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GNA14 and GNAQ somatic mutations cause spinal and intracranial extra-axial cavernous hemangiomas Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-06-24 Jian Ren, Ziwei Cui, Chendan Jiang, Leiming Wang, Yunqian Guan, Yeqing Ren, Shikun Zhang, Tianqi Tu, Jiaxing Yu, Ye Li, Wanru Duan, Jian Guan, Kai Wang, Hongdian Zhang, Dong Xing, Mark L. Kahn, Hongqi Zhang, Tao Hong
Extra-axial cavernous hemangiomas (ECHs) are complex vascular lesions mainly found in the spine and cavernous sinus. Their removal poses significant risk due to their vascularity and diffuse nature, and their genetic underpinnings remain incompletely understood. Our approach involved genetic analyses on 31 tissue samples of ECHs employing whole-exome sequencing and targeted deep sequencing. We explored
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Evaluation of polygenic scoring methods in five biobanks shows larger variation between biobanks than methods and finds benefits of ensemble learning Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-06-21 Remo Monti, Lisa Eick, Georgi Hudjashov, Kristi Läll, Stavroula Kanoni, Brooke N. Wolford, Benjamin Wingfield, Oliver Pain, Sophie Wharrie, Bradley Jermy, Aoife McMahon, Tuomo Hartonen, Henrike Heyne, Nina Mars, Samuel Lambert, Genes and Health Research Team, Kristian Hveem, Michael Inouye, David A. van Heel, Reedik Mägi, Pekka Marttinen, Samuli Ripatti, Andrea Ganna, Christoph Lippert
Methods of estimating polygenic scores (PGSs) from genome-wide association studies are increasingly utilized. However, independent method evaluation is lacking, and method comparisons are often limited. Here, we evaluate polygenic scores derived via seven methods in five biobank studies (totaling about 1.2 million participants) across 16 diseases and quantitative traits, building on a reference-standardized
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Truncated variants of MAGEL2 are involved in the etiologies of the Schaaf-Yang and Prader-Willi syndromes Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-06-21 David Heimdörfer, Alexander Vorleuter, Alexander Eschlböck, Angeliki Spathopoulou, Marta Suarez-Cubero, Hesso Farhan, Veronika Reiterer, Melanie Spanjaard, Christian P. Schaaf, Lukas A. Huber, Leopold Kremser, Bettina Sarg, Frank Edenhofer, Stephan Geley, Mariana E.G. de Araujo, Alexander Huettenhofer
The neurodevelopmental disorders Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) both arise from genomic alterations within human chromosome 15q11–q13. A deletion of the cluster, encoding small nucleolar RNAs, or frameshift mutations within result in closely related phenotypes in individuals with PWS or SYS, respectively. By investigation of their subcellular localization, we observed that
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High-throughput characterization of functional variants highlights heterogeneity and polygenicity underlying lung cancer susceptibility Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-06-20 Erping Long, Harsh Patel, Alyxandra Golden, Michelle Antony, Jinhu Yin, Karen Funderburk, James Feng, Lei Song, Jason W. Hoskins, Laufey T. Amundadottir, Rayjean J. Hung, Christopher I. Amos, Jianxin Shi, Nathaniel Rothman, Qing Lan, International Lung Cancer Consortium, Jiyeon Choi
Genome-wide association studies (GWASs) have identified numerous lung cancer risk-associated loci. However, decoding molecular mechanisms of these associations is challenging since most of these genetic variants are non-protein-coding with unknown function. Here, we implemented massively parallel reporter assays (MPRAs) to simultaneously measure the allelic transcriptional activity of risk-associated
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Identification and correction for collider bias in a genome-wide association study of diabetes-related heart failure Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-06-18 Yan V. Sun, Chang Liu, Qin Hui, Jin J. Zhou, J. Michael Gaziano, Peter W.F. Wilson, the Million Veteran Program, Jacob Joseph, Lawrence S. Phillips
Type 2 diabetes (T2D) is a major risk factor for heart failure (HF) and has elevated incidence among individuals with HF. Since genetics and HF can independently influence T2D, collider bias may occur when T2D (i.e., collider) is controlled for by design or analysis. Thus, we conducted a genome-wide association study (GWAS) of diabetes-related HF with correction for collider bias. We first performed
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Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-06-17 Claudia Manzoni, Demis A. Kia, Raffaele Ferrari, Ganna Leonenko, Beatrice Costa, Valentina Saba, Edwin Jabbari, Manuela MX. Tan, Diego Albani, Victoria Alvarez, Ignacio Alvarez, Ole A. Andreassen, Antonella Angiolillo, Andrea Arighi, Matt Baker, Luisa Benussi, Valentina Bessi, Giuliano Binetti, Daniel J. Blackburn, Merce Boada, Bradley F. Boeve, Sergi Borrego-Ecija, Barbara Borroni, Geir Bråthen, William
Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found
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Germline thymidylate synthase deficiency impacts nucleotide metabolism and causes dyskeratosis congenita Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-06-11 Hemanth Tummala, Amanda Walne, Roberto Buccafusca, Jenna Alnajar, Anita Szabo, Peter Robinson, Allyn McConkie-Rosell, Meredith Wilson, Suzanne Crowley, Veronica Kinsler, Anna-Maria Ewins, Pradeepa M. Madapura, Manthan Patel, Nikolas Pontikos, Veryan Codd, Tom Vulliamy, Inderjeet Dokal
