Human molecular genetics最新文献

{"title":"The p.(Leu97Ile) variant expands the genetic landscape of NEFL-associated Charcot-Marie-tooth neuropathies.","authors":"Menekse Oeztuerk, Sara Walli, David Muhmann, Catherine Choueiri, Vera Dobelmann, Angela Abicht, Barbara Leube, Ulrike Schara-Schmidt, Sven G Meuth, Rita Horvath, Hanns Lochmueller, Andreas Roos, Tobias Ruck","doi":"10.1093/hmg/ddag028","DOIUrl":"https://doi.org/10.1093/hmg/ddag028","url":null,"abstract":"<p><strong>Introduction: </strong>Charcot Marie Tooth neuropathies arise from diverse genetic disturbances that impair axonal structure or myelin integrity. Variants in NEFL, encoding the light chain of neurofilaments, represent a rare cause of CMT and may disrupt filament assembly, axonal transport, and cytoskeletal stability. Because NEFL variants are uncommon and phenotypes variable, the pathogenic relevance of individual substitutions is often difficult to determine. Here, we identified a previously unreported missense variant, p.(Leu97Ile), in three affected individuals. In two, a second variant, p.(Arg206Ser), was present in cis. We therefore aimed to investigate the pathogenic impact of this allele constellation using clinical, biochemical, and structural approaches.</p><p><strong>Methods: </strong>Neurological examination, CMTNS scoring, and electrophysiological studies were performed. Exome sequencing established the genotype. Variant effects were assessed using serum biomarkers, in silico modelling and quantitative immunofluorescence of patient-derived fibroblasts.</p><p><strong>Results: </strong>Patients showed differing clinical presentations, including moderate adult-onset neuropathy to severe early-onset disease and neuromuscular abnormalities in childhood. Neurophysiology revealed mixed features, and conduction slowing in the child supported classification within the CMT1F spectrum. All carriers exhibited elevated serum NfL; CK was increased in the adult patients. Descriptive biomarker differences between the patients were observed for GDF15, FGF21, Periaxin, and NCAM1. Fibroblasts displayed increased cytoplasmic NfL without altered nuclear metrics. Structural modelling predicted destabilizing effects of both substitutions, with the cis combination producing the strongest deviation.</p><p><strong>Discussion: </strong>Integrated clinical, biochemical, and structural evidence support pathogenicity of p.(Leu97Ile) and suggest that p.(Arg206Ser) in cis augments its biological impact. These findings expand the genetic and phenotypic spectrum of NEFL-associated CMT1F.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13100818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic vitamin B6 deficiency exacerbates alcohol behavioral responses, metabolism, and toxicity in Drosophila.","authors":"Benjamin Wang, Wenqin Fu, Atsushi Ueda, Hardik Shah, Chun-Fang Wu, Wanhao Chi, Xiaoxi Zhuang","doi":"10.1093/hmg/ddag032","DOIUrl":"https://doi.org/10.1093/hmg/ddag032","url":null,"abstract":"<p><p>Alcohol abuse is a leading cause of preventable deaths. Alcohol affects brain function and metabolism, including GABA transmission and vitamin B6 (VB6) levels. VB6 is a cofactor for GABA synthesis and degradation; however, the interaction between VB6 deficiency and alcohol consumption remains unknown. We utilized dietary VB6 manipulations and Drosophila models with mutations in pyridox(am)ine-5'-phosphate oxidase (PNPO), a key enzyme in converting dietary VB6 to active VB6, to examine this. Our findings demonstrate that PNPO deficiency reduces alcohol aversion and increases alcohol consumption, whereas alcohol consumption worsens VB6 deficiency, suggesting a vicious cycle. Biochemically, PNPO deficiency and alcohol exposure converge on amino acid metabolism, altering levels of inhibitory neurotransmitters GABA and glycine. Moreover, PNPO deficiency and alcohol exposure synergistically lead to lethality, which can be rescued by low dose but not high dose VB6 supplementation. These results highlight the significance of VB6 in public health, especially in alcohol use and alcohol toxicity.