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Frequencies of pharmacogenomic alleles across biogeographic groups in a large-scale biobank Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-09-26 Binglan Li, Katrin Sangkuhl, Ryan Whaley, Mark Woon, Karl Keat, Michelle Whirl-Carrillo, Marylyn D. Ritchie, Teri E. Klein
Pharmacogenomics (PGx) is an integral part of precision medicine and contributes to the maximization of drug efficacy and reduction of adverse drug event risk. Accurate information on PGx allele frequencies improves the implementation of PGx. Nonetheless, curating such information from published allele data is time and resource intensive. The limited number of allelic variants in most studies leads
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PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-09-25 Florence Petit, Mauro Longoni, Julie Wells, Richard S. Maser, Eric L. Bogenschutz, Matthew J. Dysart, Hannah T.M. Contreras, Frederic Frénois, Barbara R. Pober, Robin D. Clark, Philip F. Giampietro, Hilger H. Ropers, Hao Hu, Maria Loscertales, Richard Wagner, Xingbin Ai, Harrison Brand, Anne-Sophie Jourdain, Marie-Ange Delrue, Brigitte Gilbert-Dussardier, Frances A. High
Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense
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Literature-based predictions of Mendelian disease therapies Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-09-22 Cole A. Deisseroth, Won-Seok Lee, Jiyoen Kim, Hyun-Hwan Jeong, Ryan S. Dhindsa, Julia Wang, Huda Y. Zoghbi, Zhandong Liu
In the effort to treat Mendelian disorders, correcting the underlying molecular imbalance may be more effective than symptomatic treatment. Identifying treatments that might accomplish this goal requires extensive and up-to-date knowledge of molecular pathways—including drug-gene and gene-gene relationships. To address this challenge, we present “parsing modifiers via article annotations” (PARMESAN)
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The COPD GWAS gene ADGRG6 instructs function and injury response in human iPSC-derived type II alveolar epithelial cells Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-09-20 Rhiannon B. Werder, Kayleigh A. Berthiaume, Carly Merritt, Marissa Gallagher, Carlos Villacorta-Martin, Feiya Wang, Pushpinder Bawa, Vidhi Malik, Shawn M. Lyons, Maria C. Basil, Edward E. Morrisey, Darrell N. Kotton, Xiaobo Zhou, Michael H. Cho, Andrew A. Wilson
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Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-09-19 Warren van Loggerenberg, Shahin Sowlati-Hashjin, Jochen Weile, Rayna Hamilton, Aditya Chawla, Dayag Sheykhkarimli, Marinella Gebbia, Nishka Kishore, Laure Frésard, Sami Mustajoki, Elena Pischik, Elena Di Pierro, Michela Barbaro, Ylva Floderus, Caroline Schmitt, Laurent Gouya, Alexandre Colavin, Robert Nussbaum, Edith C.H. Friesema, Raili Kauppinen, Frederick P. Roth
Defects in hydroxymethylbilane synthase (HMBS) can cause acute intermittent porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, ∼⅓ of clinical HMBS variants are missense variants, and most clinically reported HMBS missense variants are designated as “variants of uncertain significance” (VUSs). Using saturation mutagenesis, en masse selection, and sequencing
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Demographic modeling of admixed Latin American populations from whole genomes Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-09-18 Santiago G. Medina-Muñoz, Diego Ortega-Del Vecchyo, Luis Pablo Cruz-Hervert, Leticia Ferreyra-Reyes, Lourdes García-García, Andrés Moreno-Estrada, Aaron P. Ragsdale
Demographic models of Latin American populations often fail to fully capture their complex evolutionary history, which has been shaped by both recent admixture and deeper-in-time demographic events. To address this gap, we used high-coverage whole-genome data from Indigenous American ancestries in present-day Mexico and existing genomes from across Latin America to infer multiple demographic models
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mtPGS: Leverage multiple correlated traits for accurate polygenic score construction Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-09-15 Chang Xu, Santhi K. Ganesh, Xiang Zhou
