Pub Date : 2025-02-13DOI: 10.1038/s41588-025-02085-6
Sean Wen, Pablo Kuri-Morales, Fengyuan Hu, Abhishek Nag, Ioanna Tachmazidou, Sri V. V. Deevi, Haeyam Taiy, Katherine R. Smith, Douglas P. Loesch, Oliver S. Burren, Ryan S. Dhindsa, Sebastian Wasilewski, Jesus Alegre-Díaz, Jaime Berumen, Jonathan Emberson, Jason M. Torres, Rory Collins, Keren Carss, Quanli Wang, Slavé Petrovski, Roberto Tapia-Conyer, Margarete A. Fabre, Andrew R. Harper, George S. Vassiliou, Jonathan Mitchell
The impact of genetic ancestry on the development of clonal hematopoiesis (CH) remains largely unexplored. Here, we compared CH in 136,401 participants from the Mexico City Prospective Study (MCPS) to 416,118 individuals from the UK Biobank (UKB) and observed CH to be significantly less common in MCPS compared to UKB (adjusted odds ratio = 0.59, 95% confidence interval (CI) = [0.57, 0.61], P = 7.31 × 10−185). Among MCPS participants, CH frequency was positively correlated with the percentage of European ancestry (adjusted beta = 0.84, 95% CI = [0.66, 1.03], P = 7.35 × 10−19). Genome-wide and exome-wide association analyses in MCPS identified ancestry-specific variants in the TCL1B locus with opposing effects on DNMT3A-CH versus non-DNMT3A-CH. Meta-analysis of MCPS and UKB identified five novel loci associated with CH, including polymorphisms at PARP11/CCND2, MEIS1 and MYCN. Our CH study, the largest in a non-European population to date, demonstrates the power of cross-ancestry comparisons to derive novel insights into CH pathogenesis.
{"title":"Comparative analysis of the Mexico City Prospective Study and the UK Biobank identifies ancestry-specific effects on clonal hematopoiesis","authors":"Sean Wen, Pablo Kuri-Morales, Fengyuan Hu, Abhishek Nag, Ioanna Tachmazidou, Sri V. V. Deevi, Haeyam Taiy, Katherine R. Smith, Douglas P. Loesch, Oliver S. Burren, Ryan S. Dhindsa, Sebastian Wasilewski, Jesus Alegre-Díaz, Jaime Berumen, Jonathan Emberson, Jason M. Torres, Rory Collins, Keren Carss, Quanli Wang, Slavé Petrovski, Roberto Tapia-Conyer, Margarete A. Fabre, Andrew R. Harper, George S. Vassiliou, Jonathan Mitchell","doi":"10.1038/s41588-025-02085-6","DOIUrl":"https://doi.org/10.1038/s41588-025-02085-6","url":null,"abstract":"<p>The impact of genetic ancestry on the development of clonal hematopoiesis (CH) remains largely unexplored. Here, we compared CH in 136,401 participants from the Mexico City Prospective Study (MCPS) to 416,118 individuals from the UK Biobank (UKB) and observed CH to be significantly less common in MCPS compared to UKB (adjusted odds ratio = 0.59, 95% confidence interval (CI) = [0.57, 0.61], <i>P</i> = 7.31 × 10<sup>−185</sup>). Among MCPS participants, CH frequency was positively correlated with the percentage of European ancestry (adjusted beta = 0.84, 95% CI = [0.66, 1.03], <i>P</i> = 7.35 × 10<sup>−19</sup>). Genome-wide and exome-wide association analyses in MCPS identified ancestry-specific variants in the <i>TCL1B</i> locus with opposing effects on <i>DNMT3A</i>-CH versus non-DNMT3A-CH. Meta-analysis of MCPS and UKB identified five novel loci associated with CH, including polymorphisms at <i>PARP11/CCND2</i>, <i>MEIS1</i> and <i>MYCN</i>. Our CH study, the largest in a non-European population to date, demonstrates the power of cross-ancestry comparisons to derive novel insights into CH pathogenesis.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"63 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401366","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 : 2025-02-13DOI: 10.1038/s41588-025-02081-w
Bryce Lim, Aryan Kamal, Borja Gomez Ramos, Juan M. Adrian Segarra, Ignacio L. Ibarra, Lennart Dignas, Tim Kindinger, Kai Volz, Mohammad Rahbari, Nuh Rahbari, Eric Poisel, Kanela Kafetzopoulou, Lio Böse, Marco Breinig, Danijela Heide, Suchira Gallage, Jose E. Barragan Avila, Hendrik Wiethoff, Ivan Berest, Sarah Schnabellehner, Martin Schneider, Jonas Becker, Dominic Helm, Dirk Grimm, Taija Mäkinen, Darjus F. Tschaharganeh, Mathias Heikenwalder, Judith B. Zaugg, Moritz Mall
Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. While transcription master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether plasticity is actively suppressed by lineage-specific repressors. Here we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternative fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and was sufficient to prevent liver tumorigenesis. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo and enabled the transition of hepatocellular carcinoma to cholangiocarcinoma. Conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide evidence for PROX1 as a hepatocyte-specific safeguard and support a model where cell-type-specific repressors actively suppress plasticity throughout life to safeguard lineage identity and thus prevent disease.
