American journal of human genetics最新文献

{"title":"Mitochondrial DNA disease discovery through evaluation of genotype and phenotype data: The Solve-RD experience.","authors":"Thiloka Ratnaike, Ida Paramonov, Catarina Olimpio, Alexander Hoischen, Sergi Beltran, Leslie Matalonga, Rita Horváth","doi":"10.1016/j.ajhg.2025.04.003","DOIUrl":"10.1016/j.ajhg.2025.04.003","url":null,"abstract":"<p><p>The diagnosis of mitochondrial DNA (mtDNA) diseases remains challenging with next-generation sequencing, where bioinformatic analysis is usually more focused on the nuclear genome. We developed a workflow for the evaluation of mtDNA diseases and applied it in a large European rare disease cohort (Solve-RD). A semi-automated bioinformatic pipeline with MToolBox was used to filter the unsolved Solve-RD cohort for rare mtDNA variants after validating this pipeline on exome datasets of 42 individuals previously diagnosed with mtDNA variants. Variants were filtered based on blood heteroplasmy levels (≥1%) and reported association with disease. Overall, 10,157 exome and genome datasets from 9,923 affected individuals from 9,483 families within Solve-RD met the quality inclusion criteria. 136 mtDNA variants in 135 undiagnosed individuals were prioritized using the filtering approach. A focused MitoPhen-based phenotype similarity scoring method was tested in a separate genetically diagnosed \"phenotype test cohort\" consisting of nuclear gene and mtDNA diseases using a receiving operator characteristic evaluation. We applied the MitoPhen-based phenotype similarity score of >0.3, which was highly sensitive for detecting mtDNA diseases in the phenotype test cohort, to the filtered cohort of 135 undiagnosed individuals. This aided the prioritization of 34 out of 37 (92%) individuals who received confirmed and likely causative mtDNA disease diagnoses. The phenotypic evaluation was limited by the quality of input data in some individuals. The overall pipeline led to an additional diagnostic yield of 0.4% in a cohort where mitochondrial disease was not initially suspected. This highlights the value of our mtDNA analysis pipeline in diverse datasets.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1376-1387"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962690","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":"Reannotation of cancer mutations based on expressed RNA transcripts reveals functional non-coding mutations in melanoma.","authors":"Daniele Pepe, Xander Janssens, Kalina Timcheva, Grecia M Marrón-Liñares, Benno Verbelen, Vasileios Konstantakos, Dylan De Groote, Jolien De Bie, Amber Verhasselt, Barbara Dewaele, Arne Godderis, Charlotte Cools, Mireia Franco-Tolsau, Jonathan Royaert, Jelle Verbeeck, Kim R Kampen, Karthik Subramanian, David Cabrerizo Granados, Gerben Menschaert, Kim De Keersmaecker","doi":"10.1016/j.ajhg.2025.04.005","DOIUrl":"10.1016/j.ajhg.2025.04.005","url":null,"abstract":"<p><p>The role of synonymous mutations in cancer pathogenesis is currently underexplored. We developed a method to detect significant clusters of synonymous and missense mutations in public cancer genomics data. In melanoma, we show that 22% (11/50) of these mutation clusters are misannotated as coding mutations because the reference transcripts used for their annotation are not expressed. Instead, these mutations are actually non-coding. This, for instance, applies to the mutation clusters targeting known cancer genes kinetochore localized astrin (SPAG5) binding protein (KNSTRN) and BCL2-like 12 (BCL2L12), each affecting 4%-5% of melanoma tumors. For the latter, we show that these mutations are functional non-coding mutations that target the shared promoter region of interferon regulatory factor 3 (IRF3) and BCL2L12. This results in downregulation of IRF3, BCL2L12, and tumor protein p53 (TP53) expression in a CRISPR-Cas9 primary melanocyte model and in melanoma tumors. In individuals with melanoma, these mutations were also associated with a worse response to immunotherapy. Finally, we propose a simple automated method to more accurately annotate cancer mutations based on expressed transcripts. This work shows the importance of integrating DNA- and RNA-sequencing data to properly annotate mutations and identifies a number of previously overlooked and wrongly annotated functional non-coding mutations in melanoma.