Pub Date : 2025-12-11DOI: 10.1016/j.ajhg.2025.12.003
Rebecca W.Y. Chan, Lee Serpas, Meng Ni, Stefano Volpi, Linda T. Hiraki, Lai-Shan Tam, Ali Rashidfarrokhi, Priscilla C.H. Wong, Lydia H.P. Tam, Yueyang Wang, Peiyong Jiang, Alice S.H. Cheng, Wenlei Peng, Diana S.C. Han, Patty P.P. Tse, Pik Ki Lau, Wing-Shan Lee, Alberto Magnasco, Elisa Buti, Vanja Sisirak, Nora AlMutairi, K.C. Allen Chan, Rossa W.K. Chiu, Boris Reizis, Y.M. Dennis Lo
{"title":"Plasma DNA Profile Associated with DNASE1L3 Gene Mutations: Clinical Observations, Relationships to Nuclease Substrate Preference, and In Vivo Correction","authors":"Rebecca W.Y. Chan, Lee Serpas, Meng Ni, Stefano Volpi, Linda T. Hiraki, Lai-Shan Tam, Ali Rashidfarrokhi, Priscilla C.H. Wong, Lydia H.P. Tam, Yueyang Wang, Peiyong Jiang, Alice S.H. Cheng, Wenlei Peng, Diana S.C. Han, Patty P.P. Tse, Pik Ki Lau, Wing-Shan Lee, Alberto Magnasco, Elisa Buti, Vanja Sisirak, Nora AlMutairi, K.C. Allen Chan, Rossa W.K. Chiu, Boris Reizis, Y.M. Dennis Lo","doi":"10.1016/j.ajhg.2025.12.003","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.12.003","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"9 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731083","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}
Large-scale biobanks provide comprehensive electronic health records (EHRs) that capture detailed clinical phenotypes, potentially enhancing disease prediction. However, traditional polygenic risk score (PRS) methods rely on simplified phenotype definitions or predefined trait sets, limiting their ability to represent the complex structures embedded within EHRs. To address this gap, we introduce EHR-embedding-enhanced PRS (EEPRS), leveraging phenotype embeddings derived from EHRs to improve PRSs using only genome-wide association study (GWAS) summary statistics. Employing embedding methods such as Word2Vec and GPT, we conducted EHR-embedding-based GWASs and identified a cardiovascular cluster via hierarchical clustering of genetic correlations. Across 41 traits in the UK Biobank, EEPRS consistently outperformed single-trait PRSs, particularly within this cluster. PRS-based phenome-wide association studies further demonstrated robust associations between EHR-embedding-based PRS and circulatory system diseases. We then developed EEPRS_optimal, a data-adaptive method that uses cross-validation to select the best embedding, yielding additional improvements. We also developed MTAG_EEPRS for multi-trait PRSs, which further improved prediction accuracy compared to single-trait PRSs and MTAG_PRS. Finally, we validated the benefits of EEPRS in the All of Us cohort for seven selected diseases. Overall, EEPRS represents a robust and interpretable framework, enhancing single-trait and multi-trait PRSs by integrating EHR embeddings.
大规模生物银行提供全面的电子健康记录（EHRs），捕获详细的临床表型，潜在地增强疾病预测。然而，传统的多基因风险评分（PRS）方法依赖于简化的表型定义或预定义的性状集，限制了它们表示电子病历中嵌入的复杂结构的能力。为了解决这一差距，我们引入了ehr嵌入增强PRS (EEPRS)，利用来自ehr的表型嵌入来改进PRS，仅使用全基因组关联研究（GWAS）汇总统计。采用Word2Vec和GPT等嵌入方法，进行了基于ehr嵌入的GWASs，并通过遗传相关性的分层聚类确定了心血管类。在英国生物银行的41个性状中，EEPRS的表现一直优于单性状prs，特别是在这个集群中。基于PRS的全现象关联研究进一步表明，基于ehr嵌入的PRS与循环系统疾病之间存在强大的关联。然后，我们开发了EEPRS_optimal，这是一种数据自适应方法，使用交叉验证来选择最佳嵌入，从而产生额外的改进。我们还开发了mtag_epprs，与单性状PRSs和MTAG_PRS相比，进一步提高了多性状PRSs的预测精度。最后，我们在All of Us队列中验证了epprs对7种选定疾病的益处。总体而言，eprs代表了一个强大且可解释的框架，通过集成EHR嵌入来增强单性状和多性状prs。
