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  • Bayesian Genome-wide TWAS Method to Leverage both cis- and trans-eQTL Information through Summary Statistics
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-21
    Justin M. Luningham; Junyu Chen; Shizhen Tang; Philip L. De Jager; David A. Bennett; Aron S. Buchman; Jingjing Yang

    Transcriptome-wide association studies (TWASs) have been widely used to integrate gene expression and genetic data for studying complex traits. Due to the computational burden, existing TWAS methods do not assess distant trans-expression quantitative trait loci (eQTL) that are known to explain important expression variation for most genes. We propose a Bayesian genome-wide TWAS (BGW-TWAS) method that

    更新日期:2020-09-21
  • Ovarian Cancer Risk Variants Are Enriched in Histotype-Specific Enhancers and Disrupt Transcription Factor Binding Sites
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-17
    Michelle R. Jones; Pei-Chen Peng; Simon G. Coetzee; Jonathan Tyrer; Alberto Luiz P. Reyes; Rosario I. Corona; Brian Davis; Stephanie Chen; Felipe Dezem; Ji-Heui Seo; Siddartha Kar; Eileen Dareng; Benjamin P. Berman; Matthew L. Freedman; Jasmine T. Plummer; Kate Lawrenson; Paul Pharoah; Simon A. Gayther

    Quantifying the functional effects of complex disease risk variants can provide insights into mechanisms underlying disease biology. Genome-wide association studies have identified 39 regions associated with risk of epithelial ovarian cancer (EOC). The vast majority of these variants lie in the non-coding genome, where they likely function through interaction with gene regulatory elements. In this

    更新日期:2020-09-18
  • Global Public Perceptions of Genomic Data Sharing: What Shapes the Willingness to Donate DNA and Health Data?
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-17
    Anna Middleton; Richard Milne; Mohamed A. Almarri; Shamim Anwer; Jerome Atutornu; Elena E. Baranova; Paul Bevan; Maria Cerezo; Yali Cong; Christine Critchley; Josepine Fernow; Peter Goodhand; Qurratulain Hasan; Aiko Hibino; Gry Houeland; Heidi C. Howard; S. Zakir Hussain; Charlotta Ingvoldstad Malmgren; Katherine I. Morley

    Analyzing genomic data across populations is central to understanding the role of genetic factors in health and disease. Successful data sharing relies on public support, which requires attention to whether people around the world are willing to donate their data that are then subsequently shared with others for research. However, studies of such public perceptions are geographically limited and do

    更新日期:2020-09-18
  • Generalizability of “GWAS Hits” in Clinical Populations: Lessons from Childhood Cancer Survivors
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-17
    Cindy Im; Na Qin; Zhaoming Wang; Weiyu Qiu; Carrie R. Howell; Yadav Sapkota; Wonjong Moon; Wassim Chemaitilly; Todd M. Gibson; Daniel A. Mulrooney; Kirsten K. Ness; Carmen L. Wilson; Lindsay M. Morton; Gregory T. Armstrong; Smita Bhatia; Jinghui Zhang; Melissa M. Hudson; Leslie L. Robison; Yutaka Yasui

    With mounting interest in translating genome-wide association study (GWAS) hits from large meta-analyses (meta-GWAS) in diverse clinical settings, evaluating their generalizability in target populations is crucial. Here, we consider long-term survivors of childhood cancers from the St. Jude Lifetime Cohort Study, and we show the limited generalizability of 1,376 robust SNP associations reported in

    更新日期:2020-09-18
  • De Novo and Inherited Variants in GBF1 are Associated with Axonal Neuropathy Caused by Golgi Fragmentation
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-15
    Natalia Mendoza-Ferreira; Mert Karakaya; Nur Cengiz; Danique Beijer; Karlla W. Brigatti; Claudia Gonzaga-Jauregui; Nico Fuhrmann; Irmgard Hölker; Maximilian P. Thelen; Sebastian Zetzsche; Roman Rombo; Erik G. Puffenberger; Peter De Jonghe; Tine Deconinck; Stephan Zuchner; Kevin A. Strauss; Vincent Carson; Bertold Schrank; Brunhilde Wirth

    Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are clinically and genetically heterogeneous diseases characterized primarily by motor neuron degeneration and distal weakness. The genetic cause for about half of the individuals affected by HMN/CMT2 remains unknown. Here, we report the identification of pathogenic variants in GBF1 (Golgi brefeldin A-resistant

    更新日期:2020-09-15
  • A Survey of Rare Epigenetic Variation in 23,116 Human Genomes Identifies Disease-Relevant Epivariations and CGG Expansions
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-15
    Paras Garg; Bharati Jadhav; Oscar L. Rodriguez; Nihir Patel; Alejandro Martin-Trujillo; Miten Jain; Sofie Metsu; Hugh Olsen; Benedict Paten; Beate Ritz; R. Frank Kooy; Jozef Gecz; Andrew J. Sharp

    There is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles from 23,116 individuals

    更新日期:2020-09-15
  • Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-04
    Dervla M Connaughton,Rufeng Dai,Danielle J Owen,Jonathan Marquez,Nina Mann,Adda L Graham-Paquin,Makiko Nakayama,Etienne Coyaud,Estelle M N Laurent,Jonathan R St-Germain,Lot Snijders Blok,Arianna Vino,Verena Klämbt,Konstantin Deutsch,Chen-Han Wilfred Wu,Caroline M Kolvenbach,Franziska Kause,Isabel Ottlewski,Ronen Schneider,Thomas M Kitzler,Amar J Majmundar,Florian Buerger,Ana C Onuchic-Whitford,Mao

    Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a

    更新日期:2020-09-05
  • Advancing Diverse Participation in Research with Special Consideration for Vulnerable Populations.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-03

    It is imperative for participation in genetics and genomics research to reflect humanity’s diversity so that all people can enjoy its benefits. This will take a concerted effort by the research community and must include greater engagement with individuals and communities underrepresented in research. In engaging with vulnerable populations, it is essential that researchers guard against harm resulting

    更新日期:2020-09-03
  • The Role of Host Genetic Factors in Coronavirus Susceptibility: Review of Animal and Systematic Review of Human Literature
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-12
    Marissa LoPresti; David B. Beck; Priya Duggal; Derek A.T. Cummings; Benjamin D. Solomon

    The SARS-CoV-2 pandemic raises many scientific and clinical questions. These include how host genetic factors affect disease susceptibility and pathogenesis. New work is emerging related to SARS-CoV-2; previous work has been conducted on other coronaviruses that affect different species. We reviewed the literature on host genetic factors related to coronaviruses, systematically focusing on human studies

    更新日期:2020-09-03
  • Interpretable Clinical Genomics with a Likelihood Ratio Paradigm.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-04
    Peter N Robinson,Vida Ravanmehr,Julius O B Jacobsen,Daniel Danis,Xingmin Aaron Zhang,Leigh C Carmody,Michael A Gargano,Courtney L Thaxton,,Guy Karlebach,Justin Reese,Manuel Holtgrewe,Sebastian Köhler,Julie A McMurry,Melissa A Haendel,Damian Smedley

    Human Phenotype Ontology (HPO)-based analysis has become standard for genomic diagnostics of rare diseases. Current algorithms use a variety of semantic and statistical approaches to prioritize the typically long lists of genes with candidate pathogenic variants. These algorithms do not provide robust estimates of the strength of the predictions beyond the placement in a ranked list, nor do they provide

    更新日期:2020-09-03
  • Combined Utility of 25 Disease and Risk Factor Polygenic Risk Scores for Stratifying Risk of All-Cause Mortality.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-05
    Allison Meisner,Prosenjit Kundu,Yan Dora Zhang,Lauren V Lan,Sungwon Kim,Disha Ghandwani,Parichoy Pal Choudhury,Sonja I Berndt,Neal D Freedman,Montserrat Garcia-Closas,Nilanjan Chatterjee

    While genome-wide association studies have identified susceptibility variants for numerous traits, their combined utility for predicting broad measures of health, such as mortality, remains poorly understood. We used data from the UK Biobank to combine polygenic risk scores (PRS) for 13 diseases and 12 mortality risk factors into sex-specific composite PRS (cPRS). These cPRS were moderately associated