Accurate polygenic scores (PGSs) facilitate the genetic prediction of complex traits and aid in the development of personalized medicine. Here, we develop a statistical method called multi-trait assisted PGS (mtPGS), which can construct accurate PGSs for a target trait of interest by leveraging multiple traits relevant to the target trait. Specifically, mtPGS borrows SNP effect size similarity information
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Integration of genetic fine-mapping and multi-omics data reveals candidate effector genes for hypertension Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-09-07 Stefan van Duijvenboden, Julia Ramírez, William J. Young, Kaya J. Olczak, Farah Ahmed, Mohammed J.A.Y. Alhammadi, , Christopher G. Bell, Andrew P. Morris, Patricia B. Munroe
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The ancestry and geographical origins of St Helena’s liberated Africans Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-09-07 Marcela Sandoval-Velasco, Anuradha Jagadeesan, Jazmín Ramos-Madrigal, María C. Ávila-Arcos, Cesar A. Fortes-Lima, Judy Watson, Erna Johannesdóttir, Diana I. Cruz-Dávalos, Shyam Gopalakrishnan, J. Víctor Moreno-Mayar, Jonas Niemann, Gabriel Renaud, Katharine A. Robson Brown, Helena Bennett, Andrew Pearson, Agnar Helgason, M. Thomas P. Gilbert, Hannes Schroeder
The island of St Helena played a crucial role in the suppression of the transatlantic slave trade. Strategically located in the middle of the South Atlantic, it served as a staging post for the Royal Navy and reception point for enslaved Africans who had been “liberated” from slave ships intercepted by the British. In total, St Helena received approximately 27,000 liberated Africans between 1840 and
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This month in The Journal Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-09-07 Kylee L. Spencer, Sara B. Cullinan
Abstract not available
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Genome-wide association study of esophageal squamous cell cancer identifies shared and distinct risk variants in African and Chinese populations Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-09-05 Wenlong Carl Chen, Jean-Tristan Brandenburg, Ananyo Choudhury, Mahtaab Hayat, Dhriti Sengupta, Yaniv Swiel, Chantal Babb de Villiers, Lucien Ferndale, Colleen Aldous, Cassandra C. Soo, Sang Lee, Charles Curtis, Rob Newton, Tim Waterboer, Freddy Sitas, Debbie Bradshaw, Christian C. Abnet, Michele Ramsay, M. Iqbal Parker, Elvira Singh, Christopher G. Mathew
Esophageal squamous cell carcinoma (ESCC) has a high disease burden in sub-Saharan Africa and has a very poor prognosis. Genome-wide association studies (GWASs) of ESCC in predominantly East Asian populations indicate a substantial genetic contribution to its etiology, but no genome-wide studies have been done in populations of African ancestry. Here, we report a GWAS in 1,686 African individuals with
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High-throughput transcriptome analyses from ASPIRO, a phase 1/2/3 study of gene replacement therapy for X-linked myotubular myopathy Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-09-05 Gaia Andreoletti, Oriana Romano, Hsin-Jung Chou, Mahjoubeh J. Sefid-Dashti, Andrea Grilli, Clarice Chen, Neema Lakshman, Pravin Purushothaman, Fatbardha Varfaj, Fulvio Mavilio, Silvio Bicciato, Fabrizia Urbinati
X-linked myotubular myopathy (XLMTM) is a severe congenital disease characterized by profound muscle weakness, respiratory failure, and early death. No approved therapy for XLMTM is currently available. Adeno-associated virus (AAV)-mediated gene replacement therapy has shown promise as an investigational therapeutic strategy. We aimed to characterize the transcriptomic changes in muscle biopsies of