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A scalable and robust variance components method reveals insights into the architecture of gene-environment interactions underlying complex traits Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-06-11 Ali Pazokitoroudi, Zhengtong Liu, Andrew Dahl, Noah Zaitlen, Saharon Rosset, Sriram Sankararaman
Understanding the contribution of gene-environment interactions (GxE) to complex trait variation can provide insights into disease mechanisms, explain sources of heritability, and improve genetic risk prediction. While large biobanks with genetic and deep phenotypic data hold promise for obtaining novel insights into GxE, our understanding of GxE architecture in complex traits remains limited. We introduce
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PSMD11 loss-of-function variants correlate with a neurobehavioral phenotype, obesity, and increased interferon response Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-06-11 Wallid Deb, Cory Rosenfelt, Virginie Vignard, Jonas Johannes Papendorf, Sophie Möller, Martin Wendlandt, Maja Studencka-Turski, Benjamin Cogné, Thomas Besnard, Léa Ruffier, Bérénice Toutain, Léa Poirier, Silvestre Cuinat, Amy Kritzer, Amy Crunk, Janette diMonda, Jaime Vengoechea, Sandra Mercier, Lotte Kleinendorst, Mieke M. van Haelst, Linda Zuurbier, Telma Sulem, Hildigunnur Katrínardóttir, Rún Friðriksdóttir
Primary proteasomopathies have recently emerged as a new class of rare early-onset neurodevelopmental disorders (NDDs) caused by pathogenic variants in the , , , or proteasome genes. Proteasomes are large multi-subunit protein complexes that maintain cellular protein homeostasis by clearing ubiquitin-tagged damaged, misfolded, or unnecessary proteins. In this study, we have identified as an additional
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This Month in The Journal Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-06-06 Alyson B. Barnes, Kylee L. Spencer, Sara B. Cullinan
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The impact of clinical genome sequencing in a global population with suspected rare genetic disease Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-06-05 Erin Thorpe, Taylor Williams, Chad Shaw, Evgenii Chekalin, Julia Ortega, Keisha Robinson, Jason Button, Marilyn C. Jones, Miguel del Campo, Donald Basel, Julie McCarrier, Laura Davis Keppen, Erin Royer, Romina Foster-Bonds, Milagros M. Duenas-Roque, Nora Urraca, Kerri Bosfield, Chester W. Brown, Holly Lydigsen, Henry J. Mroczkowski, Jewell Ward, Fabio Sirchia, Elisa Giorgio, Keith Vaux, Hildegard Peña
There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24
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CanCellVar: A database for single-cell variants map in human cancer Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-06-04 Changbo Yang, Yujie Liu, Chongwen Lv, Mengjia Xu, Kang Xu, Jingyi Shi, Tingting Tan, Weiwei Zhou, Dezhong Lv, Yongsheng Li, Juan Xu, Tingting Shao
Numerous variants, including both single-nucleotide variants (SNVs) in DNA and A>G RNA edits in mRNA as essential drivers of cellular proliferation and tumorigenesis, are commonly associated with cancer progression and growth. Thus, mining and summarizing single-cell variants will provide a refined and higher-resolution view of cancer and further contribute to precision medicine. Here, we established
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Impact of genome build on RNA-seq interpretation and diagnostics Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-06-03 Rachel A. Ungar, Pagé C. Goddard, Tanner D. Jensen, Fabien Degalez, Kevin S. Smith, Christopher A. Jin, Undiagnosed Diseases Network, Devon E. Bonner, Jonathan A. Bernstein, Matthew T. Wheeler, Stephen B. Montgomery
Transcriptomics is a powerful tool for unraveling the molecular effects of genetic variants and disease diagnosis. Prior studies have demonstrated that choice of genome build impacts variant interpretation and diagnostic yield for genomic analyses. To identify the extent genome build also impacts transcriptomics analyses, we studied the effect of the hg19, hg38, and CHM13 genome builds on expression
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KnockoffHybrid: A knockoff framework for hybrid analysis of trio and population designs in genome-wide association studies Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-30 Yi Yang, Qi Wang, Chen Wang, Joseph Buxbaum, Iuliana Ionita-Laza
Both trio and population designs are popular study designs for identifying risk genetic variants in genome-wide association studies (GWASs). The trio design, as a family-based design, is robust to confounding due to population structure, whereas the population design is often more powerful due to larger sample sizes. Here, we propose KnockoffHybrid, a knockoff-based statistical method for hybrid analysis
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Regional-specific calibration enables application of computational evidence for clinical classification of 5′ cis-regulatory variants in Mendelian disease Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-29 Rehan M. Villani, Maddison E. McKenzie, Aimee L. Davidson, Amanda B. Spurdle
To date, clinical genetic testing for Mendelian disease variants has focused heavily on exonic coding and intronic gene regions. This multi-step study was undertaken to provide an evidence base for selecting and applying computational approaches for use in clinical classification of 5′ -regulatory region variants. Curated datasets of clinically reported disease-causing 5′ -regulatory region variants