    更新日期:2020-09-03
  • Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-05
    Minta Thomas,Lori C Sakoda,Michael Hoffmeister,Elisabeth A Rosenthal,Jeffrey K Lee,Franzel J B van Duijnhoven,Elizabeth A Platz,Anna H Wu,Christopher H Dampier,Albert de la Chapelle,Alicja Wolk,Amit D Joshi,Andrea Burnett-Hartman,Andrea Gsur,Annika Lindblom,Antoni Castells,Aung Ko Win,Bahram Namjou,Bethany Van Guelpen,Catherine M Tangen,Qianchuan He,Christopher I Li,Clemens Schafmayer,Corinne E Joshu

    Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of

    更新日期:2020-09-03
  • Evolution of a Human-Specific Tandem Repeat Associated with ALS.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-03
    Meredith M Course,Kathryn Gudsnuk,Samuel N Smukowski,Kosuke Winston,Nitin Desai,Jay P Ross,Arvis Sulovari,Cynthia V Bourassa,Dan Spiegelman,Julien Couthouis,Chang-En Yu,Debby W Tsuang,Suman Jayadev,Mark A Kay,Aaron D Gitler,Nicolas Dupre,Evan E Eichler,Patrick A Dion,Guy A Rouleau,Paul N Valdmanis

    Tandem repeats are proposed to contribute to human-specific traits, and more than 40 tandem repeat expansions are known to cause neurological disease. Here, we characterize a human-specific 69 bp variable number tandem repeat (VNTR) in the last intron of WDR7, which exhibits striking variability in both copy number and nucleotide composition, as revealed by long-read sequencing. In addition, greater

    更新日期:2020-09-03
  • Detecting Allele-Specific Alternative Splicing from Population-Scale RNA-Seq Data.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-10
    Levon Demirdjian,Yungang Xu,Emad Bahrami-Samani,Yang Pan,Shayna Stein,Zhijie Xie,Eddie Park,Ying Nian Wu,Yi Xing

    RNA sequencing (RNA-seq) is a powerful technology for studying human transcriptome variation. We introduce PAIRADISE (Paired Replicate Analysis of Allelic Differential Splicing Events), a method for detecting allele-specific alternative splicing (ASAS) from RNA-seq data. Unlike conventional approaches that detect ASAS events one sample at a time, PAIRADISE aggregates ASAS signals across multiple individuals

    更新日期:2020-09-03
  • High Levels of Genetic Diversity within Nilo-Saharan Populations: Implications for Human Adaptation.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-10
    Julius Mulindwa,Harry Noyes,Hamidou Ilboudo,Luca Pagani,Oscar Nyangiri,Magambo Phillip Kimuda,Bernardin Ahouty,Olivier Fataki Asina,Elvis Ofon,Kelita Kamoto,Justin Windingoudi Kabore,Mathurin Koffi,Dieudonne Mumba Ngoyi,Gustave Simo,John Chisi,Issa Sidibe,John Enyaru,Martin Simuunza,Pius Alibu,Vincent Jamonneau,Mamadou Camara,Andy Tait,Neil Hall,Bruno Bucheton,Annette MacLeod,Christiane Hertz-Fowler

    Africa contains more human genetic variation than any other continent, but the majority of the population-scale analyses of the African peoples have focused on just two of the four major linguistic groups, the Niger-Congo and Afro-Asiatic, leaving the Nilo-Saharan and Khoisan populations under-represented. In order to assess genetic variation and signatures of selection within a Nilo-Saharan population

    更新日期:2020-09-03
  • Promoter CpG Density Predicts Downstream Gene Loss-of-Function Intolerance.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-14
    Leandros Boukas,Hans T Bjornsson,Kasper D Hansen

    The aggregation and joint analysis of large numbers of exome sequences has recently made it possible to derive estimates of intolerance to loss-of-function (LoF) variation for human genes. Here, we demonstrate strong and widespread coupling between genic LoF intolerance and promoter CpG density across the human genome. Genes downstream of the most CpG-rich promoters (top 10% CpG density) have a 67