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13100819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic insights into pulmonary nodules and lung cancer: similarities and differences revealed by GWAS studies.","authors":"Jiahao Zhang, Chen Zhu, Qiao Li, Ci Song, Meng Zhu, Chen Ji, Lili Wu, Lingying Zhu, Jing Lu, Qun Zhang, Feiyun Wu, Chen Jin, Yuanlin Mou, Mingxuan Zhu, Jiaying Cai, Caochen Zhang, Yating Fu, Linnan Gong, Dong Hang, Juncheng Dai, Yue Jiang, Lei Shi, Guangfu Jin, Zhibin Hu, Hongbing Shen, Lingbin Du, Hongxia Ma","doi":"10.1093/hmg/ddag030","DOIUrl":"https://doi.org/10.1093/hmg/ddag030","url":null,"abstract":"<p><p>The widespread implementation of low-dose computed tomography (LDCT) has markedly increased the detection of pulmonary nodules, yet their genetic determinants remain poorly understood. We conducted a genome-wide association study (GWAS) of 36 175 LDCT-screened individuals from Zhejiang and Jiangsu provinces in China, assessing fourteen pulmonary nodule phenotypes defined using a convolutional neural network-based computer-aided detection (CNN-CAD) system. We identified eleven independent single-nucleotide polymorphisms (SNPs) at nine loci associated with nodule phenotypes. Functional annotation prioritized six candidate genes with either missense variants or strong colocalization evidence, including TP63 at 3q28, PLA2G4F at 15q15.1, HLA-DRB6 and CYP21A2 at 6p21.32, TNFSF11 at 13q14.11, and TNFRSF11B at 8q24.12. These genes were enriched in pathways related to cell adhesion, chemotaxis, cytokine activity, and lymphocyte activation. Several of the identified variants-associated with non-solid components, nodule size, and the number of positive nodules-were also significantly associated with increased malignancy probability of pulmonary nodules. Genetic correlation analysis revealed a substantial shared genetic basis between purely ground-glass nodules (pGGNs) and lung adenocarcinoma (LUAD) (rg = 0.79; 95% CI, 0.16-1.42; P = 0.014), and Mendelian randomization (MR) further supported a potential causal relationship, with an odds ratio (OR) of 51.1 (95% CI: 1.13-2035.31). These findings offer novel insights into the genetic architecture of pulmonary nodules and highlight a substantial genetic overlap between pGGNs and LUAD, which may inform risk prediction and precision prevention in lung cancer screening.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147698494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combining polygenic risk scores to understand genetic liability to physical-mental health multimorbidity in UK Biobank.","authors":"Daniel Stow, Ruby S M Tsang, Ioanna K Katzourou, Jack F G Underwood, Peter Holmans, Inês Barroso, Hilary Martin, Marianne B M van den Bree, Sarah Finer, Nicholas J Timpson","doi":"10.1093/hmg/ddag012","DOIUrl":"https://doi.org/10.1093/hmg/ddag012","url":null,"abstract":"<p><strong>Background: </strong>Multimorbidity, also known as multiple long-term conditions, is a major public health concern. Internalising and CardioMetabolic MultiMorbidity (ICM-MM) is a common form of mental-physical health multimorbidity, yet its genetic predisposition is largely unknown. We examined the polygenic nature of ICM-MM by assessing single trait-specific polygenic risk scores (PRSTRAIT) and whether combining them could increase the proportion of variance in liability to ICM-MM explained by genetic variation.</p><p><strong>Methods: </strong>We developed PRSTRAIT using PRS-CS and summary statistics from the largest trait-specific GWAS excluding UK Biobank (UKB). We evaluated PRSTRAIT on ICM-MM risk in 206 452 UKB participants (n = 39 311 (19.0%) with ICM-MM) using logistic regression adjusted for gender and 10 genetic principal components, defining ICM-MM as lifetime occurrence of: ≥1 internalising (depression, anxiety, somatoform disorder) traits AND ≥ 1 cardiometabolic traits (type 2 diabetes, obesity, hypertension, dyslipidemia, chronic kidney disease). We used elastic net regression in a 50% training sample to generate ICM-MM-PRSTRAIT: a weighted combination of PRSTRAIT targeting ICM-MM.