{"title":"Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis","authors":"Bryce Lim, Aryan Kamal, Borja Gomez Ramos, Juan M. Adrian Segarra, Ignacio L. Ibarra, Lennart Dignas, Tim Kindinger, Kai Volz, Mohammad Rahbari, Nuh Rahbari, Eric Poisel, Kanela Kafetzopoulou, Lio Böse, Marco Breinig, Danijela Heide, Suchira Gallage, Jose E. Barragan Avila, Hendrik Wiethoff, Ivan Berest, Sarah Schnabellehner, Martin Schneider, Jonas Becker, Dominic Helm, Dirk Grimm, Taija Mäkinen, Darjus F. Tschaharganeh, Mathias Heikenwalder, Judith B. Zaugg, Moritz Mall","doi":"10.1038/s41588-025-02081-w","DOIUrl":"https://doi.org/10.1038/s41588-025-02081-w","url":null,"abstract":"<p>Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. While transcription master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether plasticity is actively suppressed by lineage-specific repressors. Here we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternative fate master regulators. In mice, <i>Prox1</i> was required for efficient hepatocyte regeneration after injury and was sufficient to prevent liver tumorigenesis. In line with patient data, <i>Prox1</i> depletion caused hepatocyte fate loss in vivo and enabled the transition of hepatocellular carcinoma to cholangiocarcinoma. Conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide evidence for PROX1 as a hepatocyte-specific safeguard and support a model where cell-type-specific repressors actively suppress plasticity throughout life to safeguard lineage identity and thus prevent disease.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"7 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401365","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 : 2025-02-12DOI: 10.1038/s41588-025-02102-8
Chiara Anania
{"title":"DNA loop extrusion is asymmetric but can switch direction","authors":"Chiara Anania","doi":"10.1038/s41588-025-02102-8","DOIUrl":"10.1038/s41588-025-02102-8","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"280-280"},"PeriodicalIF":31.7,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397434","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 : 2025-02-12DOI: 10.1038/s41588-025-02105-5
Michael Fletcher
{"title":"A model of heritable genome editing for complex traits","authors":"Michael Fletcher","doi":"10.1038/s41588-025-02105-5","DOIUrl":"10.1038/s41588-025-02105-5","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"280-280"},"PeriodicalIF":31.7,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397433","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 : 2025-02-10DOI: 10.1038/s41588-024-02058-1
Slim Mzoughi, Megan Schwarz, Xuedi Wang, Deniz Demircioglu, Gulay Ulukaya, Kevin Mohammed, Habiba Zorgati, Denis Torre, Lewis E. Tomalin, Federico Di Tullio, Carlos Company, Yuliia Dramaretska, Marc Leushacke, Bruno Giotti, Tamsin RM Lannagan, Daniel Lozano-Ojalvo, Panagiotis Karras, Peter B. Vermeulen, Dan Hasson, Robert Sebra, Alexander M. Tsankov, Owen J. Sansom, Jean-Christophe Marine, Nick Barker, Gaetano Gargiulo, Ernesto Guccione
Targeting cancer stem cells (CSCs) is crucial for effective cancer treatment, yet resistance mechanisms to LGR5+ CSC depletion in WNT-driven colorectal cancer (CRC) remain elusive. In the present study, we revealed that mutant intestinal stem cells (SCs) depart from their canonical identity, traversing a dynamic phenotypic spectrum. This enhanced plasticity is initiated by oncofetal (OnF) reprogramming, driven by YAP and AP-1, with subsequent AP-1 hyperactivation promoting lineage infidelity. The retinoid X receptor serves as a gatekeeper of OnF reprogramming and its deregulation after adenomatous polyposis coli (APC) loss of function establishes an OnF ‘memory’ sustained by YAP and AP-1. Notably, the clinical significance of OnF and LGR5+ states in isolation is constrained by their functional redundancy. Although the canonical LGR5+ state is sensitive to the FOLFIRI regimen, an active OnF program correlates with resistance, supporting its role in driving drug-tolerant states. Targeting this program in combination with the current standard of care is pivotal for achieving effective and durable CRC treatment. Oncofetal (OnF) reprogramming, driven by YAP and AP-1, induces phenotypic plasticity and therapy resistance in WNT-dependent colorectal cancer (CRC). Targeting the OnF state in combination with chemotherapy substantially attenuates tumor growth in mouse models and patient-derived CRC tumoroids.