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Response to anti-IL17 therapy in inflammatory disease is not strongly impacted by genetic background Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-09-01 Cong Zhang, Konstantin Shestopaloff, Benjamin Hollis, Chun Hei Kwok, Claudia Hon, Nicole Hartmann, Chengeng Tian, Magdalena Wozniak, Luis Santos, Dominique West, Stephen Gardiner, Ann-Marie Mallon, Aimee Readie, Ruvie Martin, Thomas Nichols, Michael T. Beste, Jonas Zierer, Enrico Ferrero, Marc Vandemeulebroecke, Luke Jostins-Dean
Response to the anti-IL17 monoclonal antibody secukinumab is heterogeneous, and not all participants respond to treatment. Understanding whether this heterogeneity is driven by genetic variation is a key aim of pharmacogenetics and could influence precision medicine approaches in inflammatory diseases. Using changes in disease activity scores across 5,218 genotyped individuals from 19 clinical trials
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The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-30 Kathryn A. McGurk, Xiaolei Zhang, Pantazis Theotokis, Kate Thomson, Andrew Harper, Rachel J. Buchan, Erica Mazaika, Elizabeth Ormondroyd, William T. Wright, Daniela Macaya, Chee Jian Pua, Birgit Funke, Daniel G. MacArthur, Sanjay K. Prasad, Stuart A. Cook, Mona Allouba, Yasmine Aguib, Magdi H. Yacoub, Declan P. O'Regan, Paul J.R. Barton, James S. Ware
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Blood-based genome-wide DNA methylation correlations across body-fat- and adiposity-related biochemical traits Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-30 Alesha A. Hatton, Robert F. Hillary, Elena Bernabeu, Daniel L. McCartney, Riccardo E. Marioni, Allan F. McRae
The recent increase in obesity levels across many countries is likely to be driven by nongenetic factors. The epigenetic modification DNA methylation (DNAm) may help to explore this, as it is sensitive to both genetic and environmental exposures. While the relationship between DNAm and body-fat traits has been extensively studied, there is limited literature on the shared associations of DNAm variation
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Dissecting the high-resolution genetic architecture of complex phenotypes by accurately estimating gene-based conditional heritability Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-25 Lin Miao, Lin Jiang, Bin Tang, Pak Chung Sham, Miaoxin Li
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Advanced variant classification framework reduces the false positive rate of predicted loss-of-function variants in population sequencing data Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-25 Moriel Singer-Berk, Sanna Gudmundsson, Samantha Baxter, Eleanor G. Seaby, Eleina England, Jordan C. Wood, Rachel G. Son, Nicholas A. Watts, Konrad J. Karczewski, Steven M. Harrison, Daniel G. MacArthur, Heidi L. Rehm, Anne O’Donnell-Luria
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An RNA-informed dosage sensitivity map reflects the intrinsic functional nature of genes Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-23 Danyue Dong, Haoyu Shen, Zhenguo Wang, Jiaqi Liu, Zhe Li, Xin Li
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GLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individuals Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-21 Menno ter Huurne, Benjamin L. Parker, Ning Qing Liu, Elizabeth Ling Qian, Celine Vivien, Kathy Karavendzas, Richard J. Mills, Jennifer T. Saville, Dad Abu-Bonsrah, Andrea F. Wise, James E. Hudson, Andrew S. Talbot, Patrick F. Finn, Paolo G.V. Martini, Maria Fuller, Sharon D. Ricardo, Kevin I. Watt, Kathy M. Nicholls, Enzo R. Porrello, David A. Elliott
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The phenotype-genotype reference map: Improving biobank data science through replication Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-21 Lisa Bastarache, Sarah Delozier, Anita Pandit, Jing He, Adam Lewis, Aubrey C. Annis, Jonathon LeFaive, Joshua C. Denny, Robert J. Carroll, Russ B. Altman, Jacob J. Hughey, Matthew Zawistowski, Josh F. Peterson
Population-scale biobanks linked to electronic health record data provide vast opportunities to extend our knowledge of human genetics and discover new phenotype-genotype associations. Given their dense phenotype data, biobanks can also facilitate replication studies on a phenome-wide scale. Here, we introduce the phenotype-genotype reference map (PGRM), a set of 5,879 genetic associations from 523
