Pub Date : 2025-11-24DOI: 10.1016/j.ajhg.2025.11.002
David R. Blair, Neil Risch
{"title":"Residual allelic activity likely underlies the low rates of disease expression for predicted loss-of-function variants in population-scale biobanks","authors":"David R. Blair, Neil Risch","doi":"10.1016/j.ajhg.2025.11.002","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.002","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"16 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583814","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 : 2025-11-20DOI: 10.1016/j.ajhg.2025.11.003
{"title":"Collaborative science in genomics: The value of data sharing and thoughtful stewardship","authors":"","doi":"10.1016/j.ajhg.2025.11.003","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.11.003","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"18 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559759","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 : 2025-11-19DOI: 10.1016/j.ajhg.2025.10.016
Diane Xue, Elizabeth E. Blue, Stephanie M. Fullerton, Nora B. Henrikson, Sarah Knerr, Anne-Marie Laberge, Lisa S. Parker, Maya Sabatello, Nirupama Nini Shridhar, Jennifer A. Smith, Benjamin S. Wilfond, Genevieve L. Wojcik, Joon-Ho Yu, Alison E. Fohner
{"title":"Training competencies and recommendations for the next generation of public health genetics: Reflections from current leaders in the field","authors":"Diane Xue, Elizabeth E. Blue, Stephanie M. Fullerton, Nora B. Henrikson, Sarah Knerr, Anne-Marie Laberge, Lisa S. Parker, Maya Sabatello, Nirupama Nini Shridhar, Jennifer A. Smith, Benjamin S. Wilfond, Genevieve L. Wojcik, Joon-Ho Yu, Alison E. Fohner","doi":"10.1016/j.ajhg.2025.10.016","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.016","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"5 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145553838","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 : 2025-11-19DOI: 10.1016/j.ajhg.2025.10.015
Brandon Bresack, Laura Renée Kohl, Alexandra Afenjar, Frédérique Audic, Lydie Burglen, Perrine Charles, Nihal Olgac Dundar, Jiddeke van de Kamp, Keren Machol, Pilar Magoulas, Odile Goze-Martineau, Mahdi Motazacker, Heike Philippi, Alejandra Reyes, Omar A.Z. Tutakhel, Aida Bertoli-Avella, Heinrich Sticht, Rami Abou Jamra, Henry Oppermann
{"title":"Genetic variants in ESRRG are associated with a dominant non-progressive congenital movement disorder with ataxia","authors":"Brandon Bresack, Laura Renée Kohl, Alexandra Afenjar, Frédérique Audic, Lydie Burglen, Perrine Charles, Nihal Olgac Dundar, Jiddeke van de Kamp, Keren Machol, Pilar Magoulas, Odile Goze-Martineau, Mahdi Motazacker, Heike Philippi, Alejandra Reyes, Omar A.Z. Tutakhel, Aida Bertoli-Avella, Heinrich Sticht, Rami Abou Jamra, Henry Oppermann","doi":"10.1016/j.ajhg.2025.10.015","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.015","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"172 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145553839","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 : 2025-11-18DOI: 10.1016/j.ajhg.2025.10.014