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1447-1467"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952548","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":"Benefits and barriers to broad implementation of genomic sequencing in the NICU.","authors":"Melissa R Goldin, Douglas M Ruderfer, Alexander Bick, Dan M Roden, Bryce A Schuler, Jamie R Robinson","doi":"10.1016/j.ajhg.2025.04.007","DOIUrl":"10.1016/j.ajhg.2025.04.007","url":null,"abstract":"<p><p>Genome (GS) and exome (ES) sequencing as first-tier diagnostic tests have the potential to increase rates of genetic diagnoses and acutely change the management of neonates in the neonatal intensive care unit (NICU). However, the widespread implementation of genomic sequencing has been limited by several barriers. In this systematic review, we analyze the current literature on the utilization of GS and ES in infants in the NICU to identify the benefits, barriers, and components of successful implementation. Across the 42 studies that discussed GS and ES in the NICU setting, six themes were identified: disease detection, timeliness of results, cost, provider attitudes, parental attitudes, and equitable access. Benefits of GS and ES include high disease detection rates, timely results, and possible reduction in healthcare costs by reducing time spent in the NICU. Additionally, clinicians find GS/ES to be important and useful, and parents and caregivers largely perceive GS/ES to be beneficial. Barriers to widespread GS/ES include availability of personnel to facilitate timely diagnosis and coverage of cost. Additionally, clinicians report worries about a lack of genetics knowledge, informed consent, results return, and potential harm. Parents consistently report low levels of anxiety, decisional conflict, harm, or regret. Finally, the lack of availability of translated consent documents limits the participation of families who do not speak English or Spanish. Continued work is essential to optimize these technologies and ensure equitable access.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1270-1285"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075502","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":"Insights on improving accessibility and usability of functional data to unlock their potential for variant interpretation.","authors":"Min Seon Park, Runjun D Kumar, Cristian Ovadiuc, Andrew Folta, Abbye E McEwen, Ashley Snyder, Rehan M Villani, Amanda B Spurdle, Douglas M Fowler, Alan F Rubin, Brian H Shirts, Lea M Starita, Andrew B Stergachis","doi":"10.1016/j.ajhg.2025.04.009","DOIUrl":"10.1016/j.ajhg.2025.04.009","url":null,"abstract":"<p><p>Variant-level functional data are a core component of clinical variant classification and can aid in reinterpreting variants of uncertain significance (VUSs). However, the usage of functional data by genetics professionals is currently unknown. An online survey was developed and distributed in the spring of 2024 to individuals actively engaged in variant interpretation. Quantitative and qualitative methods were used to assess responses. 190 eligible individuals responded, with 93% reporting interpreting 26 or more variants per year. The median respondent reported 11-20 years of experience. The most common professional roles were laboratory medical geneticists (23%) and variant review scientists (23%). 77% reported using functional data for variant interpretation in a clinical setting, and overall, respondents felt confident assessing functional data. However, 67% indicated that functional data for variants of interest were rarely or never available, and 91% considered insufficient quality metrics or confidence in the accuracy of data as barriers to their use. 94% of respondents noted that better access to primary functional data and standardized interpretation of functional data would improve usage. Respondents also indicated that handling conflicting functional data is a common challenge in variant interpretation that is not performed in a systematic manner across institutions. The results from this survey showed a demand for a comprehensive database with reliable quality metrics to support the use of functional evidence in clinical variant interpretation. The results also highlight a need for guidelines regarding how putatively conflicting functional data should be used for variant classification.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 6","pages":"1468-1478"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245919","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":"Beyond predictive R²: Quantile regression and non-equivalence tests reveal complex relationships of traits and polygenic scores.","authors":"Joel Mefford, Molly Smullen, Felix Zhang, Michal Sadowski, Richard Border, Andy Dahl, Jonathan Flint, Noah Zaitlen","doi":"10.1016/j.ajhg.2025.04.013","DOIUrl":"10.1016/j.ajhg.2025.04.013","url":null,"abstract":"<p><p>Polygenic scores (PGSs) are genetic predictions of trait values or disease risk that are increasingly finding applications in clinical predictive models and basic genetics research. However, the