{"title":"Improving polygenic risk prediction performance by integrating electronic health records through phenotype embedding.","authors":"Leqi Xu,Wangjie Zheng,Jiaqi Hu,Yingxin Lin,Jia Zhao,Gefei Wang,Tianyu Liu,Hongyu Zhao","doi":"10.1016/j.ajhg.2025.11.006","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.006","url":null,"abstract":"Large-scale biobanks provide comprehensive electronic health records (EHRs) that capture detailed clinical phenotypes, potentially enhancing disease prediction. However, traditional polygenic risk score (PRS) methods rely on simplified phenotype definitions or predefined trait sets, limiting their ability to represent the complex structures embedded within EHRs. To address this gap, we introduce EHR-embedding-enhanced PRS (EEPRS), leveraging phenotype embeddings derived from EHRs to improve PRSs using only genome-wide association study (GWAS) summary statistics. Employing embedding methods such as Word2Vec and GPT, we conducted EHR-embedding-based GWASs and identified a cardiovascular cluster via hierarchical clustering of genetic correlations. Across 41 traits in the UK Biobank, EEPRS consistently outperformed single-trait PRSs, particularly within this cluster. PRS-based phenome-wide association studies further demonstrated robust associations between EHR-embedding-based PRS and circulatory system diseases. We then developed EEPRS_optimal, a data-adaptive method that uses cross-validation to select the best embedding, yielding additional improvements. We also developed MTAG_EEPRS for multi-trait PRSs, which further improved prediction accuracy compared to single-trait PRSs and MTAG_PRS. Finally, we validated the benefits of EEPRS in the All of Us cohort for seven selected diseases. Overall, EEPRS represents a robust and interpretable framework, enhancing single-trait and multi-trait PRSs by integrating EHR embeddings.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"1 1","pages":"3030-3045"},"PeriodicalIF":9.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680628","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}
Pub Date : 2025-12-04DOI: 10.1016/j.ajhg.2025.11.004
Yasuhiro Kosaka,Brandon Lopez,Nina Kishimoto,Shancy Jacob,Emilie Montenont,Rodrigo Huallanca,Graeson Coughenour,Jorge Di Paola,Justyne Ross,Kristy Lee,Matthew T Rondina,Paul F Bray,Jesse W Rowley
The interpretation of genetic variants in inherited diseases, such as inherited platelet disorders (IPDs), remains a major clinical challenge, as most are classified as variants of uncertain significance (VUSs). A key barrier to functional evaluation is the lack of accessible, lineage-appropriate assays that reliably reflect native gene regulation and cell-specific biology. To address this gap, we developed CRIMSON HD (CRISPR-edited megakaryocytes [MKs] for surveying platelet variant functions through homology-directed repair [HDR]), a CRISPR-Cas9 HDR-based genome-editing platform applicable to CD34+ cell-derived blood lineages and optimized for evaluating platelet-associated variants. Using this system, we modeled known and candidate disease-associated variants in integrin alpha 2b (ITGA2B) and integrin beta 3 (ITGB3), which encode the platelet αIIb/β3 integrin and are causative in Glanzmann thrombasthenia (GT). We introduced precise variants into primary human MKs derived from CD34+ hematopoietic stem and progenitor cells, achieving >90% editing efficiency. Edited MKs faithfully recapitulated both expression and functional phenotypes of known type I, II, and III GT variants. CRIMSON HD enabled functional evaluation and reclassification of several GT VUSs, including αIIb Gly201Ala, a population variant now shown to cause near-complete loss of αIIb/β3 expression; αIIb Ala777Asp, which results in intermediate αIIb/β3 expression and impaired agonist-induced integrin binding; and β3 Arg119Gln, previously linked to the loss of anti-HPA1a antibody binding in fetal and neonatal alloimmune thrombocytopenia (FNAIT), now shown to impair integrin surface expression. These findings demonstrate the importance of lineage-specific, physiologically relevant assays for the functional classification of platelet-related variants, providing mechanistic information and clinically meaningful insights for individuals with IPDs.
