Pub Date : 2025-11-06Epub Date: 2025-10-18DOI: 10.1016/j.ajhg.2025.10.010
Dmitrijs Rots, Taryn E Jakub, Crystal Keung, Adam Jackson, Siddharth Banka, Rolph Pfundt, Bert B A de Vries, Richard H van Jaarsveld, Saskia M J Hopman, Ellen van Binsbergen, Irene Valenzuela, Maja Hempel, Tatjana Bierhals, Fanny Kortüm, Francois Lecoquierre, Alice Goldenberg, Jens Michael Hertz, Charlotte Brasch Andersen, Maria Kibæk, Eloise J Prijoles, Roger E Stevenson, David B Everman, Wesley G Patterson, Linyan Meng, Charul Gijavanekar, Karl De Dios, Shenela Lakhani, Tess Levy, Matias Wagner, Dagmar Wieczorek, Paul J Benke, María Soledad Lopez Garcia, Renee Perrier, Sergio B Sousa, Pedro M Almeida, Maria José Simões, Bertrand Isidor, Wallid Deb, Andrew A Schmanski, Omar Abdul-Rahman, Christophe Philippe, Ange-Line Bruel, Laurence Faivre, Antonio Vitobello, Christel Thauvin, Jeroen J Smits, Livia Garavelli, Stefano G Caraffi, Francesca Peluso, Laura Davis-Keppen, Dylan Platt, Erin Royer, Lisette Leeuwen, Margje Sinnema, Alexander P A Stegmann, Constance T R M Stumpel, George E Tiller, Daniëlle G M Bosch, Stephanus T Potgieter, Shelagh Joss, Miranda Splitt, Simon Holden, Matina Prapa, Nicola Foulds, Sofia Douzgou, Kaija Puura, Regina Waltes, Andreas G Chiocchetti, Christine M Freitag, F Kyle Satterstrom, Silvia De Rubeis, Joseph Buxbaum, Bruce D Gelb, Aleksic Branko, Itaru Kushima, Jennifer Howe, Stephen W Scherer, Alessia Arado, Chiara Baldo, Olivier Patat, Demeer Bénédicte, Diego Lopergolo, Filippo M Santorelli, Tobias B Haack, Andreas Dufke, Miriam Bertrand, Ruth J Falb, Angelika Rieß, Peter Krieg, Stephanie Spranger, Maria Francesca Bedeschi, Maria Iascone, Sarah Josephi-Taylor, Tony Roscioli, Michael F Buckley, Jan Liebelt, Aditi I Dagli, Emmelien Aten, Anna C E Hurst, Alesha Hicks, Mohnish Suri, Ermal Aliu, Sunil Naik, Richard Sidlow, Juliette Coursimault, Gaël Nicolas, Hanna Küpper, Florence Petit, Veyan Ibrahim, Deniz Top, Francesca Di Cara, Raymond J Louie, Elliot Stolerman, Han G Brunner, Lisenka E L M Vissers, Jamie M Kramer, Tjitske Kleefstra
{"title":"The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder.","authors":"Dmitrijs Rots, Taryn E Jakub, Crystal Keung, Adam Jackson, Siddharth Banka, Rolph Pfundt, Bert B A de Vries, Richard H van Jaarsveld, Saskia M J Hopman, Ellen van Binsbergen, Irene Valenzuela, Maja Hempel, Tatjana Bierhals, Fanny Kortüm, Francois Lecoquierre, Alice Goldenberg, Jens Michael Hertz, Charlotte Brasch Andersen, Maria Kibæk, Eloise J Prijoles, Roger E Stevenson, David B Everman, Wesley G Patterson, Linyan Meng, Charul Gijavanekar, Karl De Dios, Shenela Lakhani, Tess Levy, Matias Wagner, Dagmar Wieczorek, Paul J Benke, María Soledad Lopez Garcia, Renee Perrier, Sergio B Sousa, Pedro M Almeida, Maria José Simões, Bertrand Isidor, Wallid Deb, Andrew A Schmanski, Omar Abdul-Rahman, Christophe Philippe, Ange-Line Bruel, Laurence Faivre, Antonio Vitobello, Christel Thauvin, Jeroen J Smits, Livia Garavelli, Stefano G Caraffi, Francesca Peluso, Laura Davis-Keppen, Dylan Platt, Erin Royer, Lisette Leeuwen, Margje Sinnema, Alexander P A Stegmann, Constance T R M Stumpel, George E Tiller, Daniëlle G M Bosch, Stephanus T Potgieter, Shelagh Joss, Miranda Splitt, Simon Holden, Matina Prapa, Nicola Foulds, Sofia Douzgou, Kaija