predictive value of a PGS can vary within similar population groups, depending on characteristics such as the environmental exposures, sex, age, or socioeconomic status of the individuals. To maximize the value of a PGS, approaches to screen trait-PGS pairs for evidence of such heterogeneity without having to specify the relevant exposure or individual characteristics would be useful. Here, in analyses from the UK Biobank, we show that a PGS's predictive accuracy depends on the quantile of the phenotypic distribution to which the PGS is being applied. We quantify differences in predictive value across the phenotypic range using quantile regression linear models to estimate quantile-specific effect sizes for linear models of phenotype values as a function of PGS. Of 25 continuous traits, only three have no quantile-specific effect sizes that varied by at least 1.2-fold from the ordinary least squares estimate. Through simulation, we demonstrate that this heterogeneity of PGS predictive value can arise from gene-by-environment interactions. Our approach can be used to flag traits where the use of PGSs warrants extra caution, and perhaps stratification variables should be sought and used because PGSs perform substantially differently in portions of the sampled population than expected from quoted predictive R² or incremental R² values that represent average performance across a dataset.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 6","pages":"1363-1375"},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245917","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":"Prioritizing disease-associated missense variants with chemoproteomic-detected amino acids.","authors":"Maria F Palafox,Lisa Boatner,Blake R Wilde,Heather Christofk,Keriann M Backus,Valerie A Arboleda","doi":"10.1016/j.ajhg.2025.04.017","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.04.017","url":null,"abstract":"Missense variants are the most common type of protein-altering genetic variation. Due to their wide-ranging potential functional consequences, missense variants are challenging to interpret and, as a result, are often classified as unknown pathogenicity or as variants of uncertain significance (VUSs). Genomic-based predictive tools have made significant inroads into the challenge of accurately pinpointing functional missense variants by providing genome-wide assessments of deleteriousness or potential pathogenicity. Complementary to these tools, here we provide an initial study into the utility of harnessing protein-based measures of amino acid reactivity to delineate functionally significant missense variants. These reactivity measurements, which are generated using mass spectrometry-based chemoproteomic methods, have already proved capable of pinpointing functional sites on proteins, which provide the added value of delineating potential sites suitable for drug-development efforts. Here, using published chemoproteomic datasets for three specific privileged amino acids, cysteine, lysine, and tyrosine, we assessed the utility of proteomic reactivity measurements to identify clinically important variants and regions within monogenic-disease-associated genes. We found that genes where amino acids are detected via chemoproteomics are enriched for monogenic-disease phenotypes, indicative of functional importance. Chemoproteomic-detected amino acids (CpDAAs) are enriched at and around sites with known pathogenic missense variants when assessed with either one- or three-dimensional protein structures. To further illustrate the utility of our findings, we found that regions at or around CpDAAs in fumarate hydratase (FH) were enriched for VUSs and pathogenic variants, which we validate through demonstration of an altered FH oligomerization state. Collectively, our study highlights the potential of chemoproteomic and genetic data integration for enhancing the identification of functional genetic variants and protein sites with potential value for drug-development efforts.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"34 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First steps toward building natural history of diseases computationally: Lessons learned from the Noonan syndrome use case.","authors":"Tudor Groza, Warittha Rayabsri, Dylan Gration, Harshini Hariram, Saumya Shekhar Jamuar, Gareth Baynam","doi":"10.1016/j.ajhg.2025.03.014","DOIUrl":"10.1016/j.ajhg.2025.03.014","url":null,"abstract":"<p><p>Rare diseases (RDs) are conditions affecting fewer than 1 in 2,000 people, with over 7,000 identified, primarily genetic in nature, and more than half impacting children. Although each RD affects a small population, collectively, between 3.5% and 5.9% of the global population, or 262.9-446.2 