American journal of human genetics最新文献

{"title":"A missense variant effect map for the human tumor-suppressor protein CHK2.","authors":"Marinella Gebbia, Daniel Zimmerman, Rosanna Jiang, Maria Nguyen, Jochen Weile, Roujia Li, Michelle Gavac, Nishka Kishore, Song Sun, Rick A Boonen, Rayna Hamilton, Jennifer N Dines, Alexander Wahl, Jason Reuter, Britt Johnson, Douglas M Fowler, Fergus J Couch, Haico van Attikum, Frederick P Roth","doi":"10.1016/j.ajhg.2024.10.013","DOIUrl":"10.1016/j.ajhg.2024.10.013","url":null,"abstract":"<p><p>The tumor suppressor CHEK2 encodes the serine/threonine protein kinase CHK2 which, upon DNA damage, is important for pausing the cell cycle, initiating DNA repair, and inducing apoptosis. CHK2 phosphorylation of the tumor suppressor BRCA1 is also important for mitotic spindle assembly and chromosomal stability. Consistent with its cell-cycle checkpoint role, both germline and somatic variants in CHEK2 have been linked to breast and other cancers. Over 90% of clinical germline CHEK2 missense variants are classified as variants of uncertain significance, complicating diagnosis of CHK2-dependent cancer. We therefore sought to test the functional impact of all possible missense variants in CHK2. Using a scalable multiplexed assay based on the ability of human CHK2 to complement DNA sensitivity of Saccharomyces cerevisiae cells lacking the CHEK2 ortholog, RAD53, we generated a systematic \"missense variant effect map\" for CHEK2 missense variation. The map reflects known biochemical features of CHK2 while offering new biological insights. It also provides strong evidence toward pathogenicity for some clinical missense variants and supporting evidence toward benignity for others. Overall, this comprehensive missense variant effect map contributes to understanding of both known and yet-to-be-observed CHK2 variants.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"111 12","pages":"2675-2692"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3D genome topology distinguishes molecular subgroups of medulloblastoma.","authors":"John J Y Lee, Michael J Johnston, Hamza Farooq, Huey-Miin Chen, Subhi Talal Younes, Raul Suarez, Melissa Zwaig, Nikoleta Juretic, William A Weiss, Jiannis Ragoussis, Nada Jabado, Michael D Taylor, Marco Gallo","doi":"10.1016/j.ajhg.2024.10.003","DOIUrl":"10.1016/j.ajhg.2024.10.003","url":null,"abstract":"<p><p>Four main medulloblastoma (MB) molecular subtypes have been identified based on transcriptional, DNA methylation, and genetic profiles. However, it is currently not known whether 3D genome architecture differs between MB subtypes. To address this question, we performed in situ Hi-C to reconstruct the 3D genome architecture of MB subtypes. In total, we generated Hi-C and matching transcriptome data for 28 surgical specimens and Hi-C data for one patient-derived xenograft. The average resolution of the Hi-C maps was 6,833 bp. Using these data, we found that insulation scores of topologically associating domains (TADs) were effective at distinguishing MB molecular subgroups. TAD insulation score differences between subtypes were globally not associated with differential gene expression, although we identified few exceptions near genes expressed in the lineages of origin of specific MB subtypes. Our study therefore supports the notion that TAD insulation scores can distinguish MB subtypes independently of their transcriptional differences.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2720-2734"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomes and epigenomes of matched normal and tumor breast tissue reveal diverse evolutionary trajectories and tumor-host interactions.","authors":"Bin Zhu, Avraam Tapinos, Hela Koka, Priscilla Ming Yi Lee, Tongwu Zhang, Wei Zhu, Xiaoyu Wang, Alyssa Klein, DongHyuk Lee, Gary M Tse, Koon-Ho Tsang, Cherry Wu, Min Hua, Chad A Highfill, Petra Lenz, Weiyin Zhou, Difei Wang, Wen Luo, Kristine Jones, Amy Hutchinson, Belynda Hicks, Montserrat Garcia-Closas, Stephen Chanock, Lap Ah Tse, David C Wedge, Xiaohong R Yang","doi":"10.1016/j.ajhg.2024.10.005","DOIUrl":"10.1016/j.ajhg.2024.10.005","url":null,"abstract":"<p><p>Normal tissues adjacent to the tumor (NATs) may harbor early breast carcinogenesis events driven by