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Systematic evaluation of genome sequencing for the diagnostic assessment of autism spectrum disorder and fetal structural anomalies Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-17 Chelsea Lowther, Elise Valkanas, Jessica L. Giordano, Harold Z. Wang, Benjamin B. Currall, Kathryn O’Keefe, Emma Pierce-Hoffman, Nehir E. Kurtas, Christopher W. Whelan, Stephanie P. Hao, Ben Weisburd, Vahid Jalili, Jack Fu, Isaac Wong, Ryan L. Collins, Xuefang Zhao, Christina A. Austin-Tse, Emily Evangelista, Gabrielle Lemire, Vimla S. Aggarwal, Michael E. Talkowski
Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). To assess the clinical utility
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AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-14 Paulien Terhal, Anton J. Venhuizen, Davor Lessel, Wen-Hann Tan, Abdulrahman Alswaid, Regina Grün, Hamad I. Alzaidan, Simon von Kroge, Nada Ragab, Maja Hempel, Christian Kubisch, Eduardo Novais, Alba Cristobal, Kornelia Tripolszki, Peter Bauer, Björn Fischer-Zirnsak, Rutger A.J. Nievelstein, Atty van Dijk, Peter Nikkels, Ralf Oheim, Uwe Kornak
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Integrative splicing-quantitative-trait-locus analysis reveals risk loci for non-small-cell lung cancer Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-09 Yuzhuo Wang, Yue Ding, Su Liu, Cheng Wang, Erbao Zhang, Congcong Chen, Meng Zhu, Jing Zhang, Chen Zhu, Mengmeng Ji, Juncheng Dai, Guangfu Jin, Zhibin Hu, Hongbing Shen, Hongxia Ma
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Genetic insights into the age-specific biological mechanisms governing human ovarian aging Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-04 Sven E. Ojavee, Liza Darrous, Marion Patxot, Kristi Läll, Krista Fischer, Reedik Mägi, Zoltan Kutalik, Matthew R. Robinson
There is currently little evidence that the genetic basis of human phenotype varies significantly across the lifespan. However, time-to-event phenotypes are understudied and can be thought of as reflecting an underlying hazard, which is unlikely to be constant through life when values take a broad range. Here, we find that 74% of 245 genome-wide significant genetic associations with age at natural
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This month in The Journal Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-03 Kylee L. Spencer, Sara B. Cullinan
Abstract not available
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Beyond the exome: What’s next in diagnostic testing for Mendelian conditions Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-03 Monica H. Wojcik, Chloe M. Reuter, Shruti Marwaha, Medhat Mahmoud, Michael H. Duyzend, Hayk Barseghyan, Bo Yuan, Philip M. Boone, Emily E. Groopman, Emmanuèle C. Délot, Deepti Jain, Alba Sanchis-Juan, , Lea M. Starita, Michael Talkowski, Stephen B. Montgomery, Michael J. Bamshad, Jessica X. Chong, Matthew T. Wheeler, Seth I. Berger, Danny E. Miller
Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple
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Combined CRISPRi and proteomics screening reveal a cohesin-CTCF-bound allele contributing to increased expression of RUVBL1 and prostate cancer progression Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-03 Yijun Tian, Dandan Dong, Zixian Wang, Lang Wu, Jong Y. Park, , Gong-Hong Wei, Liang Wang
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Genome sequencing and comprehensive rare-variant analysis of 465 families with neurodevelopmental disorders Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-03 Alba Sanchis-Juan, Karyn Megy, Jonathan Stephens, Camila Armirola Ricaurte, Eleanor Dewhurst, Kayyi Low, Courtney E. French, Detelina Grozeva, Kathleen Stirrups, Marie Erwood, Amy McTague, Christopher J. Penkett, Olga Shamardina, Salih Tuna, Louise C. Daugherty, Nicholas Gleadall, Sofia T. Duarte, Antonio Hedrera-Fernández, Julie Vogt, Gautam Ambegaonkar, Keren J. Carss