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MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-29 Remzi Karayol, Maria Carla Borroto, Sadegheh Haghshenas, Anoja Namasivayam, Jack Reilly, Michael A. Levy, Raissa Relator, Jennifer Kerkhof, Haley McConkey, Maria Shvedunova, Andrea K. Petersen, Kari Magnussen, Christiane Zweier, Georgia Vasileiou, André Reis, Juliann M. Savatt, Meghan R. Mulligan, Louise S. Bicknell, Gemma Poke, Aya Abu-El-Haija, Jessica Duis, Vickie Hannig, Siddharth Srivastava, Elizabeth
Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression
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Haploinsufficiency underlies the neurodevelopmental consequences of SLC6A1 variants Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-22 Dina Buitrago Silva, Marena Trinidad, Alicia Ljungdahl, Jezrael L. Revalde, Geoffrey Y. Berguig, William Wallace, Cory S. Patrick, Lorenzo Bomba, Michelle Arkin, Shan Dong, Karol Estrada, Keino Hutchinson, Jonathan H. LeBowitz, Avner Schlessinger, Katrine M. Johannesen, Rikke S. Møller, Kathleen M. Giacomini, Steven Froelich, Stephan J. Sanders, Arthur Wuster
Heterozygous variants in , encoding the GAT-1 GABA transporter, are associated with seizures, developmental delay, and autism. The majority of affected individuals carry missense variants, many of which are recurrent germline mutations, raising the possibility of gain-of-function or dominant-negative effects. To understand the functional consequences, we performed an GABA uptake assay for 213 unique
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Oral and non-oral lichen planus show genetic heterogeneity and differential risk for autoimmune disease and oral cancer Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-21 Mary Pat Reeve, Mari Vehviläinen, Shuang Luo, Jarmo Ritari, Juha Karjalainen, Javier Gracia-Tabuenca, Juha Mehtonen, Shanmukha Sampath Padmanabhuni, Nikita Kolosov, Mykyta Artomov, Harri Siirtola, Hanna M. Ollila, FinnGen, Daniel Graham, Jukka Partanen, Ramnik J. Xavier, Mark J. Daly, Samuli Ripatti, Tuula Salo, Maria Siponen
Lichen planus (LP) is a T-cell-mediated inflammatory disease affecting squamous epithelia in many parts of the body, most often the skin and oral mucosa. Cutaneous LP is usually transient and oral LP (OLP) is most often chronic, so we performed a large-scale genetic and epidemiological study of LP to address whether the oral and non-oral subgroups have shared or distinct underlying pathologies and
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The impact of inversions across 33,924 families with rare disease from a national genome sequencing project Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-21 Alistair T. Pagnamenta, Jing Yu, Susan Walker, Alexandra J. Noble, Jenny Lord, Prasun Dutta, Mona Hashim, Carme Camps, Hannah Green, Smrithi Devaiah, Lina Nashef, Jason Parr, Carl Fratter, Rana Ibnouf Hussein, Sarah J. Lindsay, Fiona Lalloo, Benito Banos-Pinero, David Evans, Lucy Mallin, Adrian Waite, Julie Evans, Andrew Newman, Zoe Allen, Cristina Perez-Becerril, Gavin Ryan, Rachel Hart, John Taylor
Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease
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Etiological involvement of KCND1 variants in an X-linked neurodevelopmental disorder with variable expressivity Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-20 Tassja Kalm, Claudia Schob, Hanna Völler, Thatjana Gardeitchik, Christian Gilissen, Rolph Pfundt, Chiara Klöckner, Konrad Platzer, Annick Klabunde-Cherwon, Markus Ries, Steffen Syrbe, Francesca Beccaria, Francesca Madia, Marcello Scala, Federico Zara, Floris Hofstede, Marleen E.H. Simon, Richard H. van Jaarsveld, Renske Oegema, Koen L.I. van Gassen, Sjoerd J.B. Holwerda, Tahsin Stefan Barakat, Arjan
Utilizing trio whole-exome sequencing and a gene matching approach, we identified a cohort of 18 male individuals from 17 families with hemizygous variants in , including two missense variants, three maternally inherited protein-truncating variants, and 12 maternally inherited missense variants. Affected subjects present with a neurodevelopmental disorder characterized by diverse neurological abnormalities
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Genome-wide DNA methylation changes in human spermatogenesis Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-16 Lara M. Siebert-Kuss, Verena Dietrich, Sara Di Persio, Jahnavi Bhaskaran, Martin Stehling, Jann-Frederik Cremers, Sarah Sandmann, Julian Varghese, Sabine Kliesch, Stefan Schlatt, Juan M. Vaquerizas, Nina Neuhaus, Sandra Laurentino
Sperm production and function require the correct establishment of DNA methylation patterns in the germline. Here, we examined the genome-wide DNA methylation changes during human spermatogenesis and its alterations in disturbed spermatogenesis. We found that spermatogenesis is associated with remodeling of the methylome, comprising a global decline in DNA methylation in primary spermatocytes followed
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An integrative framework to prioritize genes in more than 500 loci associated with body mass index Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-15 Daiane Hemerich, Victor Svenstrup, Virginia Diez Obrero, Michael Preuss, Arden Moscati, Joel N. Hirschhorn, Ruth J.F. Loos
Obesity is a major risk factor for a myriad of diseases, affecting >600 million people worldwide. Genome-wide association studies (GWASs) have identified hundreds of genetic variants that influence body mass index (BMI), a commonly used metric to assess obesity risk. Most variants are non-coding and likely act through regulating genes nearby. Here, we apply multiple computational methods to prioritize