</p><p><strong>Results: </strong>The strongest associations were between ICM-MM and PRSTRAIT for depression and type 2 diabetes-both odds ratios (OR) 1.18, [95% confidence interval (CI) 1.17-1.20] per standard deviation increase in PRSTRAIT. ICM-MM-PRSTRAIT retained five PRSTRAIT, with stronger associations (OR = 1.31, [95%CI 1.29-1.34]) than any PRSTRAIT in the testing sample.</p><p><strong>Discussion: </strong>Combining several PRS explains more variance in ICM-MM liability than single-trait PRSs alone. ICM-MM-PRSTRAIT is a measure of genetic risk that could be used to examine premorbid stages of ICM-MM in external and youth cohorts, supporting awareness of earlier presentation and potentially avoidance or intervention.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13116345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rats lacking emerin develop muscle pathologies and molecular alterations found in humans with X-linked EDMD.","authors":"Mikayla C Lopes, Mary Flordelys Avila, Arvin Soepriatna, Cora C Hart, Thomas Taetzsch, Kareen Coulombe, David W Hammers, Gregorio Valdez","doi":"10.1093/hmg/ddag029","DOIUrl":"10.1093/hmg/ddag029","url":null,"abstract":"<p><p>Emery-Dreifuss Muscular Dystrophy (EDMD) is a progressive disease characterized by cardiac and skeletal muscle dysfunction. A primary cause of EDMD is loss of function of the X-chromosome gene emerin (EMD). Although emerin mutations were discovered over three decades ago, X-linked EDMD (X-EDMD) remains understudied largely due to the absence of an animal model with pathological features found in humans. Here, we show that rats lacking emerin (EMD(-/y)) develop motor issues and suddenly die, a major risk factor for patients with X-EDMD. Additionally, EMD(-/y) rats present with other hallmarks of X-EDMD. We found significant fibrosis, abnormal nuclear morphologies, functional deficits and left ventricular wall thinning in the heart of EMD(-/y) rats. Skeletal muscles of EMD(-/y) rats also exhibit altered myonuclei morphology in addition to reduced muscle fiber size. In both cardiac and skeletal muscles of EMD(-/y) rats, we identified altered expression of genes with roles in the cytoskeleton, fibrosis, and muscle contraction. Some of these genes have been previously found to be dysregulated in human muscles lacking emerin. Altogether, these findings identify EMD(-/y) rats as a preclinical model of X-EDMD that phenocopies many aspects of the disease in humans. This work also revealed genes that could potentially be used as biomarkers and targets to treat X-EDMD.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13097028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147698508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MeCP2 NID interaction with RNA: implications for Rett syndrome-relevant protein regulation.","authors":"Katrina V Good, Hilmar Strickfaden, Tahir Muhammad, John B Vincent, Michael Hendzel, Christopher J Nelson, Juan Ausió","doi":"10.1093/hmg/ddag031","DOIUrl":"10.1093/hmg/ddag031","url":null,"abstract":"<p><p>Mutations in the X-linked MECP2 gene cause the progressive neurodevelopmental disorder Rett syndrome. Pathogenic missense mutation hotspots exist in the protein's Methyl DNA binding Domain (MBD), and the Nuclear receptor Co-Repressor (NCoR) Interaction Domain (NID), indicating these regions as critical for MeCP2 function. The NID binds to a co-repressor complex allowing transcriptional repression at target genes. A putative RNA Binding Domain (RBD) was identified that overlaps with the NID, yet the role that RNA interaction plays in MeCP2 function remains underexplored. Using cell-based and in vitro molecular assays, we validated RNA interaction at the NID/RBD of MeCP2 both to a dsRNA probe in vitro and to the lncRNA NEAT1_2 in cells. As expected, this region did not appear to affect MeCP2-chromatin interactions; however, we found that RNA-RBD interaction precludes MeCP2-NCoR binding in cells. Taken together, we find that RNA interaction at this non-canonical RNA binding domain regulates important MeCP2-protein interactions and therefore may be a key part of the pathophysiology of Rett syndrome.