Despite significant progress in unraveling the genetic causes of neurodevelopmental disorders (NDDs), a substantial proportion of individuals with NDDs remain without a genetic diagnosis after microarray and/or exome sequencing. Here, we aimed to assess the power of short-read genome sequencing (GS), complemented with long-read GS, to identify causal variants in participants with NDD from the National
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HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-03 Eva Niggl, Arjan Bouman, Lauren C. Briere, Remco M. Hoogenboezem, Ilse Wallaard, Joohyun Park, Jakob Admard, Martina Wilke, Emilio D.R.O. Harris-Mostert, Minetta Elgersma, Jennifer Bain, Meena Balasubramanian, Siddharth Banka, Paul J. Benke, Miriam Bertrand, Alyssa E. Blesson, Jill Clayton-Smith, Jamie M. Ellingford, Madelyn A. Gillentine, Dana H. Goodloe, Annelot C.M. van Esbroeck
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Ethical considerations when co-analyzing ancient DNA and data from private genetic databases Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-08-03 Éadaoin Harney, Kendra Sirak, Jakob Sedig, Steven Micheletti, Roslyn Curry, Samantha Ancona Esselmann, David Reich
Ancient DNA studies have begun to explore the possibility of identifying identical DNA segments shared between historical and living people. This research requires access to large genetic datasets to maximize the likelihood of identifying previously unknown, close genetic connections. Direct-to-consumer genetic testing companies, such as 23andMe, Inc., manage by far the largest and most diverse genetic
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High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-07-27 Yuan-Yuan Duan, Xiao-Feng Chen, Ren-Jie Zhu, Ying-Ying Jia, Xiao-Ting Huang, Meng Zhang, Ning Yang, Shan-Shan Dong, Mengqi Zeng, Zhihui Feng, Dong-Li Zhu, Hao Wu, Feng Jiang, Wei Shi, Wei-Xin Hu, Xin Ke, Hao Chen, Yunlong Liu, Rui-Hua Jing, Yan Guo, Tie-Lin Yang
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Population screening shows risk of inherited cancer and familial hypercholesterolemia in Oregon Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-07-27 Timothy D. O’Brien, Amiee B. Potter, Catherine C. Driscoll, Gregory Goh, John H. Letaw, Sarah McCabe, Jane Thanner, Arpita Kulkarni, Rossana Wong, Samuel Medica, Tiana Week, Jacob Buitrago, Aaron Larson, Katie Johnson Camacho, Kim Brown, Rachel Crist, Casey Conrad, Sara Evans-Dutson, Ryan Lutz, Asia Mitchell, C. Sue Richards
The Healthy Oregon Project (HOP) is a statewide effort that aims to build a large research repository and influence the health of Oregonians through providing no-cost genetic screening to participants for a next-generation sequencing 32-gene panel comprising genes related to inherited cancers and familial hypercholesterolemia. This type of unbiased population screening can detect at-risk individuals
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An allelic-series rare-variant association test for candidate-gene discovery Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-07-25 Zachary R. McCaw, Colm O’Dushlaine, Hari Somineni, Michael Bereket, Christoph Klein, Theofanis Karaletsos, Francesco Paolo Casale, Daphne Koller, Thomas W. Soare
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A form of inherited hyperferritinemia associated with bi-allelic pathogenic variants of STAB1 Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-07-24 Edoardo Monfrini, Sara Pelucchi, Maija Hollmén, Miro Viitala, Raffaella Mariani, Francesca Bertola, Silvia Majore, Alessio Di Fonzo, Alberto Piperno
Hyperferritinemia is a frequent finding in several conditions, both genetic and acquired. We previously studied eleven healthy subjects from eight different families presenting with unexplained hyperferritinemia. Their findings suggested the existence of an autosomal-recessive disorder. We carried out whole-exome sequencing to detect the genetic cause of hyperferritinemia. Immunohistochemistry and
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Genotype error due to low-coverage sequencing induces uncertainty in polygenic scoring Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-07-24 Ella Petter, Yi Ding, Kangcheng Hou, Arjun Bhattacharya, Alexander Gusev, Noah Zaitlen, Bogdan Pasaniuc