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De novo missense variants in exon 9 of SEPHS1 cause a neurodevelopmental condition with developmental delay, poor growth, hypotonia, and dysmorphic features Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-14 Sureni V. Mullegama, Kaitlyn A. Kiernan, Erin Torti, Ethan Pavlovsky, Nicholas Tilton, Austin Sekula, Hua Gao, Joseph T. Alaimo, Kendra Engleman, Eric T. Rush, Karli Blocker, Katrina M. Dipple, Veronica M. Fettig, Heather Hare, Ian Glass, Dorothy K. Grange, Michael Griffin, Chanika Phornphutkul, Lauren Massingham, Lakshmi Mehta, Danny E. Miller, Jenny Thies, J Lawrence Merritt II, Eric Muller II, Matthew
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Therapeutic validation of MMR-associated genetic modifiers in a human ex vivo model of Huntington disease Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-14 Ross Ferguson, Robert Goold, Lucy Coupland, Michael Flower, Sarah J. Tabrizi
The pathological huntingtin () trinucleotide repeat underlying Huntington disease (HD) continues to expand throughout life. Repeat length correlates both with earlier age at onset (AaO) and faster progression, making slowing its expansion an attractive therapeutic approach. Genome-wide association studies have identified candidate variants associated with altered AaO and progression, with many found
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Joint host-pathogen genomic analysis identifies hepatitis B virus mutations associated with human NTCP and HLA class I variation Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-14 Zhi Ming Xu, Gnimah Eva Gnouamozi, Sina Rüeger, Patrick R. Shea, Maria Buti, Henry LY. Chan, Patrick Marcellin, Dylan Lawless, Olivier Naret, Matthias Zeller, Arne Schneuing, Andreas Scheck, Thomas Junier, Darius Moradpour, Ondrej Podlaha, Vithika Suri, Anuj Gaggar, Mani Subramanian, Bruno Correia, David Gfeller, Stephan Urban, Jacques Fellay
Evolutionary changes in the hepatitis B virus (HBV) genome could reflect its adaptation to host-induced selective pressure. Leveraging paired human exome and ultra-deep HBV genome-sequencing data from 567 affected individuals with chronic hepatitis B, we comprehensively searched for the signatures of this evolutionary process by conducting “genome-to-genome” association tests between all human genetic
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Missense variants in ANO4 cause sporadic encephalopathic or familial epilepsy with evidence for a dominant-negative effect Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-13 Fang Yang, Anais Begemann, Nadine Reichhart, Akvile Haeckel, Katharina Steindl, Eyk Schellenberger, Ronja Fini Sturm, Magalie Barth, Sissy Bassani, Paranchai Boonsawat, Thomas Courtin, Bruno Delobel, EuroEPINOMICS-RES Dravet working group, Boudewijn Gunning, Katia Hardies, Mélanie Jennesson, Louis Legoff, Tarja Linnankivi, Clément Prouteau, Noor Smal, Marta Spodenkiewicz, Sandra P. Toelle, Koen Van
Anoctamins are a family of Ca-activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease association. Here, we identified five and two inherited missense variants in (alias ) as a cause of fever-sensitive developmental and epileptic or epileptic encephalopathy (DEE/EE) and generalized epilepsy with febrile seizures plus (GEFS+)
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A multi-tissue, splicing-based joint transcriptome-wide association study identifies susceptibility genes for breast cancer Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-10 Guimin Gao, Julian McClellan, Alvaro N. Barbeira, Peter N. Fiorica, James L. Li, Zepeng Mu, Olufunmilayo I. Olopade, Dezheng Huo, Hae Kyung Im
Splicing-based transcriptome-wide association studies (splicing-TWASs) of breast cancer have the potential to identify susceptibility genes. However, existing splicing-TWASs test the association of individual excised introns in breast tissue only and thus have limited power to detect susceptibility genes. In this study, we performed a multi-tissue joint splicing-TWAS that integrated splicing-TWAS signals
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A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3 Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-08 Maimuna S. Paul, Sydney L. Michener, Hongling Pan, Hiuling Chan, Jessica M. Pfliger, Jill A. Rosenfeld, Vanesa C. Lerma, Alyssa Tran, Megan A. Longley, Richard A. Lewis, Monika Weisz-Hubshman, Mir Reza Bekheirnia, Nasim Bekheirnia, Lauren Massingham, Michael Zech, Matias Wagner, Hartmut Engels, Kirsten Cremer, Elisabeth Mangold, Sophia Peters, Jessica Trautmann, Claudia Perne, Jessica L. Mester, Maria
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Cis- and trans-eQTL TWASs of breast and ovarian cancer identify more than 100 susceptibility genes in the BCAC and OCAC consortia Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-08 S. Taylor Head, Felipe Dezem, Andrei Todor, Jingjing Yang, Jasmine Plummer, Simon Gayther, Siddhartha Kar, Joellen Schildkraut, Michael P. Epstein
Transcriptome-wide association studies (TWASs) have investigated the role of genetically regulated transcriptional activity in the etiologies of breast and ovarian cancer. However, methods performed to date have focused on the regulatory effects of risk-associated SNPs thought to act in on a nearby target gene. With growing evidence for distal () regulatory effects of variants on gene expression, we