Ariane Kröll-Hermi, Corinne Stoetzel, Christelle Etard, Levon Halabelian, Elise Schaefer, Sophie Scheidecker, Kimia Kahrizi, Jamali Payman, Véronique Geoffroy, Megana Prasad, Cathy Obringer, Laurie Ruch, Amandine Girard, Hong Zeng, Fengling Li, Damien Plassard, Céline Keime, Francesca Mattioli, Claire Feger, Amélie Piton, Atsushi Fujita, Naomichi Matsumoto, Matheus Augusto Araujo Castro, Kim Chong Ae, Lyse Ruaud, Jonathan Levy, Blandine Dozières, Anne-Claude Tabet, Ingrid M. Wentzensen, Teresa Santiago-Sim, Roman Yusupov, Kristian Tveten, Marie Falkenberg Smeland, Ebba Alkhunaizi, Gina Cowing, Chumei Li, Saskia B. Wortmann, René G. Feichtinger, Johannes A. Mayr, Herman Gonorazky, Gan Jing, Xiaodong Wang, Jia Wang, Tatjana Bierhals, Lev Grinstein, Theresia Herget, Anna Ruiz, Elisabeth Gabau, Antje Kampmeier, Olivier Kassel, Alma Kuechler, Konrad Platzer, Rami Abou Jamra, Audrey Woerner, Michaela Idleburg, Susanne Gerit Kircher, Franco Laccone, Barbara Golob, Borut Peterlin, Goran Čuturilo, Velibor Tasic, Caroline M. Kolvenbach, Friedhelm Hildebrandt, Luiza L.P. Ramos, Fernando Kok, Cecilia Barbosa Buck, Ingrid M.B.H. van de Laar, Stella A. de Man, Elifcan Taşdelen, Abdullah Sezer, Afife Büke, Zehra Yavuz, Selim Selçuk Çomoğlu, Carrie Costin, Frédéric Tran Mau Them, Elodie Lacaze, Thomas Courtin, Delphine Héron, Boris Keren, Sandra Whalen, Joelle Roume, Yanzhong Yang, Mariëtte J.V. Hoffer, Arie van Haeringen, Hossein Najmabadi, Cheryl H. Arrowsmith, Uwe Strähle, Hélène Dollfus, Jean Muller
{"title":"Bi-allelic PRMT9 loss-of-function variants cause a syndromic form of intellectual disability","authors":"Ariane Kröll-Hermi, Corinne Stoetzel, Christelle Etard, Levon Halabelian, Elise Schaefer, Sophie Scheidecker, Kimia Kahrizi, Jamali Payman, Véronique Geoffroy, Megana Prasad, Cathy Obringer, Laurie Ruch, Amandine Girard, Hong Zeng, Fengling Li, Damien Plassard, Céline Keime, Francesca Mattioli, Claire Feger, Amélie Piton, Atsushi Fujita, Naomichi Matsumoto, Matheus Augusto Araujo Castro, Kim Chong Ae, Lyse Ruaud, Jonathan Levy, Blandine Dozières, Anne-Claude Tabet, Ingrid M. Wentzensen, Teresa Santiago-Sim, Roman Yusupov, Kristian Tveten, Marie Falkenberg Smeland, Ebba Alkhunaizi, Gina Cowing, Chumei Li, Saskia B. Wortmann, René G. Feichtinger, Johannes A. Mayr, Herman Gonorazky, Gan Jing, Xiaodong Wang, Jia Wang, Tatjana Bierhals, Lev Grinstein, Theresia Herget, Anna Ruiz, Elisabeth Gabau, Antje Kampmeier, Olivier Kassel, Alma Kuechler, Konrad Platzer, Rami Abou Jamra, Audrey Woerner, Michaela Idleburg, Susanne Gerit Kircher, Franco Laccone, Barbara Golob, Borut Peterlin, Goran Čuturilo, Velibor Tasic, Caroline M. Kolvenbach, Friedhelm Hildebrandt, Luiza L.P. Ramos, Fernando Kok, Cecilia Barbosa Buck, Ingrid M.B.H. van de Laar, Stella A. de Man, Elifcan Taşdelen, Abdullah Sezer, Afife Büke, Zehra Yavuz, Selim Selçuk Çomoğlu, Carrie Costin, Frédéric Tran Mau Them, Elodie Lacaze, Thomas Courtin, Delphine Héron, Boris Keren, Sandra Whalen, Joelle Roume, Yanzhong Yang, Mariëtte J.V. Hoffer, Arie van Haeringen, Hossein Najmabadi, Cheryl H. Arrowsmith, Uwe Strähle, Hélène Dollfus, Jean Muller","doi":"10.1016/j.ajhg.2025.10.014","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.014","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"8 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545461","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 : 2025-11-13DOI: 10.1016/j.ajhg.2025.10.017
Meer Jacob Rahimi, Nicole Urban, Meret Wegler, Heinrich Sticht, Michael Schaefer, Bernt Popp, Frank Gaunitz, Manuela Morleo, Vincenzo Nigro, Silvia Maitz, Grazia M.S. Mancini, Claudia Ruivenkamp, Eun-Kyung Suk, Tobias Bartolomaeus, Andreas Merkenschlager, Daniel Koboldt, Dennis Bartholomew, Alexander P.A. Stegmann, Margje Sinnema, Irma Duynisveld, Ramona Salvarinova, Simone Race, Bert B.A. de Vries, Aurélien Trimouille, Sophie Naudion, Daphna Marom, Uri Hamiel, Noa Henig, Florence Demurger, Nils Rahner, Enrika Bartels, J. Austin Hamm, Abbey M. Putnam, Richard Person, Rami Abou Jamra, Henry Oppermann
