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This Month in The Journal Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-02-01 Alyson B. Barnes, Kylee L. Spencer, Sara B. Cullinan
Abstract not available
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Cell-type deconvolution of bulk-blood RNA-seq reveals biological insights into neuropsychiatric disorders Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-02-01 Toni Boltz, Tommer Schwarz, Merel Bot, Kangcheng Hou, Christa Caggiano, Sandra Lapinska, Chenda Duan, Marco P. Boks, Rene S. Kahn, Noah Zaitlen, Bogdan Pasaniuc, Roel Ophoff
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CRISPR activation to characterize splice-altering variants in easily accessible cells Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-24 Thorkild Terkelsen, Nanna Steengaard Mikkelsen, Ebbe Norskov Bak, Johan Vad-Nielsen, Jenny Blechingberg, Simone Weiss, Simon Opstrup Drue, Henning Andersen, Brage Storstein Andresen, Rasmus O. Bak, Uffe Birk Jensen
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Mutations in SAMD7 cause autosomal-recessive macular dystrophy with or without cone dysfunction Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-24 Miriam Bauwens, Elifnaz Celik, Dinah Zur, Siying Lin, Mathieu Quinodoz, Michel Michaelides, Andrew R. Webster, Filip Van Den Broeck, Bart P. Leroy, Leah Rizel, Abigail R. Moye, Audrey Meunier, Hoai Viet Tran, Alexandre P. Moulin, Quinten Mahieu, Mattias Van Heetvelde, Gavin Arno, Carlo Rivolta, Elfride De Baere, Tamar Ben-Yosef
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Role of CAMK2D in neurodevelopment and associated conditions Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-24 Pomme M.F. Rigter, Charlotte de Konink, Matthew J. Dunn, Martina Proietti Onori, Jennifer B. Humberson, Matthew Thomas, Caitlin Barnes, Carlos E. Prada, K. Nicole Weaver, Thomas D. Ryan, Oana Caluseriu, Jennifer Conway, Emily Calamaro, Chin-To Fong, Wim Wuyts, Marije Meuwissen, Eva Hordijk, Carsten N. Jonkers, Lucas Anderson, Berfin Yuseinova, Geeske M. van Woerden
The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family consists of four different isozymes, encoded by four different genes—CAMK2A, CAMK2B, CAMK2G, and CAMK2D—of which the first three have been associated recently with neurodevelopmental disorders. CAMK2D is one of the major CAMK2 proteins expressed in the heart and has been associated with cardiac anomalies. Although this CAMK2 isoform
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The shared ancestry between the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles using haplotype sharing trees and HAPTK Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-18 Osma S. Rautila, Karri Kaivola, Harri Rautila, Laura Hokkanen, Jyrki Launes, Timo E. Strandberg, Hannu Laaksovirta, Johanna Palmio, Pentti J. Tienari
The C9orf72 hexanucleotide repeat expansion (HRE) is a common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The inheritance is autosomal dominant, but a high proportion of subjects with the mutation are simplex cases. One possible explanation is de novo expansions of unstable intermediate-length alleles (IAs). Using haplotype sharing trees (HSTs) with the haplotype
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Regulatory features aid interpretation of 3′UTR variants Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-17 Lindsay Romo, Scott D. Findlay, Christopher B. Burge
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Neuronal MAPT expression is mediated by long-range interactions with cis-regulatory elements Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-16 Brianne B. Rogers, Ashlyn G. Anderson, Shelby N. Lauzon, M. Natalie Davis, Rebecca M. Hauser, Sydney C. Roberts, Ivan Rodriguez-Nunez, Katie Trausch-Lowther, Erin A. Barinaga, Paige I. Hall, Matthew T. Knuesel, Jared W. Taylor, Mark Mackiewicz, Brian S. Roberts, Sara J. Cooper, Lindsay F. Rizzardi, Richard M. Myers, J. Nicholas Cochran
Tauopathies are a group of neurodegenerative diseases defined by abnormal aggregates of tau, a microtubule-associated protein encoded by MAPT. MAPT expression is near absent in neural progenitor cells (NPCs) and increases during differentiation. This temporally dynamic expression pattern suggests that MAPT expression could be controlled by transcription factors and cis-regulatory elements specific