    更新日期:2020-09-03
  • Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-27
    Marialetizia Motta,Luca Pannone,Francesca Pantaleoni,Gianfranco Bocchinfuso,Francesca Clementina Radio,Serena Cecchetti,Andrea Ciolfi,Martina Di Rocco,Mariet W Elting,Eva H Brilstra,Stefania Boni,Laura Mazzanti,Federica Tamburrino,Larry Walsh,Katelyn Payne,Alberto Fernández-Jaén,Mythily Ganapathi,Wendy K Chung,Dorothy K Grange,Ashita Dave-Wala,Shalini C Reshmi,Dennis W Bartholomew,Danielle Mouhlas

    Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in

    更新日期:2020-09-03
  • Bi-allelic Loss-of-function Variants in CFAP58 Cause Flagellar Axoneme and Mitochondrial Sheath Defects and Asthenoteratozoospermia in Humans and Mice.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-12
    Xiaojin He,Chunyu Liu,Xiaoyu Yang,Mingrong Lv,Xiaoqing Ni,Qiang Li,Huiru Cheng,Wangjie Liu,Shixiong Tian,Huan Wu,Yang Gao,Chenyu Yang,Qing Tan,Jiangshan Cong,Dongdong Tang,Jingjing Zhang,Bing Song,Yading Zhong,Hang Li,Weiwei Zhi,Xiaohong Mao,Feifei Fu,Lei Ge,Qunshan Shen,Manyu Zhang,Hexige Saiyin,Li Jin,Yuping Xu,Ping Zhou,Zhaolian Wei,Feng Zhang,Yunxia Cao

    Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenoteratozoospermia. Although recent studies have revealed several MMAF-associated genes and demonstrated MMAF to be a genetically heterogeneous disease, at least one-third of the cases are still not well understood for their etiology. Here, we identified bi-allelic loss-of-function variants in CFAP58 by using

    更新日期:2020-09-03
  • Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-05
    Stefan Haskamp,Heiko Bruns,Madelaine Hahn,Markus Hoffmann,Anne Gregor,Sabine Löhr,Jonas Hahn,Christine Schauer,Mark Ringer,Cindy Flamann,Benjamin Frey,Adam Lesner,Christian T Thiel,Arif B Ekici,Stephan von Hörsten,Gunter Aßmann,Claudia Riepe,Maximilien Euler,Knut Schäkel,Sandra Philipp,Jörg C Prinz,Rotraut Mößner,Florina Kersting,Michael Sticherling,Abdelaziz Sefiani,Jaber Lyahyai,Wiebke Sondermann

    Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%–41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome

    更新日期:2020-09-03
  • Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-05
    Marta Vergnano,Maja Mockenhaupt,Natashia Benzian-Olsson,Maren Paulmann,Katarzyna Grys,Satveer K Mahil,Charlotte Chaloner,Ines A Barbosa,Suzannah August,A David Burden,Siew-Eng Choon,Hywel Cooper,Alex A Navarini,Nick J Reynolds,Shyamal Wahie,Richard B Warren,Andrew Wright,,Ulrike Huffmeier,Patrick Baum,Sudha Visvanathan,Jonathan N Barker,Catherine H Smith,Francesca Capon

    The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals

    更新日期:2020-09-03
  • Variants in SCAF4 Cause a Neurodevelopmental Disorder and Are Associated with Impaired mRNA Processing.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-29
    Anna Fliedner,Philipp Kirchner,Antje Wiesener,Irma van de Beek,Quinten Waisfisz,Mieke van Haelst,Daryl A Scott,Seema R Lalani,Jill A Rosenfeld,Mahshid S Azamian,Fan Xia,Marina Dutra-Clarke,Julian A Martinez-Agosto,Hane Lee,,Grace J Noh,Natalie Lippa,Anna Alkelai,Vimla Aggarwal,Katherine E Agre,Ralitza Gavrilova,Ghayda M Mirzaa,Rachel Straussberg,Rony Cohen,Brooke Horist,Vidya Krishnamurthy,Kirsty McWalter

    RNA polymerase II interacts with various other complexes and factors to ensure correct initiation, elongation, and termination of mRNA transcription. One of these proteins is SR-related CTD-associated factor 4 (SCAF4), which is important for correct usage of polyA sites for mRNA termination. Using exome sequencing and international matchmaking, we identified nine likely pathogenic germline variants