field cancerization. Although previous studies have characterized copy-number (CN) and transcriptomic alterations, the evolutionary history of NATs in breast cancer (BC) remains poorly characterized. Utilizing whole-genome sequencing (WGS), methylation profiling, and RNA sequencing (RNA-seq), we analyzed paired germline, NATs, and tumor samples from 43 individuals with BC in Hong Kong (HK). We found that single-nucleotide variants (SNVs) were common in NATs, with one-third of NAT samples exhibiting SNVs in driver genes, many of which were present in paired tumor samples. The most frequently mutated genes in both tumor and NAT samples were PIK3CA, TP53, GATA3, and AKT1. In contrast, large-scale aberrations such as somatic CN alterations (SCNAs) and structural variants (SVs) were rarely detected in NAT samples. We generated phylogenetic trees to investigate the evolutionary history of paired NAT and tumor samples. They could be categorized into tumor only, shared, and multiple-tree groups, the last of which is concordant with non-genetic field cancerization. These groups exhibited distinct genomic and epigenomic characteristics in both NAT and tumor samples. Specifically, NAT samples in the shared-tree group showed higher number of mutations, while NAT samples belonging to the multiple-tree group showed a less inflammatory tumor microenvironment (TME), characterized by a higher proportion of regulatory T cells (Tregs) and lower presence of CD14 cell populations. In summary, our findings highlight the diverse evolutionary history in BC NAT/tumor pairs and the impact of field cancerization and TME in shaping the genomic evolutionary history of tumors.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2773-2788"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteome-wide Mendelian randomization and functional studies uncover therapeutic targets for polycystic ovarian syndrome.","authors":"Feida Ni, Feixia Wang, Jing Sun, Mixue Tu, Jianpeng Chen, Xiling Shen, Xiaohang Ye, Ruixue Chen, Yifeng Liu, Xiao Sun, Jianhua Chen, Xue Li, Dan Zhang","doi":"10.1016/j.ajhg.2024.10.008","DOIUrl":"10.1016/j.ajhg.2024.10.008","url":null,"abstract":"<p><p>Polycystic ovarian syndrome (PCOS) is an endocrine syndrome that affects a large portion of women worldwide. This proteogenomic and functional study aimed to uncover candidate therapeutic targets for PCOS. We comprehensively investigated the causal association between circulating proteins and PCOS using two-sample Mendelian randomization analysis. Cis-protein quantitative trait loci were derived from six genome-wide association studies (GWASs) on plasma proteome. Genetic associations with PCOS were obtained from a large-scale GWAS meta-analysis, FinnGen cohort, and UK Biobank. Colocalization analyses were performed to prioritize the causal role of candidate proteins. Protein-protein interaction (PPI) and druggability evaluation assessed the druggability of candidate proteins. We evaluated the enrichment of tier 1 and 2 candidate proteins in individuals with PCOS and a mouse model and explored the potential application of the identified drug target. Genetically predicted levels of 65 proteins exhibited associations with PCOS risk, with 30 proteins showing elevated levels and 35 proteins showing decreased levels linked to higher susceptibility. PPI analyses revealed that FSHB, POSTN, CCN2, and CXCL11 interacted with targets of current PCOS medications. Eighty medications targeting 20 proteins showed their potential for repurposing as therapeutic targets for PCOS. EGLN1 levels were elevated in granulosa cells and the plasma of individuals with PCOS and in the plasma and ovaries of dehydroepiandrosterone (DHEA)-induced PCOS mouse model. As an EGLN1 inhibitor, administration of roxadustat in the PCOS mouse model elucidated the EGLN1-HIF1α-ferroptosis axis in inducing PCOS and validated its therapeutic effect in PCOS. Our study identifies candidate proteins causally associated with PCOS risk and suggests that targeting EGLN1 provides a promising treatment strategy.