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Adaptation of a mutual exclusivity framework to identify driver mutations within oncogenic pathways Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-16 Xinjun Wang, Caroline Kostrzewa, Allison Reiner, Ronglai Shen, Colin Begg
Distinguishing genomic alterations in cancer-associated genes that have functional impact on tumor growth and disease progression from the ones that are passengers and confer no fitness advantage have important clinical implications. Evidence-based methods for nominating drivers are limited by existing knowledge on the oncogenic effects and therapeutic benefits of specific variants from clinical trials
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A common NFKB1 variant detected through antibody analysis in UK Biobank predicts risk of infection and allergy Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-16 Amanda Y. Chong, Nicole Brenner, Andres Jimenez-Kaufmann, Adrian Cortes, Michael Hill, Thomas J. Littlejohns, James J. Gilchrist, Benjamin P. Fairfax, Julian C. Knight, Flavia Hodel, Jacques Fellay, Gil McVean, Andres Moreno-Estrada, Tim Waterboer, Adrian V.S. Hill, Alexander J. Mentzer
Infectious agents contribute significantly to the global burden of diseases through both acute infection and their chronic sequelae. We leveraged the UK Biobank to identify genetic loci that influence humoral immune response to multiple infections. From 45 genome-wide association studies in 9,611 participants from UK Biobank, we identified NFKB1 as a locus associated with quantitative antibody responses
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STIGMA: Single-cell tissue-specific gene prioritization using machine learning Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-15 Saranya Balachandran, Cesar A. Prada-Medina, Martin A. Mensah, Naseebullah Kakar, Inga Nagel, Jelena Pozojevic, Enrique Audain, Marc-Phillip Hitz, Martin Kircher, Varun K.A. Sreenivasan, Malte Spielmann
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A comprehensive analysis of clinical and polygenic germline influences on somatic mutational burden Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-10 Kodi Taraszka, Stefan Groha, David King, Robert Tell, Kevin White, Elad Ziv, Noah Zaitlen, Alexander Gusev
Tumor mutational burden (TMB), the total number of somatic mutations in the tumor, and copy number burden (CNB), the corresponding measure of aneuploidy, are established fundamental somatic features and emerging biomarkers for immunotherapy. However, the genetic and non-genetic influences on TMB/CNB and, critically, the manner by which they influence patient outcomes remain poorly understood. Here
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A Bayesian approach to Mendelian randomization using summary statistics in the univariable and multivariable settings with correlated pleiotropy Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-04 Andrew J. Grant, Stephen Burgess
Mendelian randomization uses genetic variants as instrumental variables to make causal inferences on the effect of an exposure on an outcome. Due to the recent abundance of high-powered genome-wide association studies, many putative causal exposures of interest have large numbers of independent genetic variants with which they associate, each representing a potential instrument for use in a Mendelian
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This Month in The Journal Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-04 Alyson B. Barnes, Kylee L. Spencer, Sara B. Cullinan
Abstract not available
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Building a vertically integrated genomic learning health system: The biobank at the Colorado Center for Personalized Medicine Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-04 Laura K. Wiley, Jonathan A. Shortt, Emily R. Roberts, Jan Lowery, Elizabeth Kudron, Meng Lin, David Mayer, Melissa Wilson, Tonya M. Brunetti, Sameer Chavan, Tzu L. Phang, Nikita Pozdeyev, Joseph Lesny, Stephen J. Wicks, Ethan T. Moore, Joshua L. Morgenstern, Alanna N. Roff, Elise L. Shalowitz, Adrian Stewart, Cole Williams, Christopher R. Gignoux