Puura, Regina Waltes, Andreas G Chiocchetti, Christine M Freitag, F Kyle Satterstrom, Silvia De Rubeis, Joseph Buxbaum, Bruce D Gelb, Aleksic Branko, Itaru Kushima, Jennifer Howe, Stephen W Scherer, Alessia Arado, Chiara Baldo, Olivier Patat, Demeer Bénédicte, Diego Lopergolo, Filippo M Santorelli, Tobias B Haack, Andreas Dufke, Miriam Bertrand, Ruth J Falb, Angelika Rieß, Peter Krieg, Stephanie Spranger, Maria Francesca Bedeschi, Maria Iascone, Sarah Josephi-Taylor, Tony Roscioli, Michael F Buckley, Jan Liebelt, Aditi I Dagli, Emmelien Aten, Anna C E Hurst, Alesha Hicks, Mohnish Suri, Ermal Aliu, Sunil Naik, Richard Sidlow, Juliette Coursimault, Gaël Nicolas, Hanna Küpper, Florence Petit, Veyan Ibrahim, Deniz Top, Francesca Di Cara, Raymond J Louie, Elliot Stolerman, Han G Brunner, Lisenka E L M Vissers, Jamie M Kramer, Tjitske Kleefstra","doi":"10.1016/j.ajhg.2025.10.010","DOIUrl":"10.1016/j.ajhg.2025.10.010","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2814"},"PeriodicalIF":8.1,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12808979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328158","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 : 2025-11-06Epub Date: 2025-10-10DOI: 10.1016/j.ajhg.2025.09.013
Sen Zhao, Jefferson C Sinson, Shenglan Li, Jill A Rosenfeld, Gladys Zapata, Kristina Macakova, Mezthly Pena, Becky Maywald, Kim C Worley, Lindsay C Burrage, Monika Weisz-Hubshman, Shamika Ketkar, William Craigen, Lisa Emrick, Tyson Clark, Gila Yanai Lithwick, Zohar Shipony, Christine Eng, Brendan Lee, Pengfei Liu
RNA sequencing (RNA-seq) has emerged as a powerful tool for resolving variants of uncertain significance (VUSs), particularly those affecting gene expression and splicing. However, most reference datasets and diagnostic protocols employ relatively modest sequencing depths (∼50-150 million reads), which may fail to detect low-abundance transcripts and rare splicing events critical for accurate diagnosis. We evaluated the diagnostic and translational utility of ultra-high-depth (up to ∼1 billion unique reads) RNA-seq in four clinically accessible tissues using the Ultima sequencing platform. After validating the performance of Ultima RNA-seq, we investigated how increasing sequencing depth affects gene and isoform detection, splicing variant discovery, and clinical interpretation of VUSs. Deep RNA-seq substantially improved sensitivity for detecting lowly expressed genes and isoforms, achieving near saturation for detection at 1 billion reads. In two probands with VUSs, pathogenic splicing abnormalities were undetectable at 50 million reads but emerged at 200 million reads, becoming even more pronounced at 1 billion reads. Using deep RNA-seq data, we constructed a resource, MRSD-deep, to estimate the minimum required sequencing depth to achieve desired coverage thresholds. MRSD-deep provided gene- and junction-level guidelines, helping labs select appropriate coverage targets for specific applications. Leveraging deep RNA-seq data on fibroblasts, we also built an expanded splicing-variation reference that successfully identified low-abundance splicing events missed by standard-depth data. Our findings underscore the diagnostic and research benefits of deep RNA-seq for Mendelian disease investigations.