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2799-2813"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toward trustable use of machine learning models of variant effects in the clinic.","authors":"Mafalda Dias, Rose Orenbuch, Debora S Marks, Jonathan Frazer","doi":"10.1016/j.ajhg.2024.10.011","DOIUrl":"10.1016/j.ajhg.2024.10.011","url":null,"abstract":"<p><p>There has been considerable progress in building models to predict the effect of missense substitutions in protein-coding genes, fueled in large part by progress in applying deep learning methods to sequence data. These models have the potential to enable clinical variant annotation on a large scale and hence increase the impact of patient sequencing in guiding diagnosis and treatment. To realize this potential, it is essential to provide reliable assessments of model performance, scope of applicability, and robustness. As a response to this need, the ClinGen Sequence Variant Interpretation Working Group, Pejaver et al., recently proposed a strategy for validation and calibration of in-silico predictions in the context of guidelines for variant annotation. While this work marks an important step forward, the strategy presented still has important limitations. We propose core principles and recommendations to overcome these limitations that can enable both more reliable and more impactful use of variant effect prediction models in the future.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2589-2593"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resolution of ring chromosomes, Robertsonian translocations, and complex structural variants from long-read sequencing and telomere-to-telomere assembly.","authors":"Yulia Mostovoy, Philip M Boone, Yongqing Huang, Kiran V Garimella, Kar-Tong Tan, Bianca E Russell, Monica Salani, Celine E F de Esch, John Lemanski, Benjamin Curall, Jen Hauenstein, Diane Lucente, Tera Bowers, Tim DeSmet, Stacey Gabriel, Cynthia C Morton, Matthew Meyerson, Alex R Hastie, James Gusella, Fabiola Quintero-Rivera, Harrison Brand, Michael E Talkowski","doi":"10.1016/j.ajhg.2024.10.006","DOIUrl":"10.1016/j.ajhg.2024.10.006","url":null,"abstract":"<p><p>Delineation of structural variants (SVs) at sequence resolution in highly repetitive genomic regions has long been intractable. The sequence properties, origins, and functional effects of classes of genomic rearrangements such as ring chromosomes and Robertsonian translocations thus remain unknown. To resolve these complex structures, we leveraged several recent milestones in the field, including (1) the emergence of long-read sequencing, (2) the gapless telomere-to-telomere (T2T) assembly, and (3) a tool (BigClipper) to discover chromosomal rearrangements from long reads. We applied these technologies across 13 cases with ring chromosomes, Robertsonian translocations, and complex SVs that were unresolved by short reads, followed by validation using optical genome mapping (OGM). Our analyses resolved 10 of 13 cases, including a Robertsonian translocation and all ring chromosomes. Multiple breakpoints were localized to genomic regions previously recalcitrant to sequencing such as acrocentric p-arms, ribosomal DNA arrays, and telomeric repeats, and involved complex structures such as a deletion-inversion and interchromosomal dispersed duplications. We further performed methylation profiling from long-read data to discover phased differential methylation in a gene promoter proximal to a ring fusion, suggesting a long-range position effect (LRPE) with heterochromatin spreading. Breakpoint sequences suggested mechanisms of SV formation such as microhomology-mediated and non-homologous end-joining, as well as non-allelic homologous recombination. These methods provide some of the first glimpses into the sequence resolution of Robertsonian translocations and illuminate the structural diversity of ring chromosomes and complex chromosomal rearrangements with implications for genome biology, prediction of LRPEs from integrated multi-omics technologies, and molecular diagnostics in rare disease cases.