{"title":"Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer","authors":"Slim Mzoughi, Megan Schwarz, Xuedi Wang, Deniz Demircioglu, Gulay Ulukaya, Kevin Mohammed, Habiba Zorgati, Denis Torre, Lewis E. Tomalin, Federico Di Tullio, Carlos Company, Yuliia Dramaretska, Marc Leushacke, Bruno Giotti, Tamsin RM Lannagan, Daniel Lozano-Ojalvo, Panagiotis Karras, Peter B. Vermeulen, Dan Hasson, Robert Sebra, Alexander M. Tsankov, Owen J. Sansom, Jean-Christophe Marine, Nick Barker, Gaetano Gargiulo, Ernesto Guccione","doi":"10.1038/s41588-024-02058-1","DOIUrl":"10.1038/s41588-024-02058-1","url":null,"abstract":"Targeting cancer stem cells (CSCs) is crucial for effective cancer treatment, yet resistance mechanisms to LGR5+ CSC depletion in WNT-driven colorectal cancer (CRC) remain elusive. In the present study, we revealed that mutant intestinal stem cells (SCs) depart from their canonical identity, traversing a dynamic phenotypic spectrum. This enhanced plasticity is initiated by oncofetal (OnF) reprogramming, driven by YAP and AP-1, with subsequent AP-1 hyperactivation promoting lineage infidelity. The retinoid X receptor serves as a gatekeeper of OnF reprogramming and its deregulation after adenomatous polyposis coli (APC) loss of function establishes an OnF ‘memory’ sustained by YAP and AP-1. Notably, the clinical significance of OnF and LGR5+ states in isolation is constrained by their functional redundancy. Although the canonical LGR5+ state is sensitive to the FOLFIRI regimen, an active OnF program correlates with resistance, supporting its role in driving drug-tolerant states. Targeting this program in combination with the current standard of care is pivotal for achieving effective and durable CRC treatment. Oncofetal (OnF) reprogramming, driven by YAP and AP-1, induces phenotypic plasticity and therapy resistance in WNT-dependent colorectal cancer (CRC). Targeting the OnF state in combination with chemotherapy substantially attenuates tumor growth in mouse models and patient-derived CRC tumoroids.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"402-412"},"PeriodicalIF":31.7,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02058-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375432","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}
Pub Date : 2025-02-10DOI: 10.1038/s41588-025-02079-4
Appolinaire Djikeng, Victor E. Olori, Isidore Houaga, Samuel E. Aggrey, Okeyo Mwai, Eveline M. Ibeagha-Awemu, Raphael Mrode, Mizeck G. G. Chagunda, Christian K. Tiambo, Romdhane Rekaya, Oyenkanmi Nash, Zabron Nziku, Oluyinka Opoola, Mapholi Ntanganedzeni, Chinyere Ekine-Dzivenu, Alexander Kahi, Tobias Okeno, John M. Hickey, Negussie Enyew, Edward J. O. Rege
Transforming Africa’s agricultural production and food systems is an imperative to achieve the United Nations Sustainable Development Goals and deliver on the Africa Union’s 2063 vision, ‘the Africa we want’. Transforming livestock systems through genetic improvement will sustainably increase productivity and proffer an inclusive socioeconomic development of farming communities. The African Animal Breeding Network (AABNet) is a platform of highly knowledgeable geneticists, animal breeders and professionals willing to provide information, training, advice and support across the continent. It will leverage available human resources among its members, facilitate partnerships and investment and develop infrastructure for innovative livestock genetic improvement in Africa.