{"title":"Functional classification of platelet gene variants using CRISPR HDR in CD34+ cell-derived megakaryocytes.","authors":"Yasuhiro Kosaka,Brandon Lopez,Nina Kishimoto,Shancy Jacob,Emilie Montenont,Rodrigo Huallanca,Graeson Coughenour,Jorge Di Paola,Justyne Ross,Kristy Lee,Matthew T Rondina,Paul F Bray,Jesse W Rowley","doi":"10.1016/j.ajhg.2025.11.004","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.004","url":null,"abstract":"The interpretation of genetic variants in inherited diseases, such as inherited platelet disorders (IPDs), remains a major clinical challenge, as most are classified as variants of uncertain significance (VUSs). A key barrier to functional evaluation is the lack of accessible, lineage-appropriate assays that reliably reflect native gene regulation and cell-specific biology. To address this gap, we developed CRIMSON HD (CRISPR-edited megakaryocytes [MKs] for surveying platelet variant functions through homology-directed repair [HDR]), a CRISPR-Cas9 HDR-based genome-editing platform applicable to CD34+ cell-derived blood lineages and optimized for evaluating platelet-associated variants. Using this system, we modeled known and candidate disease-associated variants in integrin alpha 2b (ITGA2B) and integrin beta 3 (ITGB3), which encode the platelet αIIb/β3 integrin and are causative in Glanzmann thrombasthenia (GT). We introduced precise variants into primary human MKs derived from CD34+ hematopoietic stem and progenitor cells, achieving >90% editing efficiency. Edited MKs faithfully recapitulated both expression and functional phenotypes of known type I, II, and III GT variants. CRIMSON HD enabled functional evaluation and reclassification of several GT VUSs, including αIIb Gly201Ala, a population variant now shown to cause near-complete loss of αIIb/β3 expression; αIIb Ala777Asp, which results in intermediate αIIb/β3 expression and impaired agonist-induced integrin binding; and β3 Arg119Gln, previously linked to the loss of anti-HPA1a antibody binding in fetal and neonatal alloimmune thrombocytopenia (FNAIT), now shown to impair integrin surface expression. These findings demonstrate the importance of lineage-specific, physiologically relevant assays for the functional classification of platelet-related variants, providing mechanistic information and clinically meaningful insights for individuals with IPDs.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"5 1","pages":"2888-2901"},"PeriodicalIF":9.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680629","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}
Pub Date : 2025-12-04DOI: 10.1016/j.ajhg.2025.10.009
Bruce R Korf
{"title":"Transitions in interesting times.","authors":"Bruce R Korf","doi":"10.1016/j.ajhg.2025.10.009","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.009","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 12","pages":"2815-2816"},"PeriodicalIF":8.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145686805","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}
Pub Date : 2025-12-04DOI: 10.1016/j.ajhg.2025.11.005
Paul W. Hook, Alyson B. Barnes
{"title":"This month in The Journal","authors":"Paul W. Hook, Alyson B. Barnes","doi":"10.1016/j.ajhg.2025.11.005","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.005","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"2 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689938","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}
Pub Date : 2025-12-04DOI: 10.1016/j.ajhg.2025.11.001
Teri A Manolio, Alauna Rupert, Jahnavi Narula, Carol J Bult, Rex L Chisholm, Geoffrey S Ginsburg, Gillian W Hooker, Gail P Jarvik, George A Mensah, Dan M Roden, Robb Rowley, Casey Overby Taylor, Simona Volpi, Marc S Williams
{"title":"Genomic medicine year in review: 2025.","authors":"Teri A Manolio, Alauna Rupert, Jahnavi Narula, Carol J Bult, Rex L Chisholm, Geoffrey S Ginsburg, Gillian W Hooker, Gail P Jarvik, George A Mensah, Dan M Roden, Robb Rowley, Casey Overby Taylor, Simona Volpi, Marc S Williams","doi":"10.1016/j.ajhg.2025.11.001","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.001","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 12","pages":"2822-2825"},"PeriodicalIF":8.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145686740","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}
Pub Date : 2025-12-04DOI: 10.1016/j.ajhg.2025.11.011
James Fasham,Julia Rankin,Rachel Schot,Susan M White,Katrina M Bell,Matthew N Wakeling,Lucy J Mallin,Alex Shah,Michelle G de Silva,David I Francis,Maie Walsh,Emily E Jones,Kayal Vijayakumar,Katie Johnson,Francis H Sansbury,Johann Te Water Naudé,Paola Giunti,Marios Hadjivassiliou,Andrea H Nemeth,George K Tofaris,Carlo Rinaldi,Benito Banos-Pinero,Marianna Selikhva,Nishanka Ubeyratna,Anneke Kievit,Frank Sleutels,Joey van Giessen,Tahsin Stefan Barakat,Timothy S Hall,Alan Whone,Eleanor Thomas,Joseph S Leslie,Rosemary A Bamford,Aaron R Jeffries,Jenny Lord,Susan Walker,Tjakko J van Ham,Sue L Hill,Lucy McGavin,Andrew Parrish,Andrew H Crosby,Emma L Baple,Alistair T Pagnamenta