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Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-07-18 Daniel G. Calame, Tianyu Guo, Chen Wang, Lillian Garrett, Angad Jolly, Moez Dawood, Alina Kurolap, Noa Zunz Henig, Jawid M. Fatih, Isabella Herman, Haowei Du, Tadahiro Mitani, Lore Becker, Birgit Rathkolb, Raffaele Gerlini, Claudia Seisenberger, Susan Marschall, Jill V. Hunter, Amanda Gerard, Alexis Heidlebaugh, James R. Lupski
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De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-07-13 Manuela Morleo, Rossella Venditti, Evangelos Theodorou, Lauren C. Briere, Marion Rosello, Alfonsina Tirozzi, Roberta Tammaro, Nour Al-Badri, Frances A. High, Jiahai Shi
Phosphoinositides (PIs) are membrane phospholipids produced through the local activity of PI kinases and phosphatases that selectively add or remove phosphate groups from the inositol head group. PIs control membrane composition and play key roles in many cellular processes including actin dynamics, endosomal trafficking, autophagy, and nuclear functions. Mutations in phosphatidylinositol 4,5 bisphosphate
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Genetic underpinning of the comorbidity between type 2 diabetes and osteoarthritis Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-07-10 Ana Luiza Arruda, April Hartley, Georgia Katsoula, George Davey Smith, Andrew P. Morris, Eleftheria Zeggini
Multimorbidity is a rising public health challenge with important implications for health management and policy. The most common multimorbidity pattern is the combination of cardiometabolic and osteoarticular diseases. Here, we study the genetic underpinning of the comorbidity between type 2 diabetes and osteoarthritis. We find genome-wide genetic correlation between the two diseases and robust evidence
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This month in The Journal Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-07-06 Kylee L. Spencer, Sara B. Cullinan
Abstract not available
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Multi-response Mendelian randomization: Identification of shared and distinct exposures for multimorbidity and multiple related disease outcomes Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-07-06 Verena Zuber, Alex Lewin, Michael G. Levin, Alexander Haglund, Soumaya Ben-Aicha, Costanza Emanueli, Scott Damrauer, Stephen Burgess, Dipender Gill, Leonardo Bottolo
The existing framework of Mendelian randomization (MR) infers the causal effect of one or multiple exposures on one single outcome. It is not designed to jointly model multiple outcomes, as would be necessary to detect causes of more than one outcome and would be relevant to model multimorbidity or other related disease outcomes. Here, we introduce multi-response Mendelian randomization (MR2), an MR
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Approaches to studying the impact of 22q11.2 copy number variants Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-07-06 Anne S. Bassett, Donna M. McDonald-McGinn, Erik Boot, Sólveig Óskarsdóttir, Ryan K.C. Yuen
Abstract not available
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Response to Bassett et al. Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-07-06 Malú Zamariolli, Chiara Auwerx, Marie C. Sadler, Adriaan van der Graaf, Kaido Lepik, Tabea Schoeler, Mariana Moysés-Oliveira, Anelisa G. Dantas, Maria Isabel Melaragno, Zoltán Kutalik
Abstract not available
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Implications of family history and polygenic risk scores for causation Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-07-06 Shuai Li, John L. Hopper
Abstract not available
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Response to Li and Hopper Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-07-06 Nina Mars, Joni V. Lindbohm, Pietro della Briotta Parolo, Elisabeth Widén, Jaakko Kaprio, Aarno Palotie, , Samuli Ripatti
Abstract not available