{"title":"The utility of ultra-deep RNA sequencing in Mendelian disorder diagnostics.","authors":"Sen Zhao, Jefferson C Sinson, Shenglan Li, Jill A Rosenfeld, Gladys Zapata, Kristina Macakova, Mezthly Pena, Becky Maywald, Kim C Worley, Lindsay C Burrage, Monika Weisz-Hubshman, Shamika Ketkar, William Craigen, Lisa Emrick, Tyson Clark, Gila Yanai Lithwick, Zohar Shipony, Christine Eng, Brendan Lee, Pengfei Liu","doi":"10.1016/j.ajhg.2025.09.013","DOIUrl":"10.1016/j.ajhg.2025.09.013","url":null,"abstract":"<p><p>RNA sequencing (RNA-seq) has emerged as a powerful tool for resolving variants of uncertain significance (VUSs), particularly those affecting gene expression and splicing. However, most reference datasets and diagnostic protocols employ relatively modest sequencing depths (∼50-150 million reads), which may fail to detect low-abundance transcripts and rare splicing events critical for accurate diagnosis. We evaluated the diagnostic and translational utility of ultra-high-depth (up to ∼1 billion unique reads) RNA-seq in four clinically accessible tissues using the Ultima sequencing platform. After validating the performance of Ultima RNA-seq, we investigated how increasing sequencing depth affects gene and isoform detection, splicing variant discovery, and clinical interpretation of VUSs. Deep RNA-seq substantially improved sensitivity for detecting lowly expressed genes and isoforms, achieving near saturation for detection at 1 billion reads. In two probands with VUSs, pathogenic splicing abnormalities were undetectable at 50 million reads but emerged at 200 million reads, becoming even more pronounced at 1 billion reads. Using deep RNA-seq data, we constructed a resource, MRSD-deep, to estimate the minimum required sequencing depth to achieve desired coverage thresholds. MRSD-deep provided gene- and junction-level guidelines, helping labs select appropriate coverage targets for specific applications. Leveraging deep RNA-seq data on fibroblasts, we also built an expanded splicing-variation reference that successfully identified low-abundance splicing events missed by standard-depth data. Our findings underscore the diagnostic and research benefits of deep RNA-seq for Mendelian disease investigations.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2578-2590"},"PeriodicalIF":8.1,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12777520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273393","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 : 2025-11-05DOI: 10.1016/j.ajhg.2025.10.011
Yassine Souilmi, Adrien Oliva, Roberta Davidson, Matthew P. Williams, Shyamsundar Ravishankar, Xavier Roca-Rada, Vilma Peréz, Raymond Tobler, Bastien Llamas
{"title":"Lessons learned: Recommendations for reproducible paleogenomic data analyses","authors":"Yassine Souilmi, Adrien Oliva, Roberta Davidson, Matthew P. Williams, Shyamsundar Ravishankar, Xavier Roca-Rada, Vilma Peréz, Raymond Tobler, Bastien Llamas","doi":"10.1016/j.ajhg.2025.10.011","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.011","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"86 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145442018","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 : 2025-11-04DOI: 10.1016/j.ajhg.2025.10.002
Eddie Park, Yi Xing
{"title":"Origins and implications of intron retention quantitative trait loci in human tissues","authors":"Eddie Park, Yi Xing","doi":"10.1016/j.ajhg.2025.10.002","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.002","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"26 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145434935","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 : 2025-10-31DOI: 10.1016/j.ajhg.2025.10.006
Rebecca C. Ahrens-Nicklas, Kiran Musunuru
{"title":"How to create personalized gene editing platforms: Next steps toward interventional genetics","authors":"Rebecca C. Ahrens-Nicklas, Kiran Musunuru","doi":"10.1016/j.ajhg.2025.10.006","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.006","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"25 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404827","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 : 2025-10-31DOI: 10.1016/j.ajhg.2025.10.004
Bailey M. Tibben, Andrea Gaedigk, Li Gong, Katrin Sangkuhl, Michelle Whirl-Carrillo, Mary V. Relling, Roseann S. Donnelly, Teri E. Klein, Kelly E. Caudle