million people, live with an RD. Most RDs lack established treatment protocols, highlighting the need for proper care pathways addressing prognosis, diagnosis, and management. Advances in generative AI and large language models (LLMs) offer new opportunities to document the temporal progression of phenotypic features, addressing gaps in current knowledge bases. This study proposes an LLM-based framework to capture the natural history of diseases, specifically focusing on Noonan syndrome. The framework aims to document phenotypic trajectories, validate against RD knowledge bases, and integrate insights into care coordination using electronic health record (EHR) data from the Undiagnosed Diseases Program Singapore.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 5","pages":"1158-1172"},"PeriodicalIF":8.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12120186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953688","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":"Interplay and cooperation between GLI2 and master transcription factors promote progression of esophageal squamous cell carcinoma.","authors":"Yin-Qiao Liu, Ze-Jun Zheng, Wang-Kai Fang, Yan-Shang Li, Chun Li, Min Yang, Dong-Chen Han, Jun-Hua Zhou, Ying-Hua Xie, Yu-Ying Zhang, Zhuo-Ying Kang, Yi-Wei Xu, Jian-Jun Xie","doi":"10.1016/j.ajhg.2025.03.001","DOIUrl":"10.1016/j.ajhg.2025.03.001","url":null,"abstract":"<p><p>The establishment of gene expression programs that drive cell identity is governed by tightly regulated transcription factors (TFs) that engage in auto- and cross-regulation in a feedforward manner, forming core regulatory circuitries (CRCs). Here, we identify and validate an important interconnected CRC formed by three master TFs-GLI2, TP63, and RUNX1-in esophageal squamous cell carcinoma (ESCC). Furthermore, master TFs co-bind to their own and each other's super-enhancers, forming an interconnected auto-regulatory loop. Mechanistically, these master TFs occupy the majority of ESCC super-enhancers and cooperatively orchestrate the ESCC transcription program. Functionally, GLI2, a master TF, is essential for ESCC viability, migration, invasion, and the growth of xenograft tumors. Moreover, the overexpression of GLI2 is significantly associated with shorter overall survival of patients with ESCC. Downstream, this CRC apparatus coordinately regulates gene expression networks in ESCC, controlling important cancer-promoting pathways, including Hedgehog, glycolysis, and epidermal growth factor receptor signaling pathways. Together, these findings offer significant mechanistic insights into the transcriptional dysregulation in ESCC and recognize GLI2 as a potential therapeutic target and prognostic marker for ESCC. More importantly, CRC-downstream genes and signaling pathways may contain potential therapeutic targets for this malignancy.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1039-1061"},"PeriodicalIF":8.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12120187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741947","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":"Bi-allelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder.","authors":"Stephanie Efthymiou, Cailyn P Leo, Chenghong Deng, Sheng-Jia Lin, Reza Maroofian, Renee Lin, Irem Karagoz, Kejia Zhang, Rauan Kaiyrzhanov, Annarita Scardamaglia, Daniel Owrang, Valentina Turchetti, Friederike Jahnke, Kevin Huang, Cassidy Petree, Anna V Derrick, Mark I Rees, Javeria Raza Alvi, Tipu Sultan, Chumei Li, Marie-Line Jacquemont, Frederic Tran-Mau-Them, Maria Valenzuela-Palafoll, Rich Sidlow, Grace Yoon, Michelle M Morrow, Deanna Alexis Carere, Mary O'Connor, Julie Fleischer, Erica H Gerkes, Chanika Phornphutkul, Bertrand Isidor, Clotilde Rivier-Ringenbach, Christophe Philippe, Semra Hiz Kurul, Didem Soydemir, Bulent Kara, Deniz Sunnetci-Akkoyunlu, Viktoria Bothe, Konrad Platzer, Dagmar Wieczorek, Margarete Koch-Hogrebe, Nils Rahner, Ann-Charlotte Thuresson, Hans Matsson, Carina Frykholm, Sevcan Tuğ Bozdoğan, Atil Bisgin, Nicolas Chatron, Gaetan Lesca, Sara Cabet, Zeynep Tümer, Tina D Hjortshøj, Gitte Rønde, Thorsten Marquardt, Janine Reunert, Erum Afzal, Mina Zamani, Reza Azizimalamiri, Hamid Galehdari, Pardis Nourbakhsh, Niloofar Chamanrou, Seo-Kyung Chung, Mohnish Suri, Paul J Benke, Maha S Zaki, Joseph G Gleeson, Daniel G Calame, Davut Pehlivan, Halil I Yilmaz, Alper Gezdirici, Aboulfazl Rad, Iman Sabri Abumansour, Gabriela Oprea, Muhammed Burak Bereketoğlu, Guillaume Banneau, Sophie Julia, Jawaher Zeighami, Saeed Ashoori, Gholamreza Shariati, Alireza Sedaghat, Alihossein Sabri, Mohammad Hamid, Sahere Parvas, Tajul Arifin Tajudin, Uzma Abdullah, Shahid Mahmood Baig, Wendy K Chung, Olga O Glazunova, Sigaudy Sabine, Huma