Precision medicine initiatives across the globe have led to a revolution of repositories linking large-scale genomic data with electronic health records, enabling genomic analyses across the entire phenome. Many of these initiatives focus solely on research insights, leading to limited direct benefit to patients. We describe the biobank at the Colorado Center for Personalized Medicine (CCPM Biobank)
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Systematic identification of genotype-dependent enhancer variants in eosinophilic esophagitis Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-05 Molly S. Shook, Xiaoming Lu, Xiaoting Chen, Sreeja Parameswaran, Lee Edsall, Michael P. Trimarchi, Kevin Ernst, Marissa Granitto, Carmy Forney, Omer A. Donmez, Arame A. Diouf, Andrew VonHandorf, Marc E. Rothenberg, Matthew T. Weirauch, Leah C. Kottyan
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75 years of The American Journal of Human Genetics Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-04 Bruce R. Korf
Abstract not available
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An interactive atlas of three-dimensional syndromic facial morphology Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-04 J. David Aponte, Jordan J. Bannister, Hanne Hoskens, Harold Matthews, Kaitlin Katsura, Cassidy Da Silva, Tim Cruz, Julie H.M. Pilz, Richard A. Spritz, Nils D. Forkert, Peter Claes, Francois P. Bernier, Ophir D. Klein, David C. Katz, Benedikt Hallgrímsson
Craniofacial phenotyping is critical for both syndrome delineation and diagnosis because craniofacial abnormalities occur in 30% of characterized genetic syndromes. Clinical reports, textbooks, and available software tools typically provide two-dimensional, static images and illustrations of the characteristic phenotypes of genetic syndromes. In this work, we provide an interactive web application
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A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3 Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-04 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, Hsiao-Tuan Chao
PPFIA3 encodes the protein-tyrosine phosphatase, receptor-type, F-polypeptide-interacting-protein-alpha-3 (PPFIA3), which is a member of the LAR-protein-tyrosine phosphatase-interacting-protein (liprin) family involved in synapse formation and function, synaptic vesicle transport, and presynaptic active zone assembly. The protein structure and function are evolutionarily well conserved, but human diseases
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Interaction molecular QTL mapping discovers cellular and environmental modifiers of genetic regulatory effects Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-04 Silva Kasela, François Aguet, Sarah Kim-Hellmuth, Brielin C. Brown, Daniel C. Nachun, Russell P. Tracy, Peter Durda, Yongmei Liu, Kent D. Taylor, W. Craig Johnson, David Van Den Berg, Stacey Gabriel, Namrata Gupta, Joshua D. Smith, Thomas W. Blackwell, Jerome I. Rotter, Kristin G. Ardlie, Ani Manichaikul, Stephen S. Rich, R. Graham Barr, Tuuli Lappalainen
Bulk-tissue molecular quantitative trait loci (QTLs) have been the starting point for interpreting disease-associated variants, and context-specific QTLs show particular relevance for disease. Here, we present the results of mapping interaction QTLs (iQTLs) for cell type, age, and other phenotypic variables in multi-omic, longitudinal data from the blood of individuals of diverse ancestries. By modeling
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omicSynth: An open multi-omic community resource for identifying druggable targets across neurodegenerative diseases Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-04 Chelsea X. Alvarado, Mary B. Makarious, Cory A. Weller, Dan Vitale, Mathew J. Koretsky, Sara Bandres-Ciga, Hirotaka Iwaki, Kristin Levine, Andrew Singleton, Faraz Faghri, Mike A. Nalls, Hampton L. Leonard
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Genetic determinants of IgG antibody response to COVID-19 vaccination Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-04 Shengzhe Bian, Xinxin Guo, Xilai Yang, Yuandan Wei, Zijing Yang, Shiyao Cheng, Jiaqi Yan, Yongkun Chen, Guo-Bo Chen, Xiangjun Du, Stephen S. Francis, Yuelong Shu, Siyang Liu
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A Bayesian fine-mapping model using a continuous global-local shrinkage prior with applications in prostate cancer analysis Am. J. Hum. Genet. (IF 9.8) Pub Date : 2024-01-02 Xiang Li, Pak Chung Sham, Yan Dora Zhang