{"title":"The Clinical Pharmacogenetics Implementation Consortium’s consensus-based framework for assigning allele function","authors":"Bailey M. Tibben, Andrea Gaedigk, Li Gong, Katrin Sangkuhl, Michelle Whirl-Carrillo, Mary V. Relling, Roseann S. Donnelly, Teri E. Klein, Kelly E. Caudle","doi":"10.1016/j.ajhg.2025.10.004","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.004","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"153 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404833","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 : 2025-10-30DOI: 10.1016/j.ajhg.2025.10.007
Sharon E. Johnatty, Emma Tudini, Michael T. Parsons, Kyriaki Michailidou, Maria Zanti, Daffodil M. Canson, Aimee L. Davidson, Tamar Berger, Rasim Ozgur Rosti, Christian P. Kratz, Reinhard Kalb, Lisa J. McReynolds, Neelam Giri, Marcy E. Richardson, Tina Pesaran, Jordi Surrallés, Roser Pujol, Babu Rao Vundinti, Merin George, Kara N. Maxwell, Kate Nathanson, Susan Domchek, Moisés Ó. Fiesco-Roa, Sara Frias, Benilde García-de-Teresa, Marjolijn Jongmans, Seema Lalani, Merel Maiburg, Katrina Prescott, Rachel Robinson, Sulekha Rajagopalan, Lot Snijders Blok, Suzanna E.L. Temple, Kathy Tucker, Arleen D. Auerbach, Maria I. Cancio, Jennifer A. Kennedy, Margaret L. MacMillan, Rebecca Tryon, John E. Wagner, Michael Walsh, Nicholas J. Boddicker, Chunling Hu, Jeffrey N. Weitzel, Alexander J.M. Dingemans, Johanna Hadler, Nitsan Rotenberg, Lobna Ramadane-Morchadi, Miguel de la Hoya, Paul James, Thomas Van Overeem Hansen, Maaike P.G. Vreeswijk, Logan C. Walker, Shyam K. Sharan, Douglas F. Easton, Fergus Couch, Agata Smogorzewska, Adam Nelson, Joanne Ngeow, Marc Tischkowitz, Encarnacion Gomez-Garcia, Amanda B. Spurdle
{"title":"BRCA1-, BRCA2-, and PALB2-related Fanconi anemia: Scope to expand disease phenotypic features and predict breast cancer risk in heterozygotes","authors":"Sharon E. Johnatty, Emma Tudini, Michael T. Parsons, Kyriaki Michailidou, Maria Zanti, Daffodil M. Canson, Aimee L. Davidson, Tamar Berger, Rasim Ozgur Rosti, Christian P. Kratz, Reinhard Kalb, Lisa J. McReynolds, Neelam Giri, Marcy E. Richardson, Tina Pesaran, Jordi Surrallés, Roser Pujol, Babu Rao Vundinti, Merin George, Kara N. Maxwell, Kate Nathanson, Susan Domchek, Moisés Ó. Fiesco-Roa, Sara Frias, Benilde García-de-Teresa, Marjolijn Jongmans, Seema Lalani, Merel Maiburg, Katrina Prescott, Rachel Robinson, Sulekha Rajagopalan, Lot Snijders Blok, Suzanna E.L. Temple, Kathy Tucker, Arleen D. Auerbach, Maria I. Cancio, Jennifer A. Kennedy, Margaret L. MacMillan, Rebecca Tryon, John E. Wagner, Michael Walsh, Nicholas J. Boddicker, Chunling Hu, Jeffrey N. Weitzel, Alexander J.M. Dingemans, Johanna Hadler, Nitsan Rotenberg, Lobna Ramadane-Morchadi, Miguel de la Hoya, Paul James, Thomas Van Overeem Hansen, Maaike P.G. Vreeswijk, Logan C. Walker, Shyam K. Sharan, Douglas F. Easton, Fergus Couch, Agata Smogorzewska, Adam Nelson, Joanne Ngeow, Marc Tischkowitz, Encarnacion Gomez-Garcia, Amanda B. Spurdle","doi":"10.1016/j.ajhg.2025.10.007","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.007","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"148 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145396744","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 : 2025-10-30DOI: 10.1016/j.ajhg.2025.10.005
Alejandro Mejia-Garcia, Alex Diaz-Papkovich, Guillaume Sillon, Daniela D'Agostino, Anne-Laure Chong, George Chong, Ken Sin Lo, Laurence Baret, Nancy Hamel, Vincent Chapdelaine, William D. Foulkes, Daniel Taliun, Adam J. Shapiro, Guillaume Lettre, Simon Gravel
{"title":"Using the ancestral recombination graph to study the history of rare variants in founder populations","authors":"Alejandro Mejia-Garcia, Alex Diaz-Papkovich, Guillaume Sillon, Daniela D'Agostino, Anne-Laure Chong, George Chong, Ken Sin Lo, Laurence Baret, Nancy Hamel, Vincent Chapdelaine, William D. Foulkes, Daniel Taliun, Adam J. Shapiro, Guillaume Lettre, Simon Gravel","doi":"10.1016/j.ajhg.2025.10.005","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.005","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"22 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404839","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 : 2025-10-29DOI: 10.1016/j.ajhg.2025.10.003
Jennifer M. Deger, Shabab B. Hannan, Mingxue Gu, Colleen E. Strohlein, Lindsey D. Goodman, Sasidhar Pasupuleti, Zahid Shaik, Liwen Ma, Yarong Li, Jiayang Li, Morgan C. Stephens, Michal Tyrlík, Zhandong Liu, Ismael Al-Ramahi, Juan Botas, Chad A. Shaw, Oguz Kanca, Hugo J. Bellen, Joshua M. Shulman
{"title":"Revealing the nervous system requirements of Alzheimer disease risk genes in Drosophila","authors":"Jennifer M. Deger, Shabab B. Hannan, Mingxue Gu, Colleen E. Strohlein, Lindsey D. Goodman, Sasidhar Pasupuleti, Zahid Shaik, Liwen Ma, Yarong Li, Jiayang Li, Morgan C. Stephens, Michal Tyrlík, Zhandong Liu, Ismael Al-Ramahi, Juan Botas, Chad A. Shaw, Oguz Kanca, Hugo J. Bellen, Joshua M. Shulman","doi":"10.1016/j.ajhg.2025.10.003","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.003","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"43 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145383232","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 : 2025-10-23DOI: 10.1016/j.ajhg.2025.10.001