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Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-08 Eileen O. Dareng, Simon G. Coetzee, Jonathan P. Tyrer, Pei-Chen Peng, Will Rosenow, Stephanie Chen, Brian D. Davis, Felipe Segato Dezem, Ji-Heui Seo, Robbin Nameki, Alberto L. Reyes, Katja K.H. Aben, Hoda Anton-Culver, Natalia N. Antonenkova, Gerasimos Aravantinos, Elisa V. Bandera, Laura E. Beane Freeman, Matthias W. Beckmann, Alicia Beeghly-Fadiel, Javier Benitez, Marcus Q. Bernardini, Line Bjorge
To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions ( value <5 × 10) and confirmed previously reported associations for
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shaPRS: Leveraging shared genetic effects across traits or ancestries improves accuracy of polygenic scores Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-05-03 Martin Kelemen, Elena Vigorito, Laura Fachal, Carl A. Anderson, Chris Wallace
We present shaPRS, a method that leverages widespread pleiotropy between traits or shared genetic effects across ancestries, to improve the accuracy of polygenic scores. The method uses genome-wide summary statistics from two diseases or ancestries to improve the genetic effect estimate and standard error at SNPs where there is homogeneity of effect between the two datasets. When there is significant
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Telomere-lengthening germline variants predispose to a syndromic papillary thyroid cancer subtype Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-04-29 Emily A. DeBoy, Anna M. Nicosia, Sandya Liyanarachchi, Sheila S. Iyer, Manisha H. Shah, Matthew D. Ringel, Pamela Brock, Mary Armanios
Papillary thyroid cancer (PTC) is the most common endocrine malignancy. 10% to 15% of individuals show familial clustering with three or more affected members, but the factors underlying this risk are unknown. In a group of recently studied individuals with pathogenic variants and ultra-long telomere length, PTC was the second most common solid tumor. We tested whether variants in and four other telomere-maintenance
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Managing differential performance of polygenic risk scores across groups: Real-world experience of the eMERGE Network Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-04-29 Anna C.F. Lewis, Rex L. Chisholm, John J. Connolly, Edward D. Esplin, Joe Glessner, Adam Gordon, Robert C. Green, Hakon Hakonarson, Margaret Harr, Ingrid A. Holm, Gail P. Jarvik, Elizabeth Karlson, Eimear E. Kenny, Leah Kottyan, Niall Lennon, Jodell E. Linder, Yuan Luo, Lisa J. Martin, Emma Perez, Megan J. Puckelwartz, Laura J. Rasmussen-Torvik, Maya Sabatello, Richard R. Sharp, Jordan W. Smoller,
The differential performance of polygenic risk scores (PRSs) by group is one of the major ethical barriers to their clinical use. It is also one of the main practical challenges for any implementation effort. The social repercussions of how people are grouped in PRS research must be considered in communications with research participants, including return of results. Here, we outline the decisions
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Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-04-22 Sonoko Saito, Yuki Saito, Showbu Sato, Satomi Aoki, Harumi Fujita, Yoshihiro Ito, Noriko Ono, Takeru Funakoshi, Tomoko Kawai, Hisato Suzuki, Takashi Sasaki, Tomoyo Tanaka, Masukazu Inoie, Kenichiro Hata, Keisuke Kataoka, Kenjiro Kosaki, Masayuki Amagai, Kazuhiko Nakabayashi, Akiharu Kubo.
Porokeratosis is a clonal keratinization disorder characterized by solitary, linearly arranged, or generally distributed multiple skin lesions. Previous studies showed that genetic alterations in , , , or —genes in the mevalonate pathway—cause hereditary porokeratosis, with skin lesions harboring germline and lesion-specific somatic variants on opposite alleles. Here, we identified non-hereditary porokeratosis
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Aspiring toward equitable benefits from genomic advances to individuals of ancestrally diverse backgrounds Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-04-19 Ying Wang, Yixuan He, Yue Shi, David C. Qian, Kathryn J. Gray, Robert Winn, Alicia R. Martin
Advancements in genomic technologies have shown remarkable promise for improving health trajectories. The Human Genome Project has catalyzed the integration of genomic tools into clinical practice, such as disease risk assessment, prenatal testing and reproductive genomics, cancer diagnostics and prognostication, and therapeutic decision making. Despite the promise of genomic technologies, their full
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MagicalRsq-X: A cross-cohort transferable genotype imputation quality metric Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-04-17 Quan Sun, Yingxi Yang, Jonathan D. Rosen, Jiawen Chen, Xihao Li, Wyliena Guan, Min-Zhi Jiang, Jia Wen, Rhonda G. Pace, Scott M. Blackman, Michael J. Bamshad, Ronald L. Gibson, Garry R. Cutting, Wanda K. O’Neal, Michael R. Knowles, Charles Kooperberg, Alexander P. Reiner, Laura M. Raffield, April P. Carson, Stephen S. Rich, Jerome I. Rotter, Ruth J.F. Loos, Eimear Kenny, Byron C. Jaeger, Yuan-I Min
Since genotype imputation was introduced, researchers have been relying on the estimated imputation quality from imputation software to perform post-imputation quality control (QC). However, this quality estimate (denoted as Rsq) performs less well for lower-frequency variants. We recently published MagicalRsq, a machine-learning-based imputation quality calibration, which leverages additional typed