The aim of fine mapping is to identify genetic variants causally contributing to complex traits or diseases. Existing fine-mapping methods employ Bayesian discrete mixture priors and depend on a pre-specified maximum number of causal variants, which may lead to sub-optimal solutions. In this work, we propose a Bayesian fine-mapping method called h2-D2, utilizing a continuous global-local shrinkage
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A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-12-22 Erica L. Harris, Vincent Roy, Martin Montagne, Ailsa M.S. Rose, Helen Livesey, Margot R.F. Reijnders, Emma Hobson, Francis H. Sansbury, Marjolein H. Willemsen, Rolph Pfundt, Daniel Warren, Vernon Long, Ian M. Carr, Han G. Brunner, Eamonn G. Sheridan, Helen V. Firth, Pierre Lavigne, James A. Poulter
Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located
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Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-12-20 Vincenzo Salpietro, Reza Maroofian, Maha S. Zaki, Jamie Wangen, Andrea Ciolfi, Sabina Barresi, Stephanie Efthymiou, Angelique Lamaze, Gabriel N. Aughey, Fuad Al Mutairi, Aboulfazl Rad, Clarissa Rocca, Elisa Calì, Andrea Accogli, Federico Zara, Pasquale Striano, Majid Mojarrad, Huma Tariq, Edoardo Giacopuzzi, Jenny C. Taylor, Henry Houlden
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A statistical method for image-mediated association studies discovers genes and pathways associated with four brain disorders Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-12-19 Jingni He, Lilit Antonyan, Harold Zhu, Karen Ardila, Qing Li, David Enoma, William Zhang, Andy Liu, Thierry Chekouo, Bo Cao, M. Ethan MacDonald, Paul D. Arnold, Quan Long
Brain imaging and genomics are critical tools enabling characterization of the genetic basis of brain disorders. However, imaging large cohorts is expensive and may be unavailable for legacy datasets used for genome-wide association studies (GWASs). Using an integrated feature selection/aggregation model, we developed an image-mediated association study (IMAS), which utilizes borrowed imaging/genomics
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ClinGen guidance for use of the PP1/BS4 co-segregation and PP4 phenotype specificity criteria for sequence variant pathogenicity classification Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-12-15 Leslie G. Biesecker, Alicia B. Byrne, Steven M. Harrison, Tina Pesaran, Alejandro A. Schäffer, Brian H. Shirts, Sean V. Tavtigian, Heidi L. Rehm
The 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant classification publication established a standard employed internationally to guide laboratories in variant assessment. Those recommendations included both pathogenic (PP1) and benign (BS4) criteria for evaluating the inheritance patterns of variants, but details of how to apply those criteria
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Systematic analysis of variants escaping nonsense-mediated decay uncovers candidate Mendelian diseases Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-12-12 Rebecca I. Torene, Maria J. Guillen Sacoto, Francisca Millan, Zhancheng Zhang, Stephen McGee, Matthew Oetjens, Elizabeth Heise, Karen Chong, Richard Sidlow, Lauren O’Grady, Inderneel Sahai, Christa L. Martin, David H. Ledbetter, Scott M. Myers, Kevin J. Mitchell, Kyle Retterer
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Will variants of uncertain significance still exist in 2030? Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-12-11 Douglas M. Fowler, Heidi L. Rehm
In 2020, the National Human Genome Research Institute (NHGRI) made ten “bold predictions,” including that “the clinical relevance of all encountered genomic variants will be readily predictable, rendering the diagnostic designation ‘variant of uncertain significance (VUS)’ obsolete.” We discuss the prospects for this prediction, arguing that many, if not most, VUS in coding regions will be resolved
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H. Eldon Sutton, PhD (1927–2023): A long and full life Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-12-07 Barbara R. DuPont, Roberta Palmour, Patricia Howard-Peebles, Chih-Lin Hsieh