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Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-07-07 Annalisa Vetro, Cristiana Pelorosso, Simona Balestrini, Alessio Masi, Sophie Hambleton, Emanuela Argilli, Valerio Conti, Simone Giubbolini, Rebekah Barrick, Gaber Bergant, Karin Writzl, Emilia K. Bijlsma, Theresa Brunet, Pilar Cacheiro, Davide Mei, Anita Devlin, Mariëtte J.V. Hoffer, Keren Machol, Guido Mannaioni, Masamune Sakamoto, Renzo Guerrini
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Polygenic risk prediction: why and when out-of-sample prediction R2 can exceed SNP-based heritability Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-06-27 Xiaotong Wang, Alicia Walker, Joana A. Revez, Guiyan Ni, Mark J. Adams, Andrew M. McIntosh
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Epilepsies of presumed genetic etiology show enrichment of rare variants that occur in the general population Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-06-26 Linnaeus Bundalian, Yin-Yuan Su, Siwei Chen, Akhil Velluva, Anna Sophia Kirstein, Antje Garten, Saskia Biskup, Florian Battke, Dennis Lal, Henrike O. Heyne, Konrad Platzer, Chen-Ching Lin, Johannes R. Lemke, Diana Le Duc
Previous studies suggested that severe epilepsies, e.g., developmental and epileptic encephalopathies (DEEs), are mainly caused by ultra-rare de novo genetic variants. For milder disease, rare genetic variants could contribute to the phenotype. To determine the importance of rare variants for different epilepsy types, we analyzed a whole-exome sequencing cohort of 9,170 epilepsy-affected individuals
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Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-06-22 Long Guo, Smrithi Salian, Jing-yi Xue, Nicola Rath, Justine Rousseau, Hyunyun Kim, Sophie Ehresmann, Shahida Moosa, Norio Nakagawa, Hiroshi Kuroda, Jill Clayton-Smith, Juan Wang, Zheng Wang, Siddharth Banka, Adam Jackson, Yan-min Zhang, Zhen-jie Wei, Irina Hüning, Theresa Brunet, Hirofumi Ohashi, Philippe M. Campeau
ERI1 is a 3′-to-5′ exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified
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Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-06-22 Logan C. Walker, Miguel de la Hoya, George A.R. Wiggins, Amanda Lindy, Lisa M. Vincent, Michael T. Parsons, Daffodil M. Canson, Dana Bis-Brewer, Ashley Cass, Alexander Tchourbanov, Heather Zimmermann, Alicia B. Byrne, Tina Pesaran, Rachid Karam, Steven M. Harrison, Amanda B. Spurdle
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High-throughput identification of regulatory elements and functional assays to uncover susceptibility genes for nasopharyngeal carcinoma Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-06-22 Tong-Min Wang, Ruo-Wen Xiao, Yong-Qiao He, Wen-Li Zhang, Hua Diao, Minzhong Tang, Zhi-Ming Mai, Wen-Qiong Xue, Da-Wei Yang, Chang-Mi Deng, Ying Liao, Ting Zhou, Dan-Hua Li, Yan-Xia Wu, Xue-Yin Chen, Jiangbo Zhang, Xi-Zhao Li, Pei-Fen Zhang, Xiao-Hui Zheng, Shao-Dan Zhang, Wei-Hua Jia
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Studying the impact of translational genomic research: Lessons from eMERGE Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-06-20 Ellen Wright Clayton, Maureen E. Smith, Katherine C. Anderson, Wendy K. Chung, John J. Connolly, Stephanie M. Fullerton, Michelle L. McGowan, Josh F. Peterson, Cynthia A. Prows, Maya Sabatello, Ingrid A. Holm
Two major goals of the Electronic Medical Record and Genomics (eMERGE) Network are to learn how best to return research results to patient/participants and the clinicians who care for them and also to assess the impact of placing these results in clinical care. Yet since its inception, the Network has confronted a host of challenges in achieving these goals, many of which had ethical, legal, or social
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CGG repeat expansion in LRP12 in amyotrophic lateral sclerosis Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-06-19 Kodai Kume, Takashi Kurashige, Keiko Muguruma, Hiroyuki Morino, Yui Tada, Mai Kikumoto, Tatsuo Miyamoto, Silvia Natsuko Akutsu, Yukiko Matsuda, Shinya Matsuura, Masahiro Nakamori, Ayumi Nishiyama, Rumiko Izumi, Tetsuya Niihori, Masashi Ogasawara, Nobuyuki Eura, Tamaki Kato, Mamoru Yokomura, Yoshiaki Nakayama, Hidefumi Ito, Hideshi Kawakami