    更新日期:2020-09-03
  • Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-05
    Michael S Breen,Paras Garg,Lara Tang,Danielle Mendonca,Tess Levy,Mafalda Barbosa,Anne B Arnett,Evangeline Kurtz-Nelson,Emanuele Agolini,Agatino Battaglia,Andreas G Chiocchetti,Christine M Freitag,Alicia Garcia-Alcon,Paola Grammatico,Irva Hertz-Picciotto,Yunin Ludena-Rodriguez,Carmen Moreno,Antonio Novelli,Mara Parellada,Giulia Pascolini,Flora Tassone,Dorothy E Grice,Daniele Di Marino,Raphael A Bernier

    Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental

    更新日期:2020-09-03
  • De Novo KAT5 Variants Cause a Syndrome with Recognizable Facial Dysmorphisms, Cerebellar Atrophy, Sleep Disturbance, and Epilepsy.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-20
    Jonathan Humbert,Smrithi Salian,Periklis Makrythanasis,Gabrielle Lemire,Justine Rousseau,Sophie Ehresmann,Thomas Garcia,Rami Alasiri,Armand Bottani,Sylviane Hanquinet,Erin Beaver,Jennifer Heeley,Ann C M Smith,Seth I Berger,Stylianos E Antonarakis,Xiang-Jiao Yang,Jacques Côté,Philippe M Campeau

    KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with

    更新日期:2020-09-03
  • Genome-wide Study Identifies Association between HLA-B∗55:01 and Self-Reported Penicillin Allergy.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-03
    Kristi Krebs,Jonas Bovijn,Neil Zheng,Maarja Lepamets,Jenny C Censin,Tuuli Jürgenson,Dage Särg,Erik Abner,Triin Laisk,Yang Luo,Line Skotte,Frank Geller,Bjarke Feenstra,Wei Wang,Adam Auton,,Soumya Raychaudhuri,Tõnu Esko,Andres Metspalu,Sven Laur,Dan M Roden,Wei-Qi Wei,Michael V Holmes,Cecilia M Lindgren,Elizabeth J Phillips,Reedik Mägi,Lili Milani,João Fadista

    Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000

    更新日期:2020-09-03
  • Inferring Gene-by-Environment Interactions with a Bayesian Whole-Genome Regression Model.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-03
    Matthew Kerin,Jonathan Marchini

    The contribution of gene-by-environment (GxE) interactions for many human traits and diseases is poorly characterized. We propose a Bayesian whole-genome regression model for joint modeling of main genetic effects and GxE interactions in large-scale datasets, such as the UK Biobank, where many environmental variables have been measured. The method is called LEMMA (Linear Environment Mixed Model Analysis)

    更新日期:2020-09-03
  • Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-03
    Sabrina Mechaussier,Basamat Almoallem,Christina Zeitz,Kristof Van Schil,Laila Jeddawi,Jo Van Dorpe,Alfredo Dueñas Rey,Christel Condroyer,Olivier Pelle,Michel Polak,Nathalie Boddaert,Nadia Bahi-Buisson,Mara Cavallin,Jean-Louis Bacquet,Alexandra Mouallem-Bézière,Olivia Zambrowski,José Alain Sahel,Isabelle Audo,Josseline Kaplan,Jean-Michel Rozet,Elfride De Baere,Isabelle Perrault

    更新日期:2020-09-03
  • Genomic Analyses Reveal Mutational Signatures and Frequently Altered Genes in Esophageal Squamous Cell Carcinoma.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-03
    Ling Zhang,Yong Zhou,Caixia Cheng,Heyang Cui,Le Cheng,Pengzhou Kong,Jiaqian Wang,Yin Li,Wenliang Chen,Bin Song,Fang Wang,Zhiwu Jia,Lin Li,Yaoping Li,Bin Yang,Jing Liu,Ruyi Shi,Yanghui Bi,Yanyan Zhang,Juan Wang,Zhenxiang Zhao,Xiaoling Hu,Jie Yang,Hongyi Li,Zhibo Gao,Gang Chen,Xuanlin Huang,Xukui Yang,Shengqing Wan,Chao Chen,Bin Li,Yongkai Tan,Longyun Chen,Minghui He,Sha Xie,Xiangchun Li,Xuehan Zhuang

