HGG Advances最新文献

{"title":"Multiple molecular diagnoses identified through genome sequencing in individuals with suspected rare disease.","authors":"Alka Malhotra, Erin Thorpe, Alison J Coffey, Revathi Rajkumar, Josephine Adjeman, Naomi Dianne Naa Adjeley Adjetey, Sharron Aglobitse, Felix Allotey, Todor Arsov, Joyce Ashong, Ebenezer Vincent Badoe, Donald Basel, Yvonne Brew, Chester Brown, Kerri Bosfield, Kari Casas, Mario Cornejo-Olivas, Laura Davis-Keppen, Abbey Freed, Kate Gibson, Parul Jayakar, Marilyn C Jones, Martina Kawome, Aimé Lumaka, Ursula Maier, Prince Makay, Gioconda Manassero, Marilyn Marbell-Wilson, Charles Marcuccilli, Diane Masser-Frye, Julie McCarrier, Hannah-Sharon Mills, Jeny Balazar Montoya, Gerrye Mubungu, Mamy Ngole, Jorge Perez, Eniko Pivnick, Milagros M Duenas Roque, Hildegard Pena Salguero, Arturo Serize, Marwan Shinawi, Fabio Sirchia, Claudia Soler-Alfonso, Alan Taylor, Lauren Thompson, Gail Vance, Adeline Vanderver, Keith Vaux, Danita Velasco, Samuel Wiafe, Ryan J Taft, Denise L Perry, Akanchha Kesari","doi":"10.1016/j.xhgg.2025.100430","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100430","url":null,"abstract":"<p><p>Genome sequencing is a powerful and comprehensive test that detects multiple variants of different types. The interrogation of variants across the genome enables the identification of multiple molecular diagnoses (MMDs) in a single individual. In this retrospective study, we describe individuals in whom MMDs were associated with the proband's indication for testing (IFT), secondary findings, or incidental findings. An MMD is considered where at least one of the findings is associated with the primary IFT and all variants are classified as either likely pathogenic or pathogenic. Clinical genome sequencing was performed for all individuals as part of the iHope program at the Illumina Laboratory Services between September 2017-December 2023. The iHope cohort included 1846 affected individuals with 872 (47.2%) found to have at least one likely pathogenic or pathogenic variant associated with the primary IFT. Of these, 81 (9.3%) individuals had multiple clinically significant molecular findings, including 76 individuals with reported variants associated with two different conditions, and five individuals with more than two molecular findings. Thirty-two individuals (3.7%) had at least two molecular diagnoses related to the primary IFT, while in 49 (5.6%) individuals, the variant(s) reported for the second condition constituted a secondary or incidental finding. Our study highlights that among individuals with a likely pathogenic or pathogenic finding identified through genome sequencing, nine percent have MMDs, which may have been missed with different testing methods. Of note, approximately 60% of the 81 individuals with an MMD had a potentially actionable secondary or incidental finding.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100430"},"PeriodicalIF":3.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4.","authors":"Audrey Winkelsas, Athena Apfel, Brian Johnson, George Harmison, Kimberly Diaz Perez, Dongjun Li, Vivian G Cheung, Christopher Grunseich","doi":"10.1016/j.xhgg.2025.100435","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100435","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis 4 (ALS4) is an autosomal dominant motor neuron disease that is molecularly characterized by reduced R-loop levels and caused by pathogenic variants in senataxin (SETX). SETX encodes an RNA/DNA helicase that resolves three-stranded nucleic acid structures called R-loops. Currently, there are no disease-modifying therapies available for ALS4. Given that SETX is haplosufficient, removing the product of the mutated allele presents a potential therapeutic strategy. We designed a series of siRNAs to selectively target the RNA transcript from the ALS4 allele containing the c.1166T>C mutation (p.Leu389Ser). Transfection of HEK293 cells with siRNA and plasmids encoding either wild-type or mutant (Leu389Ser) epitope-tagged SETX revealed that three siRNAs specifically reduced mutant SETX protein levels while having minimal effect on the wild-type SETX protein. In ALS4 primary fibroblasts, siRNA treatment silenced the endogenous mutant SETX allele, while sparing the wild-type allele, and restored R-loop levels in patient cells. Our findings demonstrate that mutant SETX, differing from wild-type by a single nucleotide, can be effectively and specifically silenced by RNA interference.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100435"},"PeriodicalIF":3.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Severe Joubert syndrome in family with homozygous POC1B p.Arg106Pro variant is due to a co-inherited deep-intronic mutation in the neighboring CEP290 gene.","authors":"Christian Betz, Björn Reusch, Thomas Langmann, Sandra Habbig, Bodo B Beck, Hanno J Bolz","doi":"10.1016/j.xhgg.2025.100429","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100429","url":null,"abstract":"<p><p>'En bloc' inheritance of point mutations in adjacent genes has rarely been described. We have previously reported a family with severe, mostly early-lethal, Joubert syndrome (JBTS) with early-onset severe retinal dystrophy (EOSRD) and polycystic kidney disease (PKD), which had then been attributed to a homozygous pathogenic missense variant, p.