{"title":"The African Animal Breeding Network as a pathway towards genetic improvement of livestock","authors":"Appolinaire Djikeng, Victor E. Olori, Isidore Houaga, Samuel E. Aggrey, Okeyo Mwai, Eveline M. Ibeagha-Awemu, Raphael Mrode, Mizeck G. G. Chagunda, Christian K. Tiambo, Romdhane Rekaya, Oyenkanmi Nash, Zabron Nziku, Oluyinka Opoola, Mapholi Ntanganedzeni, Chinyere Ekine-Dzivenu, Alexander Kahi, Tobias Okeno, John M. Hickey, Negussie Enyew, Edward J. O. Rege","doi":"10.1038/s41588-025-02079-4","DOIUrl":"https://doi.org/10.1038/s41588-025-02079-4","url":null,"abstract":"<p>Transforming Africa’s agricultural production and food systems is an imperative to achieve the United Nations Sustainable Development Goals and deliver on the Africa Union’s 2063 vision, ‘the Africa we want’. Transforming livestock systems through genetic improvement will sustainably increase productivity and proffer an inclusive socioeconomic development of farming communities. The African Animal Breeding Network (AABNet) is a platform of highly knowledgeable geneticists, animal breeders and professionals willing to provide information, training, advice and support across the continent. It will leverage available human resources among its members, facilitate partnerships and investment and develop infrastructure for innovative livestock genetic improvement in Africa.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"26 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375431","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 : 2025-02-10DOI: 10.1038/s41588-025-02084-7
Marijn Schipper, Christiaan A. de Leeuw, Bernardo A. P. C. Maciel, Douglas P. Wightman, Nikki Hubers, Dorret I. Boomsma, Michael C. O’Donovan, Danielle Posthuma
Genome-wide association studies (GWAS) yield large numbers of genetic loci associated with traits and diseases. Predicting the effector genes that mediate these locus-trait associations remains challenging. Here we present the FLAMES (fine-mapped locus assessment model of effector genes) framework, which predicts the most likely effector gene in a locus. FLAMES creates machine learning predictions from biological data linking single-nucleotide polymorphisms to genes, and then evaluates these scores together with gene-centric evidence of convergence of the GWAS signal in functional networks. We benchmark FLAMES on gene-locus pairs derived by expert curation, rare variant implication and domain knowledge of molecular traits. We demonstrate that combining single-nucleotide-polymorphism-based and convergence-based modalities outperforms prioritization strategies using a single line of evidence. Applying FLAMES, we resolve the FSHB locus in the GWAS for dizygotic twinning and further leverage this framework to find schizophrenia risk genes that converge with rare coding evidence and are relevant in different stages of life. FLAMES is a machine learning approach combining variant fine-mapping, SNP-to-gene annotations and convergence-based gene prioritization scores to identify candidate effector genes at genome-wide associated loci with high accuracy.
{"title":"Prioritizing effector genes at trait-associated loci using multimodal evidence","authors":"Marijn Schipper, Christiaan A. de Leeuw, Bernardo A. P. C. Maciel, Douglas P. Wightman, Nikki Hubers, Dorret I. Boomsma, Michael C. O’Donovan, Danielle Posthuma","doi":"10.1038/s41588-025-02084-7","DOIUrl":"10.1038/s41588-025-02084-7","url":null,"abstract":"Genome-wide association studies (GWAS) yield large numbers of genetic loci associated with traits and diseases. Predicting the effector genes that mediate these locus-trait associations remains challenging. Here we present the FLAMES (fine-mapped locus assessment model of effector genes) framework, which predicts the most likely effector gene in a locus. FLAMES creates machine learning predictions from biological data linking single-nucleotide polymorphisms to genes, and then evaluates these scores together with gene-centric evidence of convergence of the GWAS signal in functional networks. We benchmark FLAMES on gene-locus pairs derived by expert curation, rare variant implication and domain knowledge of molecular traits. We demonstrate that combining single-nucleotide-polymorphism-based and convergence-based modalities outperforms prioritization strategies using a single line of evidence. Applying FLAMES, we resolve the FSHB locus in the GWAS for dizygotic twinning and further leverage this framework to find schizophrenia risk genes that converge with rare coding evidence and are relevant in different stages of life. FLAMES is a machine learning approach combining variant fine-mapping, SNP-to-gene annotations and convergence-based gene prioritization scores to identify candidate effector genes at genome-wide associated loci with high accuracy.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"323-333"},"PeriodicalIF":31.7,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375433","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 : 2025-02-10DOI: 10.1038/s41588-024-02068-z