{"title":"De novo variants in ATP2B1 lead to neurodevelopmental delay","authors":"Meer Jacob Rahimi, Nicole Urban, Meret Wegler, Heinrich Sticht, Michael Schaefer, Bernt Popp, Frank Gaunitz, Manuela Morleo, Vincenzo Nigro, Silvia Maitz, Grazia M.S. Mancini, Claudia Ruivenkamp, Eun-Kyung Suk, Tobias Bartolomaeus, Andreas Merkenschlager, Daniel Koboldt, Dennis Bartholomew, Alexander P.A. Stegmann, Margje Sinnema, Irma Duynisveld, Ramona Salvarinova, Simone Race, Bert B.A. de Vries, Aurélien Trimouille, Sophie Naudion, Daphna Marom, Uri Hamiel, Noa Henig, Florence Demurger, Nils Rahner, Enrika Bartels, J. Austin Hamm, Abbey M. Putnam, Richard Person, Rami Abou Jamra, Henry Oppermann","doi":"10.1016/j.ajhg.2025.10.017","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.017","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"85 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145499113","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 : 2025-11-12DOI: 10.1016/j.ajhg.2025.10.012
David Wang, Matthew R. Gazzara, San Jewell, Benjamin D. Wales-McGrath, Kevin Yang, Christopher D. Brown, Peter S. Choi, Yoseph Barash
{"title":"A deep dive into statistical modeling of RNA splicing QTLs reveals variants that explain neurodegenerative disease","authors":"David Wang, Matthew R. Gazzara, San Jewell, Benjamin D. Wales-McGrath, Kevin Yang, Christopher D. Brown, Peter S. Choi, Yoseph Barash","doi":"10.1016/j.ajhg.2025.10.012","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.012","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"51 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145499115","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 : 2025-11-12DOI: 10.1016/j.ajhg.2025.10.013
Sara E. Stinson, Renzo F. Balboa, Mette K. Andersen, Frederik F. Stæger, Shixu He, Anne Cathrine Baun Thuesen, Long Lin, Emil Jørsboe, Peter Bjerregaard, Christina V.L. Larsen, Niels Grarup, Marit E. Jørgensen, Ida Moltke, Anders Albrechtsen, Torben Hansen
{"title":"Genetic regulation of the plasma proteome and its link to cardiometabolic disease in Greenlandic Inuit","authors":"Sara E. Stinson, Renzo F. Balboa, Mette K. Andersen, Frederik F. Stæger, Shixu He, Anne Cathrine Baun Thuesen, Long Lin, Emil Jørsboe, Peter Bjerregaard, Christina V.L. Larsen, Niels Grarup, Marit E. Jørgensen, Ida Moltke, Anders Albrechtsen, Torben Hansen","doi":"10.1016/j.ajhg.2025.10.013","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.013","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145499114","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 : 2025-11-06DOI: 10.1016/j.ajhg.2025.10.008
Paul W. Hook, Alyson B. Barnes
{"title":"This month in The Journal","authors":"Paul W. Hook, Alyson B. Barnes","doi":"10.1016/j.ajhg.2025.10.008","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.10.008","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"95 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462324","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 : 2025-11-06Epub Date: 2025-10-13DOI: 10.1016/j.ajhg.2025.09.012
Zachary R McCaw, Jianhui Gao, Rounak Dey, Simon Tucker, Yiyan Zhang, Jessica Gronsbell, Xihao Li, Emily Fox, Colm O'Dushlaine, Thomas W Soare