(Arg106Pro), in the ciliary POC1B gene. Because this and other POC1B variants were in subsequent studies only reported in patients with non-syndromic childhood or early-adult-onset macular dystrophy, we now reassessed our index patient by long-read HiFi whole-genome sequencing (LR-WGS). We identified a homozygous deep-intronic variant, c.2818-657T>G, in CEP290, a JBTS/Meckel syndrome-associated gene on chromosome 12q21, only 1.28 Mb from the N-terminus of POC1B. cDNA analysis revealed aberrant splicing with the frame-shifting inclusion of 37 bp from CEP290 intron 25, predicting loss of CEP290 function. EOSRD and PKD can fully be ascribed to this CEP290 variant whose effect outshines the \"background\" non-syndromic POC1B retinopathy and co-segregates with the severe syndromic phenotype. Our novel findings in this family no longer justify POC1B as a JBTS gene. This co-inheritance of two ciliopathies, with the clinically decisive variant hidden deep in an intron, exemplifies the importance of WGS for achieving the complete diagnosis in challenging cases.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100429"},"PeriodicalIF":3.3,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing Polygenic Scores for Cardiometabolic Traits Through Tissue- and Cell Type-Specific Functional Annotations.","authors":"Kristjan Norland, Daniel J Schaid, Iftikhar J Kullo","doi":"10.1016/j.xhgg.2025.100427","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100427","url":null,"abstract":"<p><p>Functional genomic annotations can improve polygenic scores (PGS) within and between genetic ancestry groups. While general annotations are commonly used in PGS development, tissue- and cell type-specific annotations derived from open chromatin and gene expression experiments may further enhance PGS for cardiometabolic traits. We developed PGS for 14 cardiometabolic traits in the UK Biobank using SBayesRC. We integrated GWAS summary statistics from FinnGen and GLGC with three annotation sources: i) baseline-LD model v2.2 (general annotations), ii) cell type-specific snATAC-seq peaks, and iii) tissue-specific eQTLs/sQTLs. We created PGS using two EUR LD reference panels (1.2M HapMap3 variants and 7M imputed variants). Tissue- and cell type-specific annotations showed stronger heritability enrichment than baseline-LD annotations on average, particularly coronary snATAC-seq peaks and fine-mapped eQTLs. Without annotations, HapMap3 and 7M variant PGS performed similarly. However, with all annotations, 7M variant PGS outperformed HapMap3 variant PGS (8% average increase in relative performance in EUR). Compared to using no annotations, modeling baseline-LD annotations improved performance by 5% for HapMap3 and 11% for 7M variant PGS, while modeling all annotations yielded improvements of 5% and 13%, respectively. Although annotations provided greater relative improvement for cross-ancestry prediction, they did not decrease the disparity in PGS performance between genetic ancestry groups. Functional annotations improved PGS for cardiometabolic traits. Despite strong heritability enrichment, tissue- and cell type-specific snATAC-seq and eQTL annotations provided marginal performance gains beyond general genomic annotations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100427"},"PeriodicalIF":3.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncovering the genetic architecture and evolutionary roots of androgenetic alopecia in African men.","authors":"Rohini Janivara, Ujani Hazra, Aaron Pfennig, Maxine Harlemon, Michelle S Kim, Muthukrishnan Eaaswarkhanth, Wenlong C Chen, Adebola Ogunbiyi, Paidamoyo Kachambwa, Lindsay N Petersen, Mohamed Jalloh, James E Mensah, Andrew A Adjei, Ben Adusei, Maureen Joffe, Serigne M Gueye, Oseremen I Aisuodionoe-Shadrach, Pedro W Fernandez, Thomas E Rohan, Caroline Andrews, Timothy R Rebbeck, Akindele O Adebiyi, Ilir Agalliu, Joseph Lachance","doi":"10.1016/j.xhgg.2025.100428","DOIUrl":"10.1016/j.xhgg.2025.100428","url":null,"abstract":"<p><p>Androgenetic alopecia is a highly heritable trait. However, much of our understanding about the genetics of male-pattern baldness comes from individuals of European descent. Here, we examined a dataset comprising 2,136 men from Ghana, Nigeria, Senegal, and South Africa that were genotyped using the Men of African Descent and Carcinoma of the Prostate Array. We first tested how genetic predictions of baldness generalize from Europe to Africa and found that polygenic scores from European genome-wide association studies (GWASs) yielded area under the curve statistics that ranged from 0.513 to 0.546, indicating that genetic predictions of baldness generalized poorly from European to African populations. Subsequently, we conducted an African GWAS of androgenetic alopecia, focusing on self-reported baldness patterns at age 45. After correcting for age at recruitment, population structure, and study site, we identified 266 moderately significant associations, 51 of which were independent (p < 10^-5, r² < 0.2). Most baldness associations were autosomal, and the X chromosome does not seem to have a large impact on baldness in African men. Although Neanderthal alleles have previously been associated with skin and hair phenotypes, within the limits of statistical power, we did not find evidence that continental differences in the genetic architecture of baldness are due to Neanderthal introgression. While most loci that are associated with androgenetic alopecia do not have large integrative haplotype scores or fixation index statistics, multiple baldness-associated SNPs near the EDA2R and AR genes have large allele frequency differences between continents. Collectively, our findings illustrate how population genetic differences contribute to the limited portability of polygenic predictions across ancestries.