Abstract not available
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This month in The Journal Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-12-07 Alyson B. Barnes, Kylee L. Spencer, Sara B. Cullinan
Abstract not available
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Genomic medicine year in review: 2023 Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-12-07 Teri A. Manolio, Jahnavi Narula, Carol J. Bult, Rex L. Chisholm, Patricia A. Deverka, Geoffrey S. Ginsburg, Eric D. Green, Gillian Hooker, Gail P. Jarvik, George A. Mensah, Erin M. Ramos, Dan M. Roden, Robb Rowley, Marc S. Williams
Abstract not available
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Tree-based QTL mapping with expected local genetic relatedness matrices Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-12-07 Vivian Link, Joshua G. Schraiber, Caoqi Fan, Bryan Dinh, Nicholas Mancuso, Charleston W.K. Chiang, Michael D. Edge
Understanding the genetic basis of complex phenotypes is a central pursuit of genetics. Genome-wide association studies (GWASs) are a powerful way to find genetic loci associated with phenotypes. GWASs are widely and successfully used, but they face challenges related to the fact that variants are tested for association with a phenotype independently, whereas in reality variants at different sites
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Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4: A poly-glycine disease Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-29 Joel Wallenius, Efthymia Kafantari, Emma Jhaveri, Sorina Gorcenco, Adam Ameur, Christin Karremo, Sigurd Dobloug, Kristina Karrman, Tom de Koning, Andreea Ilinca, Maria Landqvist Waldö, Andreas Arvidsson, Staffan Persson, Elisabet Englund, Hans Ehrencrona, Andreas Puschmann
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Identifying risk variants for embryo aneuploidy using ultra-low coverage whole-genome sequencing from preimplantation genetic testing Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-28 Siqi Sun, Mansour Aboelenain, Daniel Ariad, Mary E. Haywood, Charles R. Wageman, Marlena Duke, Aishee Bag, Manuel Viotti, Mandy Katz-Jaffe, Rajiv C. McCoy, Karen Schindler, Jinchuan Xing
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The NYCKidSeq randomized controlled trial: Impact of GUÍA digitally enhanced genetic results disclosure in diverse families Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-24 Sabrina A. Suckiel, Nicole R. Kelly, Jacqueline A. Odgis, Katie M. Gallagher, Monisha Sebastin, Katherine E. Bonini, Priya N. Marathe, Kaitlyn Brown, Miranda Di Biase, Michelle A. Ramos, Jessica E. Rodriguez, Laura Scarimbolo, Beverly J. Insel, Kathleen D.M. Ferar, Randi E. Zinberg, George A. Diaz, John M. Greally, Noura S. Abul-Husn, Laurie J. Bauman, Bruce D. Gelb, Eimear E. Kenny
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Improved detection of aberrant splicing with FRASER 2.0 and the intron Jaccard index Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-24 Ines F. Scheller, Karoline Lutz, Christian Mertes, Vicente A. Yépez, Julien Gagneur
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CHARR efficiently estimates contamination from DNA sequencing data Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-23 Wenhan Lu, Laura D. Gauthier, Timothy Poterba, Edoardo Giacopuzzi, Julia K. Goodrich, Christine R. Stevens, Daniel King, Mark J. Daly, Benjamin M. Neale, Konrad J. Karczewski
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Increasing diversity of functional genetics studies to advance biological discovery and human health Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-22 Sophia H.L. George, Alejandra Medina-Rivera, Youssef Idaghdour, Tuuli Lappalainen, Irene Gallego Romero
In this perspective we discuss the current lack of genetic and environmental diversity in functional genomics datasets. There is a well-described Eurocentric bias in genetic and functional genomic research that has a clear impact on the benefit this research can bring to underrepresented populations. Current research focused on genetic variant-to-function experiments aims to identify molecular QTLs