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Autoimmune alleles at the major histocompatibility locus modify melanoma susceptibility Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-06-19 James V. Talwar, David Laub, Meghana S. Pagadala, Andrea Castro, McKenna Lewis, Georg E. Luebeck, Bryan R. Gorman, Cuiping Pan, Frederick N. Dong, Kyriacos Markianos, Craig C. Teerlink, Julie Lynch, Richard Hauger, Saiju Pyarajan, Philip S. Tsao, Gerald P. Morris, Rany M. Salem, Wesley K. Thompson, Kit Curtius, Maurizio Zanetti, Hannah Carter
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Haplotype-based analysis resolves missing heritability in oculocutaneous albinism type 1B Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-06-15 Stacie K. Loftus, Meredith F. Gillis, Linnea Lundh, Laura L. Baxter, Julia C. Wedel, Dawn E. Watkins-Chow, Frank X. Donovan, , Yuri V. Sergeev, William S. Oetting, William J. Pavan, David R. Adams
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Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-06-12 Burcu F. Darst, Jiayi Shen, Ravi K. Madduri, Alexis A. Rodriguez, Yukai Xiao, Xin Sheng, Edward J. Saunders, Tokhir Dadaev, Mark N. Brook, Thomas J. Hoffmann, Kenneth Muir, Peggy Wan, Loic Le Marchand, Lynne Wilkens, Ying Wang, Johanna Schleutker, Robert J. MacInnis, Cezary Cybulski, David E. Neal, Børge G. Nordestgaard, Christopher A. Haiman
Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained
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Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-06-09 Paulina Cunha, Emilien Petit, Marie Coutelier, Giulia Coarelli, Caterina Mariotti, Jennifer Faber, Judith Van Gaalen, Joana Damasio, Zofia Fleszar, Michele Tosi, Clarissa Rocca, Giovanna De Michele, Martina Minnerop, Claire Ewenczyk, Filippo M. Santorelli, Anna Heinzmann, Thomas Bird, Matthias Amprosi, Elisabetta Indelicato, Alberto Benussi, Alexandra Durr
Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated
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Actionability of unanticipated monogenic disease risks in newborn genomic screening: Findings from the BabySeq Project Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-06-05 Robert C. Green, Nidhi Shah, Casie A. Genetti, Timothy Yu, Bethany Zettler, Melissa K. Uveges, Ozge Ceyhan-Birsoy, Matthew S. Lebo, Stacey Pereira, Pankaj B. Agrawal, Richard B. Parad, Amy L. McGuire, Kurt D. Christensen, Talia S. Schwartz, Heidi L. Rehm, Ingrid A. Holm, Alan H. Beggs
Newborn genomic sequencing (NBSeq) to screen for medically important genetic information is of considerable interest but data characterizing the actionability of such findings, and the downstream medical efforts in response to discovery of unanticipated genetic risk variants, are lacking. From a clinical trial of comprehensive exome sequencing in 127 apparently healthy infants and 32 infants in intensive
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This month in The Journal Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-06-01 Kylee L. Spencer, Sara B. Cullinan
Abstract not available
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eXclusionarY: 10 years later, where are the sex chromosomes in GWASs? Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-06-01 Lei Sun, Zhong Wang, Tianyuan Lu, Teri A. Manolio, Andrew D. Paterson
10 years ago, a detailed analysis showed that only 33% of genome-wide association study (GWAS) results included the X chromosome. Multiple recommendations were made to combat such exclusion. Here, we re-surveyed the research landscape to determine whether these earlier recommendations had been translated. Unfortunately, among the genome-wide summary statistics reported in 2021 in the NHGRI-EBI GWAS
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Progress in expanding newborn screening in the United States Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-06-01 Scott D. Grosse, Carla Cuthbert, Marcus Gaffney, Amy Gaviglio, Cynthia F. Hinton, Yvonne Kellar-Guenther, Alex R. Kemper, Sarah McKasson, Jelili Ojodu, Catharine Riley, Sikha Singh, Marci K. Sontag, Stuart K. Shapira
Abstract not available