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Genomic Answers for Kids: Toward more equitable access to genomic testing for rare diseases in rural populations Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-04-17 Ana S.A. Cohen, Courtney D. Berrios, Tricia N. Zion, Cassandra M. Barrett, Riley Moore, Emelia Boillat, Bradley Belden, Emily G. Farrow, Isabelle Thiffault, Britton D. Zuccarelli, Tomi Pastinen
Next-generation sequencing has revolutionized the speed of rare disease (RD) diagnoses. While clinical exome and genome sequencing represent an effective tool for many RD diagnoses, there is room to further improve the diagnostic odyssey of many RD patients. One recognizable intervention lies in increasing equitable access to genomic testing. Rural communities represent a significant portion of underserved
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CAG repeat mosaicism is gene specific in spinocerebellar ataxias Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-04-15 Radhia Kacher, François-Xavier Lejeune, Isabelle David, Susana Boluda, Giulia Coarelli, Sabrina Leclere-Turbant, Anna Heinzmann, Cecilia Marelli, Perrine Charles, Cyril Goizet, Nisha Kabir, Rania Hilab, Ludmila Jornea, Julie Six, Marc Dommergues, Anne-Laure Fauret, Alexis Brice, Sandrine Humbert, Alexandra Durr
Expanded CAG repeats in coding regions of different genes are the most common cause of dominantly inherited spinocerebellar ataxias (SCAs). These repeats are unstable through the germline, and larger repeats lead to earlier onset. We measured somatic expansion in blood samples collected from 30 SCA1, 50 SCA2, 74 SCA3, and 30 SCA7 individuals over a mean interval of 8.5 years, along with postmortem
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A new test for trait mean and variance detects unreported loci for blood-pressure variation Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-04-12 Joseph H. Breeyear, Brian S. Mautz, Jacob M. Keaton, Jacklyn N. Hellwege, Eric S. Torstenson, Jingjing Liang, Michael J. Bray, Ayush Giri, Helen R. Warren, Patricia B. Munroe, Digna R. Velez Edwards, Xiaofeng Zhu, Chun Li, Todd L. Edwards
Variability in quantitative traits has clinical, ecological, and evolutionary significance. Most genetic variants identified for complex quantitative traits have only a detectable effect on the mean of trait. We have developed the mean-variance test (MVtest) to simultaneously model the mean and log-variance of a quantitative trait as functions of genotypes and covariates by using estimating equations
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Toward clinical exomes in diagnostics and management of male infertility Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-04-12 Kristiina Lillepea, Anna-Grete Juchnewitsch, Laura Kasak, Anu Valkna, Avirup Dutta, Kristjan Pomm, Olev Poolamets, Liina Nagirnaja, Erik Tamp, Eisa Mahyari, Vladimir Vihljajev, Stanislav Tjagur, Sofia Papadimitriou, Antoni Riera-Escamilla, Nassim Versbraegen, Ginevra Farnetani, Helen Castillo-Madeen, Mailis Sütt, Viljo Kübarsepp, Sven Tennisberg, Paul Korrovits, Csilla Krausz, Kenneth I. Aston, Tom
Infertility, affecting ∼10% of men, is predominantly caused by primary spermatogenic failure (SPGF). We screened likely pathogenic and pathogenic (LP/P) variants in 638 candidate genes for male infertility in 521 individuals presenting idiopathic SPGF and 323 normozoospermic men in the ESTAND cohort. Molecular diagnosis was reached for 64 men with SPGF (12%), with findings in 39 genes (6%). The yield
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A regulatory variant impacting TBX1 expression contributes to basicranial morphology in Homo sapiens Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-04-11 Noriko Funato, Arja Heliövaara, Cedric Boeckx
Changes in gene regulatory elements play critical roles in human phenotypic divergence. However, identifying the base-pair changes responsible for the distinctive morphology of remains challenging. Here, we report a noncoding single-nucleotide polymorphism (SNP), rs41298798, as a potential causal variant contributing to the morphology of the skull base and vertebral structures found in . Screening
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The clinical utility and diagnostic implementation of human subject cell transdifferentiation followed by RNA sequencing Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-04-08 Shenglan Li, Sen Zhao, Jefferson C. Sinson, Aleksandar Bajic, Jill A. Rosenfeld, Matthew B. Neeley, Mezthly Pena, Kim C. Worley, Lindsay C. Burrage, Monika Weisz-Hubshman, Shamika Ketkar, William J. Craigen, Gary D. Clark, Seema Lalani, Carlos A. Bacino, Keren Machol, Hsiao-Tuan Chao, Lorraine Potocki, Lisa Emrick, Jennifer Sheppard, My T.T. Nguyen, Anahita Khoramnia, Paula Patricia Hernandez, Sandesh
RNA sequencing (RNA-seq) has recently been used in translational research settings to facilitate diagnoses of Mendelian disorders. A significant obstacle for clinical laboratories in adopting RNA-seq is the low or absent expression of a significant number of disease-associated genes/transcripts in clinically accessible samples. As this is especially problematic in neurological diseases, we developed
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This Month in The Journal Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-04-04 Alyson B. Barnes, Kylee L. Spencer, Sara B. Cullinan
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Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-04-04 Amy G. Jones, Matilde Aquilino, Rory J. Tinker, Laura Duncan, Zandra Jenkins, Gemma L. Carvill, Stephanie J. DeWard, Dorothy K. Grange, MJ Hajianpour, Benjamin J. Halliday, Muriel Holder-Espinasse, Judit Horvath, Silvia Maitz, Vincenzo Nigro, Manuela Morleo, Victoria Paul, Careni Spencer, Alina I. Esterhuizen, Tilman Polster, Alice Spano, Inés Gómez-Lozano, Abhishek Kumar, Gemma Poke, John A. Phillips