Arshad Cheema, Giovanni Zifarelli, Peter Bauer, Jai Sidpra, Kshitij Mankad, Barbara Vona, Andrew E Fry, Gaurav K Varshney, Henry Houlden, Dragony Fu","doi":"10.1016/j.ajhg.2025.03.015","DOIUrl":"10.1016/j.ajhg.2025.03.015","url":null,"abstract":"<p><p>The post-transcriptional modification of tRNAs plays a crucial role in tRNA structure and function. Pathogenic variants in tRNA-modification enzymes have been implicated in a wide range of human neurodevelopmental and neurological disorders. However, the molecular basis for many of these disorders remains unknown. Here, we describe a comprehensive cohort of 43 individuals from 31 unrelated families with bi-allelic variants in tRNA methyltransferase 1 (TRMT1). These individuals present with a neurodevelopmental disorder universally characterized by developmental delay and intellectual disability, accompanied by variable behavioral abnormalities, epilepsy, and facial dysmorphism. The identified variants include ultra-rare TRMT1 variants, comprising missense and predicted loss-of-function variants, which segregate with the observed clinical pathology. Our findings reveal that several variants lead to mis-splicing and a consequent loss of TRMT1 protein accumulation. Moreover, cells derived from individuals harboring TRMT1 variants exhibit a deficiency in tRNA modifications catalyzed by TRMT1. Molecular analysis reveals distinct regions of TRMT1 required for tRNA-modification activity and binding. Notably, depletion of Trmt1 protein in zebrafish is sufficient to induce developmental and behavioral phenotypes along with gene-expression changes associated with disrupted cell cycle, immune response, and neurodegenerative disorders. Altogether, these findings demonstrate that loss of TRMT1-catalyzed tRNA modifications leads to intellectual disability and provides insight into the molecular underpinnings of tRNA-modification deficiency caused by pathogenic TRMT1 variants.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 5","pages":"1117-1138"},"PeriodicalIF":8.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12120178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965912","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":"Rare predicted loss-of-function and damaging missense variants in CFHR5 associate with protection from age-related macular degeneration.","authors":"Aaron M Holleman, Aimee M Deaton, Rachel A Hoffing, Lynne Krohn, Philip LoGerfo, Paul Nioi, Mollie E Plekan, Sebastian Akle Serrano, Simina Ticau, Tony E Walshe, Anna Borodovsky, Lucas D Ward","doi":"10.1016/j.ajhg.2025.03.016","DOIUrl":"10.1016/j.ajhg.2025.03.016","url":null,"abstract":"<p><p>Age-related macular degeneration (AMD) is a leading cause of blindness among older adults worldwide, but treatment options are limited. Genetics studies have implicated the CFH locus, containing CFH and five CFHR genes, CFHR1-5, in AMD. While CFH has been robustly linked with AMD risk, potential additional roles for the CFHR genes remain unclear, obscured by strong linkage disequilibrium across the locus. Investigating rare coding variants can help to identify causal genes in such regions. We used whole-exome sequencing data from 406,952 UK Biobank participants to examine AMD associations with genes at the CFH locus. For each gene, we used burden testing to examine associations of rare (minor-allele frequency [MAF] < 1%) predicted loss-of-function (pLoF) and predicted damaging missense variants with AMD. We considered \"broadly defined AMD\" (ICD-10 35.3; n_cases = 10,700) and \"strictly defined AMD\" (dry or wet AMD; n_cases = 346). Adjusting for CFH-region variants known to independently associate with AMD, we find that CFHR5 rare variant burden significantly associates with a decreased risk of broadly defined AMD (odds ratio [OR] = 0.75, p = 7 × 10^-4), with this association primarily driven by pLoF variants. Furthermore, the association of CFHR5 rare variants with AMD protection is estimated to be stronger for individuals with the CFH rs1061170 AMD risk allele (p.Tyr402His [p.Y402H]; interaction p = 0.04). Corresponding analyses of strict AMD were underpowered. However, we observe that thinning of the photoreceptor layer outer segment strongly predicts strict AMD and find that CFHR5 rare variant burden is significantly associated with increased thickness of this retinal layer (+0.34 SD, p = 4 × 10^-4, n = 45,365). These findings suggest CFHR5 inhibition as a potential therapeutic approach for AMD.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 5","pages":"1062-1080"},"PeriodicalIF":8.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12120177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958909","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}