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13125762/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging academic medical biobanks for recall-by-genotype deep phenotyping studies.","authors":"Yi-An Ko, Giselle Fisher, Eleonora Scorletti, Nawar Naseer, Steven C Jones, Jenna Dever, Naman Srivastava, Giorgio Sirugo, Marylyn D Ritchie, Daniel J Rader","doi":"10.1093/hmg/ddaf162","DOIUrl":"https://doi.org/10.1093/hmg/ddaf162","url":null,"abstract":"<p><p>Biobanks have redefined how we study complex diseases, integrating genomic and phenotype data on an unprecedented scale. Population-based biobanks like the UK Biobank have provided powerful tools for epidemiology and polygenic risk stratification, while academic medical biobanks, enriched for advanced and rare diseases, leverage longitudinal electronic health records and deep phenotyping to uncover novel insights into disease mechanisms. A pivotal innovation in this space is the recall-by-genotype (RbG) study design, where individuals are recruited based on genetic variants of interest for detailed (deep) phenotypic investigation. This genome-first approach has enabled groundbreaking studies, from identifying genetic modifiers of rare conditions to leveraging polygenic risk scores for precision medicine. These studies demonstrate the potential of the RbG design to bridge genotype-phenotype relationships and drive biomedical discovery. However, most biobank studies remain underpowered in diverse populations, limiting the research and applicability of these findings. Expanding diversity in biobank datasets is not just a challenge but also an opportunity to make genomic advances equitable and impactful for all. Here, we review the transformative role of RbG studies, explore their application in academic medical biobanks, and discuss their potential to advance the frontier of precision medicine.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147591696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modification of internal RNA domains from the long non-coding RNA XIST refines roles in silencing and heterochromatin recruitment.","authors":"Maria Jose Navarro-Cobos, Bronwyn J Posynick, Christine Yang, Carolyn J Brown","doi":"10.1093/hmg/ddag022","DOIUrl":"10.1093/hmg/ddag022","url":null,"abstract":"<p><p>XIST is a paradigmatic long non-coding RNA required for the initiation of the epigenetic silencing of X chromosomes, leading to dosage compensation in mammalian females. XIST includes tandem repeat domains (A-F) that serve as binding platforms for protein complexes involved in silencing, localization, and heterochromatinization of the inactive X chromosome. XIST/Xist transgenes can silence autosomes as well as the X in both early development and somatic cells. In our quest to create a minimal but highly functional XIST transgene, we have tested both removal of non-repeat regions of XIST and duplication of repeat regions previously established as critical for XIST function. Targeting inducible XIST transgenes to an autosomal FRT site in somatic cells allows us to compare the activity of induced constructs on silencing and chromatin recruitment. We have previously identified that the CCC-dense mouse polycomb-interaction domain (PID) could restore functionality to a minimal human XIST construct lacking the B and D repeats. We now demonstrate that the density of the CCC motifs is not the sole contributor to PID functionality in the human transgene. Surprisingly, a duplication of repeat A reduces the expression from the exogenous promoter, as does removal of the region around the F repeats including six YY1 binding sites. In this context of an inducible XIST in somatic cells the internal small exons were not required; however, duplication of the E repeat region augmented functionality. Overall, the strongest correlations we observed across our diverse set of constructs were between chromatin deposition and silencing.