Boran Gao,Zheng Li,Xiang Zhou
Understanding genetic architecture across ancestries through genetic correlation analysis is critical for determining the degree to which genetic factors underlying diseases or complex traits are shared or differ among populations. Current methods for genetic correlation analysis primarily rely on method of moments approaches and focus on estimating the global genetic correlation across the entire genome. However, these methods often overlook important local genomic complexities and inadequately model the intricate linkage disequilibrium (LD) structures that vary substantially across ancestries. Here, we present Logica (local genetic correlation across ancestries), a method specifically designed to estimate local genetic correlations across ancestries and in admixed populations. Logica employs a bivariate linear mixed model that explicitly accounts for diverse LD patterns across ancestries, operates on genome-wide association study summary statistics, and utilizes a maximum-likelihood framework for robust inference. An important by-product of Logica is a joint heritability test across ancestries that yields well-calibrated p values-an aspect that existing approaches often struggle with. We conducted comprehensive evaluations of Logica through realistic simulations and analyses of 13 complex traits from multiple biobanks. Simulations showed that Logica achieves improved accuracy in local genetic correlation estimation (with mean squared errors 2.23-4.13 times lower) and enhanced power for detecting genetically correlated regions (8%-40% increase with controlled false discovery rate [FDR] at 5%). In real data, Logica produced valid genetic correlation estimates across all genomic regions, whereas existing methods failed in 23%-39% of regions. Additionally, Logica exhibited better FDR control (14%-58% improvement), identifying genetically correlated regions with greater functional relevance.
{"title":"Logica: A likelihood framework for cross-ancestry local genetic correlation estimation using summary statistics.","authors":"Boran Gao,Zheng Li,Xiang Zhou","doi":"10.1016/j.ajhg.2025.10.001","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.001","url":null,"abstract":"Understanding genetic architecture across ancestries through genetic correlation analysis is critical for determining the degree to which genetic factors underlying diseases or complex traits are shared or differ among populations. Current methods for genetic correlation analysis primarily rely on method of moments approaches and focus on estimating the global genetic correlation across the entire genome. However, these methods often overlook important local genomic complexities and inadequately model the intricate linkage disequilibrium (LD) structures that vary substantially across ancestries. Here, we present Logica (local genetic correlation across ancestries), a method specifically designed to estimate local genetic correlations across ancestries and in admixed populations. Logica employs a bivariate linear mixed model that explicitly accounts for diverse LD patterns across ancestries, operates on genome-wide association study summary statistics, and utilizes a maximum-likelihood framework for robust inference. An important by-product of Logica is a joint heritability test across ancestries that yields well-calibrated p values-an aspect that existing approaches often struggle with. We conducted comprehensive evaluations of Logica through realistic simulations and analyses of 13 complex traits from multiple biobanks. Simulations showed that Logica achieves improved accuracy in local genetic correlation estimation (with mean squared errors 2.23-4.13 times lower) and enhanced power for detecting genetically correlated regions (8%-40% increase with controlled false discovery rate [FDR] at 5%). In real data, Logica produced valid genetic correlation estimates across all genomic regions, whereas existing methods failed in 23%-39% of regions. Additionally, Logica exhibited better FDR control (14%-58% improvement), identifying genetically correlated regions with greater functional relevance.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"54 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357919","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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