Genes where a dose-response relationship exists between functionality and phenotypic impact are appealing therapeutic targets, as the effects of pharmacological modulation can be predicted from natural genetic variation. We refer to such genes as harboring allelic series and have introduced the rare coding-variant allelic series test (COAST) for their identification. The original COAST required access to individual-level data. However, these data are often unavailable due to privacy or logistical constraints. Meanwhile, single-variant summary statistics of the type produced by genome-wide association studies are plentiful. Here, we introduce COAST-SS, an extension of COAST that accepts standard summary statistics as input. As a running example, we consider identifying allelic series for circulating lipid traits, drawing on data from the UK Biobank, the Million Veteran Program, and the Trans-Omics of Precision Medicine Program. Through extensive analyses of real and simulated data, we demonstrate that COAST-SS provides p values effectively equivalent to those from the original COAST. Interestingly, we find that when linkage disequilibrium (LD) is low, as is expected among rare variants, COAST-SS is robust to misspecification of the LD matrix. We explore several strategies for annotating the pathogenicity of variants supplied to COAST-SS, finding that they often yield similar power for detecting candidate allelic series. Lastly, we employ COAST-SS to screen for lipid-trait allelic series in a meta-analyzed cohort of up to 840,000 subjects. COAST-SS has been incorporated into the publicly available AllelicSeries R package.
{"title":"A scalable framework for identifying allelic series from summary statistics.","authors":"Zachary R McCaw, Jianhui Gao, Rounak Dey, Simon Tucker, Yiyan Zhang, Jessica Gronsbell, Xihao Li, Emily Fox, Colm O'Dushlaine, Thomas W Soare","doi":"10.1016/j.ajhg.2025.09.012","DOIUrl":"10.1016/j.ajhg.2025.09.012","url":null,"abstract":"<p><p>Genes where a dose-response relationship exists between functionality and phenotypic impact are appealing therapeutic targets, as the effects of pharmacological modulation can be predicted from natural genetic variation. We refer to such genes as harboring allelic series and have introduced the rare coding-variant allelic series test (COAST) for their identification. The original COAST required access to individual-level data. However, these data are often unavailable due to privacy or logistical constraints. Meanwhile, single-variant summary statistics of the type produced by genome-wide association studies are plentiful. Here, we introduce COAST-SS, an extension of COAST that accepts standard summary statistics as input. As a running example, we consider identifying allelic series for circulating lipid traits, drawing on data from the UK Biobank, the Million Veteran Program, and the Trans-Omics of Precision Medicine Program. Through extensive analyses of real and simulated data, we demonstrate that COAST-SS provides p values effectively equivalent to those from the original COAST. Interestingly, we find that when linkage disequilibrium (LD) is low, as is expected among rare variants, COAST-SS is robust to misspecification of the LD matrix. We explore several strategies for annotating the pathogenicity of variants supplied to COAST-SS, finding that they often yield similar power for detecting candidate allelic series. Lastly, we employ COAST-SS to screen for lipid-trait allelic series in a meta-analyzed cohort of up to 840,000 subjects. COAST-SS has been incorporated into the publicly available AllelicSeries R package.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2772-2788"},"PeriodicalIF":8.1,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12808971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145290708","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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