Glutamine synthetase (GS), encoded by , catalyzes the conversion of glutamate to glutamine. GS is pivotal for the generation of the neurotransmitters glutamate and gamma-aminobutyric acid and is the primary mechanism of ammonia detoxification in the brain. GS levels are regulated post-translationally by an N-terminal degron that enables the ubiquitin-mediated degradation of GS in a glutamine-induced
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Genetic and functional correction of argininosuccinate lyase deficiency using CRISPR adenine base editors Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-04-04 Sami Jalil, Timo Keskinen, Juhana Juutila, Rocio Sartori Maldonado, Liliya Euro, Anu Suomalainen, Risto Lapatto, Emilia Kuuluvainen, Ville Hietakangas, Timo Otonkoski, Mervi E. Hyvönen, Kirmo Wartiovaara
Argininosuccinate lyase deficiency (ASLD) is a recessive metabolic disorder caused by variants in . In an essential step in urea synthesis, ASL breaks down argininosuccinate (ASA), a pathognomonic ASLD biomarker. The severe disease forms lead to hyperammonemia, neurological injury, and even early death. The current treatments are unsatisfactory, involving a strict low-protein diet, arginine supplementation
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Many roads to a gene-environment interaction Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-04-04 Kenneth E. Westerman, Tamar Sofer
Despite the importance of gene-environment interactions (GxEs) in improving and operationalizing genetic discovery, interpretation of any GxEs that are discovered can be surprisingly difficult. There are many potential biological and statistical explanations for a statistically significant finding and, likewise, it is not always clear what can be claimed based on a null result. A better understanding
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Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-04-01 Gabrielle Lemire, Alba Sanchis-Juan, Kathryn Russell, Samantha Baxter, Katherine R. Chao, Moriel Singer-Berk, Emily Groopman, Isaac Wong, Eleina England, Julia Goodrich, Lynn Pais, Christina Austin-Tse, Stephanie DiTroia, Emily O’Heir, Vijay S. Ganesh, Monica H. Wojcik, Emily Evangelista, Hana Snow, Ikeoluwa Osei-Owusu, Jack Fu, Mugdha Singh, Yulia Mostovoy, Steve Huang, Kiran Garimella, Samantha L
Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and
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Detection of elusive DNA copy-number variations in hereditary disease and cancer through the use of noncoding and off-target sequencing reads Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-03-25 Mathieu Quinodoz, Karolina Kaminska, Francesca Cancellieri, Ji Hoon Han, Virginie G. Peter, Elifnaz Celik, Lucas Janeschitz-Kriegl, Nils Schärer, Daniela Hauenstein, Bence György, Giacomo Calzetti, Vincent Hahaut, Sónia Custódio, Ana Cristina Sousa, Yuko Wada, Yusuke Murakami, Almudena Avila Fernández, Cristina Rodilla Hernández, Pablo Minguez, Carmen Ayuso, Koji M. Nishiguchi, Cristina Santos, Luisa
Copy-number variants (CNVs) play a substantial role in the molecular pathogenesis of hereditary disease and cancer, as well as in normal human interindividual variation. However, they are still rather difficult to identify in mainstream sequencing projects, especially involving exome sequencing, because they often occur in DNA regions that are not targeted for analysis. To overcome this problem, we
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De novo missense variants in exon 9 of SEPHS1 cause a neurodevelopmental condition with developmental delay, poor growth, hypotonia, and dysmorphic features Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-03-25 Sureni V. Mullegama, Kaitlyn A. Kiernan, Erin Torti, Ethan Pavlovsky, Nicholas Tilton, Austin Sekula, Hua Gao, Joseph T. Alaimo, Kendra Engleman, Eric T. Rush, Karli Blocker, Katrina M. Dipple, Veronica M. Fettig, Heather Hare, Ian Glass, Dorothy K. Grange, Michael Griffin, Chanika Phornphutkul, Lauren Massingham, Lakshmi Mehta, Danny E. Miller, Jenny Thies, J Lawrence Merritt II, Eric Muller II, Matthew
Selenophosphate synthetase (SEPHS) plays an essential role in selenium metabolism. Two mammalian SEPHS paralogues, SEPHS1 and SEPHS2, share high sequence identity and structural homology with SEPHS. Here, we report nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight of
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A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3 Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-03-20 Maimuna S. Paul, Sydney L. Michener, Hongling Pan, Hiuling Chan, Jessica M. Pfliger, Jill A. Rosenfeld, Vanesa C. Lerma, Alyssa Tran, Megan A. Longley, Richard A. Lewis, Monika Weisz-Hubshman, Mir Reza Bekheirnia, Nasim Bekheirnia, Lauren Massingham, Michael Zech, Matias Wagner, Hartmut Engels, Kirsten Cremer, Elisabeth Mangold, Sophia Peters, Jessica Trautmann, Claudia Perne, Jessica L. Mester, Maria
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Biobank-scale inference of multi-individual identity by descent and gene conversion Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-03-20 Sharon R. Browning, Brian L. Browning