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100428"},"PeriodicalIF":3.3,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of de novo variants in KCTD10 as a proposed cause for multiple congenital anomalies.","authors":"Michelle M Morrow, Erin Torti, Bobbi McGivern, Ryan Gates, Mir Reza Bekheirnia, Nasim Bekheirnia, Leandra Folk, Shannon Holtrop, Timothy Blake Palculict, Olivia L Redlich, Adi Reich, Maria J Guillen Sacoto, Lisong Shi, Ingrid M Wentzensen, Kirsty McWalter","doi":"10.1016/j.xhgg.2025.100426","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100426","url":null,"abstract":"<p><p>To date, the KCTD10 gene (MIM# 608726) has not been definitively associated with a human disease, although studies in animal models suggest that it plays a role in embryonic development. We have identified multiple unrelated individuals with de novo missense variants and overlapping phenotypes including congenital heart anomalies and congenital anomalies in other organ systems in our internal database. This report includes a detailed description of the genotype and phenotype for two consented individuals and aggregate data of additional individuals who were not available for case-specific publication. Based on the data presented here, we propose that damaging de novo missense KCTD10 variants are associated with an autosomal dominant phenotype including cardiac and other congenital anomalies. We encourage additional studies to further characterize this condition and identify a mechanism for disease.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100426"},"PeriodicalIF":3.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143693620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteasomal activation ameliorates neuronal phenotypes linked to FBXO11-deficiency.","authors":"Anne Gregor, Laila Distel, Arif B Ekici, Philipp Kirchner, Steffen Uebe, Mandy Krumbiegel, Soeren Turan, Beate Winner, Christiane Zweier","doi":"10.1016/j.xhgg.2025.100425","DOIUrl":"10.1016/j.xhgg.2025.100425","url":null,"abstract":"<p><p>Haploinsufficiency of FBXO11, encoding a ubiquitin ligase complex subunit, is associated with a variable neurodevelopmental disorder. So far, the underlying nervous system-related pathomechanisms are poorly understood, and specific therapies are lacking. Using a combined approach, we established an FBXO11-deficient human stem cell-based neuronal model using CRISPR-Cas9 and a Drosophila model using tissue-specific knockdown techniques. We performed transcriptomic analyses on iPSC-derived neurons and molecular phenotyping in both models. RNA sequencing revealed disrupted transcriptional networks related to processes important for neuronal development, such as differentiation, migration, and cell signaling. Consistently, we found that loss of FBXO11 leads to neuronal phenotypes such as impaired neuronal migration and abnormal proliferation/differentiation balance in human cultured neurons and impaired dendritic development and behavior in Drosophila. Interestingly, application of three different proteasome-activating substances could alleviate FBXO11-deficiency-associated phenotypes in both human neurons and flies. One of these substances is the long-approved drug Verapamil, opening the possibility of drug repurposing in the future. Our study shows the importance of FBXO11 for neurodevelopment and highlights the reversibility of related phenotypes, opening an avenue for potential development of therapeutic approaches through drug repurposing.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100425"},"PeriodicalIF":3.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using genetics, genomics, and transcriptomics to identify therapeutic targets in juvenile idiopathic arthritis.","authors":"Evan Tarbell, James N Jarvis","doi":"10.1016/j.xhgg.2025.100424","DOIUrl":"10.1016/j.xhgg.2025.100424","url":null,"abstract":"<p><p>Despite progress in improving outcomes for oligoarticular and polyarticular juvenile idiopathic arthritis (JIA), the field still faces considerable challenges. More than half of adults who have had JIA continue to have active disease and have developed functional limitations. Medication side effects are common and intrusive. Thus, the field continues to search for therapeutic agents that target specific aspects of disease pathobiology and will be accompanied by fewer and less intrusive side effects. We identified 28 candidate target genes that were associated with JIA according to Open Targets Genetics and were also differentially expressed in the CD4+ T cells of children with active JIA (when compared to healthy control subjects). Of the 28 candidates, the strongest new target to emerge was homeodomain-interacting protein kinase 1 (HIPK1), which suppresses T cell activation and is within the PTPN22 locus tagged by rs6679677. This locus includes an enhancer element that contacts the HIPK1 promoter, and HIPK1 shows decreased expression in JIA CD4+ T cells when compared to controls. Gene Ontology terms associated with HIPK1 were overrepresented among the differentially expressed genes between JIA and controls, and PML, a known coregulator of HIPK1, showed a similar suppressed gene expression profile. Two downstream transcription factors of HIPK1, TP53 and GATA4, showed enriched binding patterns near the promoters of JIA up-regulated genes. Taken together, these data suggest a pathogenic role for HIPK1 in JIA and make it a prime candidate for therapeutic modulation.