Complex neurodegenerative conditions have occasionally been associated with copy-number gains. Using microarray and genome sequencing on DNA samples from eleven individuals from nine unrelated families, we show that copy-number gains at 16p13.3 cause a severe, recognizable disorder characterized by early-onset progressive ataxia and cognitive decline (9-32 years). Most affected individuals also displayed peripheral neuropathy and scoliosis. Optic atrophy, nystagmus, and dystonia were more variable features. The neuroradiological phenotype comprises a distinctive combination of atrophy of the cerebellum and caudate nuclei. Co-segregation data showed that the structural variant (SV) had occurred de novo in 5 individuals and, for one other individual, had been inherited from a mosaic, unaffected parent. Triplicated segments of 16p13.3 were identified within the duplications. Although these varied in size (30-811 kb), the minimal region of overlap included a single gene (ATP6V0C) that is highly expressed in the cerebellum. RNA sequencing (RNA-seq) using whole-blood and fibroblast/lymphoblast cultures indicated increased expression of several genes within the SV, with ATP6V0C showing the most significant increase (up to 4-fold). In most cases, the central segment of the SV was proven to be inverted and lay immediately distal to a 144 kb palindrome. Across 500,000 individuals from the UK Biobank, we identified 19 duplications but no triplications at this locus. Further analysis of the consequences of ATP6V0C overexpression on the stoichiometry within the vacuolar H+-ATPase heteromer and on neurological function will provide valuable pathomechanistic insights. Together, our findings define palindrome-mediated triplication on 16p13.3 as the cause of a clinically distinct childhood-onset neurodegenerative disorder.
{"title":"Palindrome-mediated 16p13.3 triplications cause a recognizable neurodegenerative disorder with ataxia.","authors":"James Fasham,Julia Rankin,Rachel Schot,Susan M White,Katrina M Bell,Matthew N Wakeling,Lucy J Mallin,Alex Shah,Michelle G de Silva,David I Francis,Maie Walsh,Emily E Jones,Kayal Vijayakumar,Katie Johnson,Francis H Sansbury,Johann Te Water Naudé,Paola Giunti,Marios Hadjivassiliou,Andrea H Nemeth,George K Tofaris,Carlo Rinaldi,Benito Banos-Pinero,Marianna Selikhva,Nishanka Ubeyratna,Anneke Kievit,Frank Sleutels,Joey van Giessen,Tahsin Stefan Barakat,Timothy S Hall,Alan Whone,Eleanor Thomas,Joseph S Leslie,Rosemary A Bamford,Aaron R Jeffries,Jenny Lord,Susan Walker,Tjakko J van Ham,Sue L Hill,Lucy McGavin,Andrew Parrish,Andrew H Crosby,Emma L Baple,Alistair T Pagnamenta","doi":"10.1016/j.ajhg.2025.11.011","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.011","url":null,"abstract":"Complex neurodegenerative conditions have occasionally been associated with copy-number gains. Using microarray and genome sequencing on DNA samples from eleven individuals from nine unrelated families, we show that copy-number gains at 16p13.3 cause a severe, recognizable disorder characterized by early-onset progressive ataxia and cognitive decline (9-32 years). Most affected individuals also displayed peripheral neuropathy and scoliosis. Optic atrophy, nystagmus, and dystonia were more variable features. The neuroradiological phenotype comprises a distinctive combination of atrophy of the cerebellum and caudate nuclei. Co-segregation data showed that the structural variant (SV) had occurred de novo in 5 individuals and, for one other individual, had been inherited from a mosaic, unaffected parent. Triplicated segments of 16p13.3 were identified within the duplications. Although these varied in size (30-811 kb), the minimal region of overlap included a single gene (ATP6V0C) that is highly expressed in the cerebellum. RNA sequencing (RNA-seq) using whole-blood and fibroblast/lymphoblast cultures indicated increased expression of several genes within the SV, with ATP6V0C showing the most significant increase (up to 4-fold). In most cases, the central segment of the SV was proven to be inverted and lay immediately distal to a 144 kb palindrome. Across 500,000 individuals from the UK Biobank, we identified 19 duplications but no triplications at this locus. Further analysis of the consequences of ATP6V0C overexpression on the stoichiometry within the vacuolar H+-ATPase heteromer and on neurological function will provide valuable pathomechanistic insights. Together, our findings define palindrome-mediated triplication on 16p13.3 as the cause of a clinically distinct childhood-onset neurodegenerative disorder.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"138 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680627","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}