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2693-2706"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-based newborn screening for severe childhood genetic diseases has high positive predictive value and sensitivity in a NICU pilot trial.","authors":"Stephen F Kingsmore, Meredith Wright, Lauren Olsen, Brandan Schultz, Liana Protopsaltis, Dan Averbuj, Eric Blincow, Jeanne Carroll, Sara Caylor, Thomas Defay, Katarzyna Ellsworth, Annette Feigenbaum, Mia Gover, Lucia Guidugli, Christian Hansen, Lucita Van Der Kraan, Chris M Kunard, Hugh Kwon, Lakshminarasimha Madhavrao, Jeremy Leipzig, Yupu Liang, Rebecca Mardach, William R Mowrey, Hung Nguyen, Anna-Kaisa Niemi, Danny Oh, Muhammed Saad, Gunter Scharer, Jennifer Schleit, Shyamal S Mehtalia, Erica Sanford, Laurie D Smith, Mary J Willis, Kristen Wigby, Rebecca Reimers","doi":"10.1016/j.ajhg.2024.10.020","DOIUrl":"10.1016/j.ajhg.2024.10.020","url":null,"abstract":"<p><p>Large prospective clinical trials are underway or planned that examine the clinical utility and cost effectiveness of genome-based newborn screening (gNBS). One gNBS platform, BeginNGS, currently screens 53,575 variants for 412 severe childhood genetic diseases with 1,603 efficacious therapies. Retrospective evaluation of BeginNGS in 618,290 subjects suggests adequate sensitivity and positive predictive value (PPV) to proceed to prospective studies. To inform pivotal clinical trial design, we undertook a pilot clinical trial. We enrolled 120 infants in a regional neonatal intensive care unit (NICU) who were not under consideration for rapid diagnostic genome sequencing (RDGS). Each enrollee received BeginNGS and two index tests (California state NBS and RDGS). California NBS identified 4 of 4 true positive (TP) findings (TP rate 3.6%, sensitivity 100%) and 11 false positive (FP) findings (PPV 27%). RDGS identified 41 diagnostic findings in 36 neonates (diagnostic rate 30%). BeginNGS identified 5 of 6 on-target TP disorders (TP rate 4.2%, 95% confidence interval 1%-8%, sensitivity 83%) and no FPs (PPV 100%). Changes in management were anticipated following the return of 27 RDGS results in 25 enrollees (clinical utility [CU] 21%), 3 of 4 NBS TPs (CU 2.7%), and all BeginNGS TPs (CU 4.2%). The incidence of actionable genetic diseases in NICU infants not being considered for RDGS suggests (1) performance of RDGS in ∼20% of admissions misses many genetic diagnoses, (2) NICU enrollment in gNBS trials will greatly increase power to test endpoints, and (3) NICUs may be attractive for early implementation of consented BeginNGS screening.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"111 12","pages":"2643-2667"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The PRIMED Consortium: Reducing disparities in polygenic risk assessment.","authors":"Iftikhar J Kullo, Matthew P Conomos, Sarah C Nelson, Sally N Adebamowo, Ananyo Choudhury, David Conti, Stephanie M Fullerton, Stephanie M Gogarten, Ben Heavner, Whitney E Hornsby, Eimear E Kenny, Alyna Khan, Amit V Khera, Yun Li, Iman Martin, Josep M Mercader, Maggie Ng, Laura M Raffield, Alex Reiner, Robb Rowley, Daniel Schaid, Adrienne Stilp, Ken Wiley, Riley Wilson, John S Witte, Pradeep Natarajan","doi":"10.1016/j.ajhg.2024.10.010","DOIUrl":"10.1016/j.ajhg.2024.10.010","url":null,"abstract":"<p><p>By improving disease risk prediction, polygenic risk scores (PRSs) could have a significant impact on health promotion and disease prevention. Due to the historical oversampling of populations with European ancestry for genome-wide association studies, PRSs perform less well in other, understudied populations, leading to concerns that clinical use in their current forms could widen health care disparities. The PRIMED Consortium was established to develop methods to improve the performance of PRSs in global populations and individuals of diverse genetic ancestry. To this end, PRIMED is aggregating and harmonizing multiple phenotype and genotype datasets on AnVIL, an interoperable secure cloud-based platform, to perform individual- and summary-level analyses using population and statistical genetics approaches. Study sites, the coordinating center, and representatives from the NIH work alongside other NHGRI and global consortia to achieve these goals. PRIMED is also evaluating ethical and social implications of PRS implementation and investigating the joint modeling of social determinants of health and PRS in computing disease risk. The phenotypes of interest are primarily cardiometabolic diseases and cancer, the leading causes of death and disability worldwide. Early deliverables of the consortium include methods for data sharing on AnVIL, development of a common data model to harmonize phenotype and genotype data from cohort studies as well as electronic health records, adaptation of recent guidelines for population descriptors to global cohorts, and sharing of PRS methods/tools. As a multisite collaboration, PRIMED aims to foster equity in the development and use of polygenic risk assessment.