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100424"},"PeriodicalIF":3.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circadian rhythm defects in Prader-Willi syndrome neurons.","authors":"A Kaitlyn Victor, Tayler Hedgecock, Chidambaram Ramanathan, Yang Shen, Andrew C Liu, Lawrence T Reiter","doi":"10.1016/j.xhgg.2025.100423","DOIUrl":"10.1016/j.xhgg.2025.100423","url":null,"abstract":"<p><p>Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by a spectrum of symptoms, including developmental delay, intellectual disability, and increased risk of autism. PWS is an imprinting disorder caused by the loss of paternal expression of critical genes in the 15q11.2-q13 region, including MAGEL2, SNRPN/SNURF, and SNORD116. PWS patients often suffer from various sleep disorders, including sleep-disordered breathing and central hypersomnolence. Mouse models of PWS also exhibit disruptions in circadian rhythms and sleep. In cultured cells, Magel2 was shown to regulate the expression of Bmal1 and Per2, two core clock genes involved in the circadian rhythm regulatory process. Here, we investigated the circadian clock function in neurons derived from dental pulp stem cells (DPSCs) of PWS patients and neurotypical controls. To study the circadian rhythms of PWS patients in vitro, we introduced the Per2 promoter-driven luciferase reporter (Per2:luc) to these DPSC cell lines to assess their circadian rhythm by bioluminescence. These Per2:luc cells were differentiated for 4 weeks to mature neuronal reporter cell lines, followed by kinetic measurements of luciferase activity over several days. We observed significant differences in circadian period length between PWS neurons and controls. Moreover, treatment with the small molecule longdaysin effectively lengthened the period length of PWS neurons with a shorter period length, as anticipated based on the mechanism of action of this compound. This work lays the foundation for a deeper understanding of PWS pathophysiology and represents a critical first step toward developing high-throughput assays for drug discovery targeting circadian and sleep dysfunction in PWS.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100423"},"PeriodicalIF":3.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538057","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":"Transcriptome-wide analyses delineate the genetic architecture of expression variation in atopic dermatitis.","authors":"Charalabos Antonatos, Dimitra Mitsoudi, Alexandros Pontikas, Adam Akritidis, Panagiotis Xiropotamos, Georgios K Georgakilas, Sophia Georgiou, Aikaterini Tsiogka, Stamatis Gregoriou, Katerina Grafanaki, Yiannis Vasilopoulos","doi":"10.1016/j.xhgg.2025.100422","DOIUrl":"10.1016/j.xhgg.2025.100422","url":null,"abstract":"<p><p>Genome-wide association studies (GWASs) for atopic dermatitis (AD) have uncovered 81 risk loci in European participants; however, translating these findings into functional and therapeutic insights remains challenging. We conducted a transcriptome-wide association study (TWAS) in AD leveraging cis-eQTL data from sun exposed (n = 517), non-sun exposed skin (n = 602) and whole blood (n = 670) tissues and the latest GWAS of AD in Europeans (n = 864982). We implemented the OTTERS pipeline that combines polygenic risk score (PRS) techniques accommodating diverse assumptions in the architecture of gene regulation. We also used differential expression meta-analysis and co-expression networks (n = 186) to characterize the transcriptomic landscape of AD. We identified 176 gene-tissue associations covering 126 unique genes (53 previously unreported). Most TWAS risk genes were identified by adaptive PRS frameworks, with non-significant differences compared with clumping and thresholding approaches. TWAS risk genes were enriched in allergic reactions (e.g., AQP7, AFF4), skin barrier integrity (e.g., ACER3), and inflammatory pathways (e.g., TAPBPL). By integrating co-expression networks of lesional AD skin, we identified 16 hub genes previously identified as TWAS risk genes (six previously unreported) that orchestrate inflammatory responses (e.g., HSPA4) and keratinization (e.g., LCE3E, LCE3D), serving as potential drug targets through drug-gene interactions. Consistent associations between all analyses were reported for FOSL1 and RORC. Collectively, our findings provide additional risk genes for AD with potential implications in therapeutic approaches.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100422"},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11937661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524639","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}