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Assortative mating and parental genetic relatedness contribute to the pathogenicity of variably expressive variants Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-17 Corrine Smolen, Matthew Jensen, Lisa Dyer, Lucilla Pizzo, Anastasia Tyryshkina, Deepro Banerjee, Laura Rohan, Emily Huber, Laila El Khattabi, Paolo Prontera, Jean-Hubert Caberg, Anke Van Dijck, Charles Schwartz, Laurence Faivre, Patrick Callier, Anne-Laure Mosca-Boidron, Mathilde Lefebvre, Kate Pope, Penny Snell, Paul J. Lockhart, Santhosh Girirajan
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Bi-allelic loss-of-function variants in WBP4, encoding a spliceosome protein, result in a variable neurodevelopmental syndrome Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-13 Eden Engal, Kaisa Teele Oja, Reza Maroofian, Ophir Geminder, Thuy-Linh Le, Pauline Marzin, Anne Guimier, Evyatar Mor, Naama Zvi, Naama Elefant, Maha S. Zaki, Joseph G. Gleeson, Kai Muru, Sander Pajusalu, Monica H. Wojcik, Divya Pachat, Marwa Abd Elmaksoud, Won Chan Jeong, Hane Lee, Peter Bauer, Hagar Mor-Shaked
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Inferring disease architecture and predictive ability with LDpred2-auto Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-08 Florian Privé, Clara Albiñana, Julyan Arbel, Bogdan Pasaniuc, Bjarni J. Vilhjálmsson
LDpred2 is a widely used Bayesian method for building polygenic scores (PGSs). LDpred2-auto can infer the two parameters from the LDpred model, the SNP heritability h2 and polygenicity p, so that it does not require an additional validation dataset to choose best-performing parameters. The main aim of this paper is to properly validate the use of LDpred2-auto for inferring multiple genetic parameters
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Factorizing polygenic epistasis improves prediction and uncovers biological pathways in complex traits Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-02 David Tang, Jerome Freudenberg, Andy Dahl
Epistasis is central in many domains of biology, but it has not yet been proven useful for understanding the etiology of complex traits. This is partly because complex-trait epistasis involves polygenic interactions that are poorly captured in current models. To address this gap, we developed a model called Epistasis Factor Analysis (EFA). EFA assumes that polygenic epistasis can be factorized into
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RAB1A haploinsufficiency phenocopies the 2p14–p15 microdeletion and is associated with impaired neuronal differentiation Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-03 Jonathan J. Rios, Yang Li, Nandina Paria, Ryan J. Bohlender, Chad Huff, Jill A. Rosenfeld, Pengfei Liu, Weimin Bi, Kentaro Haga, Mitsunori Fukuda, Shayal Vashisth, Kiran Kaur, Maria H. Chahrour, Michael B. Bober, Angela L. Duker, Farah A. Ladha, Neil A. Hanchard, Kristhen Atala, Anas M. Khanshour, Linsley Smith, Mauricio R. Delgado
Hereditary spastic parapareses (HSPs) are clinically heterogeneous motor neuron diseases with variable age of onset and severity. Although variants in dozens of genes are implicated in HSPs, much of the genetic basis for pediatric-onset HSP remains unexplained. Here, we re-analyzed clinical exome-sequencing data from siblings with HSP of unknown genetic etiology and identified an inherited nonsense
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Efficient in vivo prime editing corrects the most frequent phenylketonuria variant, associated with high unmet medical need Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-03 Dominique L. Brooks, Madelynn N. Whittaker, Ping Qu, Kiran Musunuru, Rebecca C. Ahrens-Nicklas, Xiao Wang
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This month in The Journal Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-02 Alyson B. Barnes, Sara B. Cullinan
Abstract not available
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To boldly go: Unpacking the NHGRI’s bold predictions for human genomics by 2030 Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-02 Chris Gunter, Eric D. Green
The 2020 strategic vision for human genomics, written by the National Human Genome Research Institute (NHGRI), was punctuated by a set of provocatively audacious “bold predictions for human genomics by 2030.” Starting here, these will be unpacked and discussed in an upcoming series in the American Journal of Human Genetics.