Thomas J. Hoffmann, Rebecca E. Graff, Ravi K. Madduri, Alex A. Rodriguez, Clinton L. Cario, Karen Feng, Yu Jiang, Anqi Wang, Robert J. Klein, Brandon L. Pierce, Scott Eggener, Lin Tong, William Blot, Jirong Long, Louisa B. Goss, Burcu F. Darst, Timothy Rebbeck, Joseph Lachance, Caroline Andrews, Akindele O. Adebiyi, Ben Adusei, Oseremen I. Aisuodionoe-Shadrach, Pedro W. Fernandez, Mohamed Jalloh, Rohini Janivara, Wenlong C. Chen, James E. Mensah, Ilir Agalliu, Sonja I. Berndt, John P. Shelley, Kerry Schaffer, Mitchell J. Machiela, Neal D. Freedman, Wen-Yi Huang, Shengchao A. Li, Phyllis J. Goodman, Cathee Till, Ian Thompson, Hans Lilja, Dilrini K. Ranatunga, Joseph Presti, Stephen K. Van Den Eeden, Stephen J. Chanock, Jonathan D. Mosley, David V. Conti, Christopher A. Haiman, Amy C. Justice, Linda Kachuri, John S. Witte
We conducted a multiancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry, 58,236 African ancestry, 23,546 Hispanic/Latino and 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (P ≤ 5 × 10−8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n = 95,768). Meta-analyzing discovery and replication (n = 392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our genome-wide polygenic risk scores ranged from 11.6% to 16.6% for European ancestry, 5.5% to 9.5% for African ancestry, 13.5% to 18.2% for Hispanic/Latino and 8.6% to 15.3% for Asian ancestry and decreased with increasing age. Midlife genetically adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA levels. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, offering potential to personalize prostate cancer screening. This study shows how including different ancestry groups in a genome-wide association study for prostate-specific antigen levels can improve prostate cancer risk prediction, with implications for population screening.
{"title":"Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves prediction across ancestry groups","authors":"Thomas J. Hoffmann, Rebecca E. Graff, Ravi K. Madduri, Alex A. Rodriguez, Clinton L. Cario, Karen Feng, Yu Jiang, Anqi Wang, Robert J. Klein, Brandon L. Pierce, Scott Eggener, Lin Tong, William Blot, Jirong Long, Louisa B. Goss, Burcu F. Darst, Timothy Rebbeck, Joseph Lachance, Caroline Andrews, Akindele O. Adebiyi, Ben Adusei, Oseremen I. Aisuodionoe-Shadrach, Pedro W. Fernandez, Mohamed Jalloh, Rohini Janivara, Wenlong C. Chen, James E. Mensah, Ilir Agalliu, Sonja I. Berndt, John P. Shelley, Kerry Schaffer, Mitchell J. Machiela, Neal D. Freedman, Wen-Yi Huang, Shengchao A. Li, Phyllis J. Goodman, Cathee Till, Ian Thompson, Hans Lilja, Dilrini K. Ranatunga, Joseph Presti, Stephen K. Van Den Eeden, Stephen J. Chanock, Jonathan D. Mosley, David V. Conti, Christopher A. Haiman, Amy C. Justice, Linda Kachuri, John S. Witte","doi":"10.1038/s41588-024-02068-z","DOIUrl":"10.1038/s41588-024-02068-z","url":null,"abstract":"We conducted a multiancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry, 58,236 African ancestry, 23,546 Hispanic/Latino and 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (P ≤ 5 × 10−8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n = 95,768). Meta-analyzing discovery and replication (n = 392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our genome-wide polygenic risk scores ranged from 11.6% to 16.6% for European ancestry, 5.5% to 9.5% for African ancestry, 13.5% to 18.2% for Hispanic/Latino and 8.6% to 15.3% for Asian ancestry and decreased with increasing age. Midlife genetically adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA levels. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, offering potential to personalize prostate cancer screening. This study shows how including different ancestry groups in a genome-wide association study for prostate-specific antigen levels can improve prostate cancer risk prediction, with implications for population screening.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"334-344"},"PeriodicalIF":31.7,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02068-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375462","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}
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