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2594-2606"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Allele frequency impacts the cross-ancestry portability of gene expression prediction in lymphoblastoid cell lines.","authors":"Marie Saitou, Andy Dahl, Qingbo Wang, Xuanyao Liu","doi":"10.1016/j.ajhg.2024.10.009","DOIUrl":"10.1016/j.ajhg.2024.10.009","url":null,"abstract":"<p><p>Population-level genetic studies are overwhelmingly biased toward European ancestries. Transferring genetic predictions from European ancestries to other ancestries results in a substantial loss of accuracy. Yet, it remains unclear how much various genetic factors, such as causal effect differences, linkage disequilibrium (LD) differences, or allele frequency differences, contribute to the loss of prediction accuracy across ancestries. In this study, we used gene expression levels in lymphoblastoid cell lines to understand how much each genetic factor contributes to lowered portability of gene expression prediction from European to African ancestries. We found that cis-genetic effects on gene expression are highly similar between European and African individuals. However, we found that allele frequency differences of causal variants have a striking impact on prediction portability. For example, portability is reduced by more than 32% when the causal cis-variant is common (minor allele frequency, MAF >5%) in European samples (training population) but is rarer (MAF <5%) in African samples (prediction population). While large allele frequency differences can decrease portability through increasing LD differences, we also determined that causal allele frequency can significantly impact portability when the impact from LD is substantially controlled. This observation suggests that improving statistical fine-mapping alone does not overcome the loss of portability resulting from differences in causal allele frequency. We conclude that causal cis-eQTL effects are highly similar in European and African individuals, and allele frequency differences have a large impact on the accuracy of gene expression prediction.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2814-2825"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The methylomic landscape of human articular cartilage development contains epigenetic signatures of osteoarthritis risk.","authors":"Euan McDonnell, Sarah E Orr, Matthew J Barter, Danielle Rux, Abby Brumwell, Nicola Wrobel, Lee Murphy, Lynne M Overman, Antony K Sorial, David A Young, Jamie Soul, Sarah J Rice","doi":"10.1016/j.ajhg.2024.10.017","DOIUrl":"10.1016/j.ajhg.2024.10.017","url":null,"abstract":"<p><p>Increasing evidence is emerging to link age-associated complex musculoskeletal diseases, including osteoarthritis (OA), to developmental factors. Multiple studies have shown a functional role for DNA methylation in the genetic mechanisms of OA risk using articular cartilage samples taken from aged individuals, yet knowledge of temporal changes to the methylome during human cartilage development is limited. We quantified DNA methylation at ∼700,000 individual CpGs across the epigenome of developing human chondrocytes in 72 samples ranging from 7 to 21 post-conception weeks. We identified significant changes in 3% of all CpGs and >8,200 developmental differentially methylated regions. We further identified 24 loci at which OA genetic variants colocalize with methylation quantitative trait loci. Through integrating developmental and mature human chondrocyte datasets, we find evidence for functional effects exerted solely in development or throughout the life course. This will have profound impacts on future approaches to translating genetic pathways for therapeutic intervention.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2756-2772"},"PeriodicalIF":8.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}