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Envisioning a new era: Complete genetic information from routine, telomere-to-telomere genomes Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-02 Karen H. Miga, Evan E. Eichler
Advances in long-read sequencing and assembly now mean that individual labs can generate phased genomes that are more accurate and more contiguous than the original human reference genome. With declining costs and increasing democratization of technology, we suggest that complete genome assemblies, where both parental haplotypes are phased telomere to telomere, will become standard in human genetics
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The GenoVA study: Equitable implementation of a pragmatic randomized trial of polygenic-risk scoring in primary care Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-02 Jason L. Vassy, Charles A. Brunette, Matthew S. Lebo, Katharine MacIsaac, Thomas Yi, Morgan E. Danowski, Nicholas V.J. Alexander, Mark P. Cardellino, Kurt D. Christensen, Manish Gala, Robert C. Green, Elizabeth Harris, Natalie E. Jones, Benjamin J. Kerman, Peter Kraft, Preetika Kulkarni, Anna C.F. Lewis, Steven A. Lubitz, Pradeep Natarajan, Ashley A. Antwi
Polygenic risk scores (PRSs) hold promise for disease risk assessment and prevention. The Genomic Medicine at Veterans Affairs (GenoVA) Study is addressing three main challenges to the clinical implementation of PRSs in preventive care: defining and determining their clinical utility, implementing them in time-constrained primary care settings, and countering their potential to exacerbate healthcare
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Potentially pathogenic and pathogenic G6PD variants Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-02 Lucio Luzzatto, Caterina Nannelli, Rosario Notaro
Abstract not available
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Response to Luzzatto et al. Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-11-02 Renee C. Geck, Nicholas R. Powell, Maitreya J. Dunham
Abstract not available
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Power of inclusion: Enhancing polygenic prediction with admixed individuals Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-10-27 Yosuke Tanigawa, Manolis Kellis
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Prospective, multi-site study of healthcare utilization after actionable monogenic findings from clinical sequencing Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-10-25 Jodell E. Linder, Ran Tao, Wendy K. Chung, Krzysztof Kiryluk, Cong Liu, Chunhua Weng, John J. Connolly, Hakon Hakonarson, Margaret Harr, Kathleen A. Leppig, Gail P. Jarvik, David L. Veenstra, Sharon Aufox, Rex L. Chisholm, Adam S. Gordon, Christin Hoell, Laura J. Rasmussen-Torvik, Maureen E. Smith, Ingrid A. Holm, Erin M. Miller, Josh F. Peterson
As large-scale genomic screening becomes increasingly prevalent, understanding the influence of actionable results on healthcare utilization is key to estimating the potential long-term clinical impact. The eMERGE network sequenced individuals for actionable genes in multiple genetic conditions and returned results to individuals, providers, and the electronic health record. Differences in recommended
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An autosomal-dominant childhood-onset disorder associated with pathogenic variants in VCP Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-10-25 Annelise Y. Mah-Som, Jil Daw, Diana Huynh, Mengcheng Wu, Benjamin C. Creekmore, William Burns, Steven A. Skinner, Øystein L. Holla, Marie F. Smeland, Marc Planes, Kevin Uguen, Sylvia Redon, Tatjana Bierhals, Tasja Scholz, Jonas Denecke, Martin A. Mensah, Henrike L. Sczakiel, Heidelis Tichy, Sarah Verheyen, Jasmin Blatterer, Marwan S. Shinawi
Valosin-containing protein (VCP) is an AAA+ ATPase that plays critical roles in multiple ubiquitin-dependent cellular processes. Dominant pathogenic variants in VCP are associated with adult-onset multisystem proteinopathy (MSP), which manifests as myopathy, bone disease, dementia, and/or motor neuron disease. Through GeneMatcher, we identified 13 unrelated individuals who harbor heterozygous VCP variants