We present a method for efficiently identifying clusters of identical-by-descent haplotypes in biobank-scale sequence data. Our multi-individual approach enables much more computationally efficient inference of identity by descent (IBD) than approaches that infer pairwise IBD segments and provides locus-specific IBD clusters rather than IBD segments. Our method’s computation time, memory requirements
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Population structure and migration in the Eastern Highlands of Papua New Guinea, a region impacted by the kuru epidemic Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-03-19 Liam Quinn, Jerome Whitfield, Michael P. Alpers, Tracy Campbell, Holger Hummerich, William Pomat, Peter Siba, George Koki, Ida Moltke, John Collinge, Garrett Hellenthal, Simon Mead
Populations of the Eastern Highlands of Papua New Guinea (EHPNG, area 11,157 km) lived in relative isolation from the rest of the world until the mid-20 century, and the region contains a wealth of linguistic and cultural diversity. Notably, several populations of EHPNG were devastated by an epidemic prion disease, kuru, which at its peak in the mid-twentieth century led to some villages being almost
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Mono-allelic KCNB2 variants lead to a neurodevelopmental syndrome caused by altered channel inactivation Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-03-18 Shreyas Bhat, Justine Rousseau, Coralie Michaud, Charles Marques Lourenço, Joan M. Stoler, Raymond J. Louie, Lola K. Clarkson, Angie Lichty, Daniel C. Koboldt, Shalini C. Reshmi, Sanjay M. Sisodiya, Eva M.M. Hoytema van Konijnenburg, Klaas Koop, Peter M. van Hasselt, Florence Démurger, Christèle Dubourg, Bonnie R. Sullivan, Susan S. Hughes, Isabelle Thiffault, Elisabeth Simard Tremblay, Andrea Accogli
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Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit β-type 10 in six infants with SCID-Omenn syndrome Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-03-18 Caspar I. van der Made, Simone Kersten, Odelia Chorin, Karin R. Engelhardt, Gayatri Ramakrishnan, Helen Griffin, Ina Schim van der Loeff, Hanka Venselaar, Annick Raas Rothschild, Meirav Segev, Janneke H.M. Schuurs-Hoeijmakers, Tuomo Mantere, Rick Essers, Masoud Zamani Esteki, Amir L. Avital, Peh Sun Loo, Annet Simons, Rolph Pfundt, Adilia Warris, Marieke M. Seyger, Frank L. van de Veerdonk, Mihai G
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The association of cigarette smoking with DNA methylation and gene expression in human tissue samples Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-03-14 James L. Li, Niyati Jain, Lizeth I. Tamayo, Lin Tong, Farzana Jasmine, Muhammad G. Kibriya, Kathryn Demanelis, Meritxell Oliva, Lin S. Chen, Brandon L. Pierce
Cigarette smoking adversely affects many aspects of human health, and epigenetic responses to smoking may reflect mechanisms that mediate or defend against these effects. Prior studies of smoking and DNA methylation (DNAm), typically measured in leukocytes, have identified numerous smoking-associated regions (e.g., ). To identify smoking-associated DNAm features in typically inaccessible tissues, we
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Estimating disease heritability from complex pedigrees allowing for ascertainment and covariates Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-03-14 Doug Speed, David M. Evans
We propose TetraHer, a method for estimating the liability heritability of binary phenotypes. TetraHer has five key features. First, it can be applied to data from complex pedigrees that contain multiple types of relationships. Second, it can correct for ascertainment of cases or controls. Third, it can accommodate covariates. Fourth, it can model the contribution of common environment. Fifth, it produces
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De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-03-12 Xueyang Pan, Alice M. Tao, Shenzhao Lu, Mengqi Ma, Shabab B. Hannan, Rachel Slaugh, Sarah Drewes Williams, Lauren O'Grady, Oguz Kanca, Richard Person, Melissa T. Carter, Konrad Platzer, Franziska Schnabel, Rami Abou Jamra, Amy E. Roberts, Jane W. Newburger, Anya Revah-Politi, Jorge L. Granadillo, Alexander P.A. Stegmann, Margje Sinnema, Andrea Accogli, Vincenzo Salpietro, Valeria Capra, Lina Ghaloul-Gonzalez
FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in who present with developmental delay, intellectual disability, dysmorphic
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Guidance on use of race, ethnicity, and geographic origin as proxies for genetic ancestry groups in biomedical publications Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-03-12 W. Gregory Feero, Robert D. Steiner, Anne Slavotinek, Tiago Faial, Michael J. Bamshad, Jehannine Austin, Bruce R. Korf, Annette Flanagin, Kirsten Bibbins-Domingo
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Investigating the potential of single-cell DNA methylation data to detect allele-specific methylation and imprinting Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-03-11 Nicholas D. Johnson, David J. Cutler, Karen N. Conneely
Allele-specific methylation (ASM) is an epigenetic modification whereby one parental allele becomes methylated and the other unmethylated at a specific locus. ASM is most often driven by the presence of nearby heterozygous variants that influence methylation, but also occurs somatically in the context of genomic imprinting. In this study, we investigate ASM using publicly available single-cell reduced
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This Month in The Journal Am. J. Hum. Genet. (IF 8.1) Pub Date : 2024-03-07 Alyson B. Barnes, Kylee L. Spencer, Sara B. Cullinan