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revisiting low penetrance retinoblastoma: an integrated clinical, genetic, and bioinformatic analysis.","authors":"Eden Avnat, Guy Shapira, Yael Lustig, Jonathan Citrin, Duangnate Rojanaporn, Rossukon Kaewkhaw, Dong Hyun Jo, Jeong Hun Kim, Noam Shomron, Eitan Friedman, Ido Didi Fabian","doi":"10.1093/hmg/ddag026","DOIUrl":"10.1093/hmg/ddag026","url":null,"abstract":"<p><p>Retinoblastoma (RB) is typically associated with highly penetrant pathogenic sequence variants (PSVs) in the RB1 gene; however, some families exhibit low penetrance RB (LPRB). We aimed to determine the penetrance rate and identify genetic and clinical characteristics of LPRB. To that end two cohorts were analyzed: 250 genetically confirmed LPRB cases identified through systematic literature review and 78 classical germline RB (CGRB) from three international centers- Thailand, Korea, and Israel. Penetrance rate was estimated as the proportion of affected individuals among RB1 PSV carriers. Multivariate models assessed parent-of-origin effects and predictors of penetrance. PSVs were annotated with Combined Annotation Dependent Depletion (CADD) scores and mapped to pRB structural domains. LPRB penetrance ranged from 50% (125/250, non-age-adjusted, CI [43.8%-56.2%]) to 64% (125/196, age-adjusted, CI [56.8%-70.2%]). Paternal inheritance of RB1 PSV was associated with a significantly increased risk of LPRB in offspring (OR = 6.24; P < 0.0001). Clinically, LPRB were significantly more likely than CGRB to present with unilateral disease (OR = 9.3, P < 0.0001), diagnosed at an older age (13 Vs 6.5 months, P = 0.01), and affect males (OR = 2.4, P = 0.03). LPRB-associated PSVs showed lower CADD scores (OR = 1.5; P = 0.0008), indicating lower predicted pathogenicity, and were enriched in pRB's N- or C-terminal domains (OR = 3.2; P = 0.007), consistent with hypomorphic effects. In conclusion, LPRB shows a 50-64% penetrance rate, more likely to be paternally inherited, have unilateral presentation, and associated with hypomorphic RB1 PSVs in the terminal pRB regions. These findings support retitling 'low penetrance RB' to 'medium penetrance RB'.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13050150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147618420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional mechanisms of sex-biased gene expression and their connections to disease-associated variation.","authors":"Angela G Jones, Trisha Dalapati, Guinevere G Connelly, Liuyang Wang, Benjamin H Schott, Adrianna K San Roman, Dennis C Ko","doi":"10.1093/hmg/ddag019","DOIUrl":"10.1093/hmg/ddag019","url":null,"abstract":"<p><p>Humans display sexual dimorphism across many traits, but little is known about underlying genetic mechanisms and impacts on disease. We utilized single-cell RNA-seq of 480 lymphoblastoid cell lines (LCLs) to identify 1200 genes with significantly sex-biased expression. While reproducibility was highest among LCL datasets, 71% were found to be sex-biased in at least one GTEx tissue, with a core dataset of 21 genes displaying sex-biased expression across all datasets and tissues examined. While 7.7% of sex-biased genes can be directly explained by differences in the number of sex chromosomes, most sex-biased genes (79%) are targets of transcription factors that display sex-biased expression. FOSL1, ZNF730, ZFX, and ZNF726 appear to make the largest contribution to this based on machine learning and linear modeling approaches, and all four of these transcription factors are regulated by the number of X chromosomes. Further, by testing the difference in genetic effect size (β) of conditionally independent expression quantitative trait loci (eQTL) identified in each sex separately, we identified 2390 sex-biased eQTL (sb-eQTL) across the genome, but evidence of replication in an independent dataset was modest. However, permutation analysis demonstrated that sb-eQTL identified using real sex was more likely to have concordant direction of effect. Further exploratory analysis revealed that these sb-eQTL are enriched in over 100 GWAS phenotypes, including many loci associated with female-biased autoimmune diseases such as multiple sclerosis. Our results demonstrate widespread genetic impacts on sexual dimorphism and identify possible mechanisms and clinical targets for sex differences in diverse diseases.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13050152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147618611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}