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A scalable approach to characterize pleiotropy across thousands of human diseases and complex traits using GWAS summary statistics Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-10-24 Zixuan Zhang, Junghyun Jung, Artem Kim, Noah Suboc, Steven Gazal, Nicholas Mancuso
Genome-wide association studies (GWASs) across thousands of traits have revealed the pervasive pleiotropy of trait-associated genetic variants. While methods have been proposed to characterize pleiotropic components across groups of phenotypes, scaling these approaches to ultra-large-scale biobanks has been challenging. Here, we propose FactorGo, a scalable variational factor analysis model to identify
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Estimating heritability explained by local ancestry and evaluating stratification bias in admixture mapping from summary statistics Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-10-23 Tsz Fung Chan, Xinyue Rui, David V. Conti, Myriam Fornage, Mariaelisa Graff, Jeffrey Haessler, Christopher Haiman, Heather M. Highland, Su Yon Jung, Eimear E. Kenny, Charles Kooperberg, Loic Le Marchand, Kari E. North, Ran Tao, Genevieve Wojcik, Christopher R. Gignoux, , Charleston W.K. Chiang, Nicholas Mancuso
The heritability explained by local ancestry markers in an admixed population (hγ2) provides crucial insight into the genetic architecture of a complex disease or trait. Estimation of hγ2 can be susceptible to biases due to population structure in ancestral populations. Here, we present heritability estimation from admixture mapping summary statistics (HAMSTA), an approach that uses summary statistics
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Identification of a robust DNA methylation signature for Fanconi anemia Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-10-20 Daria Pagliara, Andrea Ciolfi, Lucia Pedace, Sadegheh Haghshenas, Marco Ferilli, Michael A. Levy, Evelina Miele, Claudia Nardini, Camilla Cappelletti, Raissa Relator, Angela Pitisci, Rita De Vito, Simone Pizzi, Jennifer Kerkhof, Haley McConkey, Francesca Nazio, Sarina G. Kant, Maddalena Di Donato, Emanuele Agolini, Marta Matraxia, Marco Tartaglia
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Rare de novo gain-of-function missense variants in DOT1L are associated with developmental delay and congenital anomalies Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-10-11 Zelha Nil, Ashish R. Deshwar, Yan Huang, Scott Barish, Xi Zhang, Sanaa Choufani, Polona Le Quesne Stabej, Ian Hayes, Patrick Yap, Chad Haldeman-Englert, Carolyn Wilson, Trine Prescott, Kristian Tveten, Arve Vøllo, Devon Haynes, Patricia G. Wheeler, Jessica Zon, Cheryl Cytrynbaum, Rebekah Jobling, Moira Blyth, Hugo J. Bellen
Misregulation of histone lysine methylation is associated with several human cancers and with human developmental disorders. DOT1L is an evolutionarily conserved gene encoding a lysine methyltransferase (KMT) that methylates histone 3 lysine-79 (H3K79) and was not previously associated with a Mendelian disease in OMIM. We have identified nine unrelated individuals with seven different de novo heterozygous
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Functional filter for whole-genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5 kb from coding DNA Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-10-09 Sihao Xiao, Zhentian Kai, Daniel Murphy, Dongyang Li, Dilip Patel, Adrianna M. Bielowka, Maria E. Bernabeu-Herrero, Awatif Abdulmogith, Andrew D. Mumford, Sarah K. Westbury, Micheala A. Aldred, Neil Vargesson, Mark J. Caulfield, , Claire L. Shovlin
Despite whole-genome sequencing (WGS), many cases of single-gene disorders remain unsolved, impeding diagnosis and preventative care for people whose disease-causing variants escape detection. Since early WGS data analytic steps prioritize protein-coding sequences, to simultaneously prioritize variants in non-coding regions rich in transcribed and critical regulatory sequences, we developed GROFFFY
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The need for an intersectionality framework in precision medicine research Am. J. Hum. Genet. (IF 9.8) Pub Date : 2023-10-05 Maya Sabatello, Gregory Diggs-Yang, Alicia Santiago, Carla Easter, Kim Jacoby Morris, Brittany M. Hollister, Michael Hahn, Kellan Baker, Alma McCormick, Ella Greene-Moton, Christina Daulton, Greta Goto