and protease genes influence North Indians' propensity for chronic obstructive pulmonary disease (COPD) and lung function parameters.","authors":"Heena Kansal, Vishal Chopra, Kranti Garg, Siddharth Sharma","doi":"10.1186/s40246-025-00821-x","DOIUrl":"10.1186/s40246-025-00821-x","url":null,"abstract":"<p><strong>Background: </strong>COPD causes persistent airflow restriction, oxidative stress, and inflammation. Proteins like MMP9, MMP12, and ADAM33, and antioxidant enzymes such as Glutathione Peroxidase, Superoxide Dismutase, and Catalase are crucial for lung homeostasis, and imbalances increase COPD risk.</p><p><strong>Methods: </strong>A case-control study was carried out with 500 healthy controls and 500 COPD patients. We did genotype on several SNPs in CAT, SOD1, SOD2, GPx, MMP9, MMP12, and ADAM33, and further MDR, CART, and logistic regression models were applied to examine gene-gene interactions, pulmonary function tests, and clinical symptoms.</p><p><strong>Results: </strong>SNPs associated with higher COPD risk were SOD2 rs4880, CAT rs1001179, MMP9 rs17576, and ADAM33 rs612709. High-order combinations like SOD2 rs4880 and ADAM33 rs612709 (AOR = 1.44, p = 0.0001) and CAT rs1001179 and ADAM33 rs2280091 (AOR = 1.4, p = 0.0009) showed combinatorial effects. The risk of mucus was greatly lowered by numerous SOD2-based combinations, such as ADAM33 rs2280091, MMP9 rs17576, and MMP12 rs2276109. FEV1, FVC, and FEV1/FVC revealed genotype-specific disparities before and after bronchodilator usage. Combinations of SOD2 rs4880, ADAM33 rs612709, and MMP9 rs3918242 changed bronchodilator responses. MDR study exhibited that CAT (rs7943316) was the best single-locus model for risk prediction towards COPD patients. CART analysis showed SOD2 (rs4880) to be a disease risk factor.</p><p><strong>Conclusion: </strong>This study is the first to show high-order interactions between selected antioxidant and protease gene variations affecting COPD risk and lung function, specifically SOD2 rs4880, CAT rs1001179, and ADAM33 rs612709. The findings support the potential use of combinatorial genetic profiles in risk stratification and personalized therapeutic strategies for COPD.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"109"},"PeriodicalIF":4.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploiting similarity in drug molecular effects for drug repurposing.","authors":"Katie Huang, Panagiotis Nikolaos Lalagkas, Beftu Sultan, Rachel Melamed","doi":"10.1186/s40246-025-00808-8","DOIUrl":"10.1186/s40246-025-00808-8","url":null,"abstract":"<p><strong>Background: </strong>Using large data to propose new uses of drugs has potential to rapidly prioritize new treatments for major diseases of public health importance. One comprehensive data set, LINCS L1000 Connectivity Map, profiles gene expression associated with thousands of compounds, including many with known clinical uses. But, some recent studies have questioned the reliability of this data, and the best approach to use this resource for drug repositioning is not well established.</p><p><strong>Methods: </strong>Here, we develop a novel generalizable approach by hypothesizing that new treatments for a disease should induce similar gene expression to existing treatments for a disease. Using the Drug Repurposing Hub compendium of known treatments, we formulate a combined logistic regression model to predict new drug indications, and we assess generalizability of our findings using independent clinical trials on experimental drug uses.</p><p><strong>Results: </strong>We support the hypothesis that drugs sharing an indication induce more similar gene expression, additionally demonstrating that the simpler Spearman correlation (p = 7.71e-38), outperforms the popular Connectivity Score (p = 5.2e-6). Our final model, combining predicted drug indications across three diverse cell lines, generalizes to predict experimental clinical trials with AUC of 0.708.</p><p><strong>Conclusions: </strong>By developing a new approach to using LINCS L1000 data for drug repositioning, we both propose plausible new disease treatments and provide an interpretable rationale for predictions. Our findings not only put forward new drug repositioning candidates, browseable at https://bsultan.shinyapps.io/web-app , but they also provide guidelines for future researchers employing L1000 data for drug repurposing.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"19 1","pages":"110"},"PeriodicalIF":4.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}