Pub Date : 2025-12-02DOI: 10.1016/j.ajhg.2025.11.009
Abdalla A. Alkhawaja, Kevin W. Currin, Hannah J. Perrin, Swarooparani Vadlamudi, Amy S. Etheridge, K. Alaine Broadaway, Gabrielle H. Cannon, Carlton W. Anderson, Anne H. Moxley, Alina C. Iuga, Erin G. Schuetz, Federico Innocenti, Terrence S. Furey, Karen L. Mohlke
{"title":"Liver single-nucleus multiome profiling reveals cell-type mechanisms for cardiometabolic traits","authors":"Abdalla A. Alkhawaja, Kevin W. Currin, Hannah J. Perrin, Swarooparani Vadlamudi, Amy S. Etheridge, K. Alaine Broadaway, Gabrielle H. Cannon, Carlton W. Anderson, Anne H. Moxley, Alina C. Iuga, Erin G. Schuetz, Federico Innocenti, Terrence S. Furey, Karen L. Mohlke","doi":"10.1016/j.ajhg.2025.11.009","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.009","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"13 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657121","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}
Pub Date : 2025-12-02DOI: 10.1016/j.ajhg.2025.11.008
Qing Li, Qingyuan Song, Zhishan Chen, Jungyoon Choi, Victor Moreno, Jie Ping, Wanqing Wen, Chao Li, Xiang Shu, Jun Yan, Xiao-ou Shu, Qiuyin Cai, Jirong Long, Jeroen R. Huyghe, Rish Pai, Stephen B. Gruber, Yaohua Yang, Graham Casey, Xusheng Wang, Adetunji T. Toriola, Li Li, Bhuminder Singh, Ken S. Lau, Li Zhou, Zichen Zhang, Chong Wu, Ulrike Peters, Wei Zheng, Quan Long, Zhijun Yin, Xingyi Guo
{"title":"Large-scale integration of omics and electronic health records to identify potential risk protein biomarkers and therapeutic drugs for cancer prevention","authors":"Qing Li, Qingyuan Song, Zhishan Chen, Jungyoon Choi, Victor Moreno, Jie Ping, Wanqing Wen, Chao Li, Xiang Shu, Jun Yan, Xiao-ou Shu, Qiuyin Cai, Jirong Long, Jeroen R. Huyghe, Rish Pai, Stephen B. Gruber, Yaohua Yang, Graham Casey, Xusheng Wang, Adetunji T. Toriola, Li Li, Bhuminder Singh, Ken S. Lau, Li Zhou, Zichen Zhang, Chong Wu, Ulrike Peters, Wei Zheng, Quan Long, Zhijun Yin, Xingyi Guo","doi":"10.1016/j.ajhg.2025.11.008","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.008","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"25 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657145","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}
Pub Date : 2025-12-01DOI: 10.1016/j.ajhg.2025.11.007
Simone Martinelli,Hélène Cavé,Alessandro De Luca,Marina DiStefano,Rachel Karchin,Ana Clara Lugones,Anne O'Donnell-Luria,Deborah I Ritter,David Tamborero,Michael Y Tolstorukov,Paulo Vidal Campregher,Marco Tartaglia,Dmitriy Sonkin
Genetic alterations influence biological function through a variety of molecular mechanisms. While common functional descriptions (such as loss of function and gain of function) are useful, they may fail to capture mechanistic complexity, particularly in cases of pleiotropy and context-dependent variant effects. To improve variant interpretation and classification, we propose a framework incorporating "context qualifiers" to address mechanistic specificity. This perspective explores the limitations of common functional descriptors and discusses the criteria needed to implement context qualifiers in variant interpretation frameworks to enhance precision medicine applications.
{"title":"Interpreting the functional impact of genetic variants: The need for context qualifiers.","authors":"Simone Martinelli,Hélène Cavé,Alessandro De Luca,Marina DiStefano,Rachel Karchin,Ana Clara Lugones,Anne O'Donnell-Luria,Deborah I Ritter,David Tamborero,Michael Y Tolstorukov,Paulo Vidal Campregher,Marco Tartaglia,Dmitriy Sonkin","doi":"10.1016/j.ajhg.2025.11.007","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.007","url":null,"abstract":"Genetic alterations influence biological function through a variety of molecular mechanisms. While common functional descriptions (such as loss of function and gain of function) are useful, they may fail to capture mechanistic complexity, particularly in cases of pleiotropy and context-dependent variant effects. To improve variant interpretation and classification, we propose a framework incorporating \"context qualifiers\" to address mechanistic specificity. This perspective explores the limitations of common functional descriptors and discusses the criteria needed to implement context qualifiers in variant interpretation frameworks to enhance precision medicine applications.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"359 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145656982","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}
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