    更新日期:2020-09-03
  • Response to Holstege et al.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-03
    J Nicholas Cochran,Richard M Myers,Jennifer S Yokoyama

    更新日期:2020-09-03
  • The Role of Age-Related Clonal Hematopoiesis in Genetic Sequencing Studies.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-09-03
    Henne Holstege,Marc Hulsman,Sven J van der Lee,Erik B van den Akker

    更新日期:2020-09-03
  • eQTL Colocalization Analyses Identify NTN4 as a Candidate Breast Cancer Risk Gene.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-31
    Jonathan Beesley,Haran Sivakumaran,Mahdi Moradi Marjaneh,Wei Shi,Kristine M Hillman,Susanne Kaufmann,Nehal Hussein,Siddhartha Kar,Luize G Lima,Sunyoung Ham,Andreas Möller,Georgia Chenevix-Trench,Stacey L Edwards,Juliet D French

    Breast cancer genome-wide association studies (GWASs) have identified 150 genomic risk regions containing more than 13,000 credible causal variants (CCVs). The CCVs are predominantly noncoding and enriched in regulatory elements. However, the genes underlying breast cancer risk associations are largely unknown. Here, we used genetic colocalization analysis to identify loci at which gene expression

    更新日期:2020-08-31
  • Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-26
    Tamara S Roman,Stephanie B Crowley,Myra I Roche,Ann Katherine M Foreman,Julianne M O'Daniel,Bryce A Seifert,Kristy Lee,Alicia Brandt,Chelsea Gustafson,Daniela M DeCristo,Natasha T Strande,Lori Ramkissoon,Laura V Milko,Phillips Owen,Sayanty Roy,Mai Xiong,Ryan S Paquin,Rita M Butterfield,Megan A Lewis,Katherine J Souris,Donald B Bailey,Christine Rini,Jessica K Booker,Bradford C Powell,Karen E Weck,Cynthia

    Newborn screening (NBS) was established as a public health program in the 1960s and is crucial for facilitating detection of certain medical conditions in which early intervention can prevent serious, life-threatening health problems. Genomic sequencing can potentially expand the screening for rare hereditary disorders, but many questions surround its possible use for this purpose. We examined the

    更新日期:2020-08-26
  • Semantic Similarity Analysis Reveals Robust Gene-Disease Relationships in Developmental and Epileptic Encephalopathies.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-26
    Peter D Galer,Shiva Ganesan,David Lewis-Smith,Sarah E McKeown,Manuela Pendziwiat,Katherine L Helbig,Colin A Ellis,Annika Rademacher,Lacey Smith,Annapurna Poduri,Simone Seiffert,Sarah von Spiczak,Hiltrud Muhle,Andreas van Baalen,,,,,Rhys H Thomas,Roland Krause,Yvonne Weber,Ingo Helbig

    More than 100 genetic etiologies have been identified in developmental and epileptic encephalopathies (DEEs), but correlating genetic findings with clinical features at scale has remained a hurdle because of a lack of frameworks for analyzing heterogenous clinical data. Here, we analyzed 31,742 Human Phenotype Ontology (HPO) terms in 846 individuals with existing whole-exome trio data and assessed

    更新日期:2020-08-26
  • Equitable Expanded Carrier Screening Needs Indigenous Clinical and Population Genomic Data.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-06
    Simon Easteal,Ruth M Arkell,Renzo F Balboa,Shayne A Bellingham,Alex D Brown,Tom Calma,Matthew C Cook,Megan Davis,Hugh J S Dawkins,Marcel E Dinger,Michael S Dobbie,Ashley Farlow,Kylie G Gwynne,Azure Hermes,Wendy E Hoy,Misty R Jenkins,Simon H Jiang,Warren Kaplan,Stephen Leslie,Bastien Llamas,Graham J Mann,Brendan J McMorran,Rebekah E McWhirter,Cliff J Meldrum,Shivashankar H Nagaraj,Saul J Newman,Jack

    Expanded carrier screening (ECS) for recessive monogenic diseases requires prior knowledge of genomic variation, including DNA variants that cause disease. The composition of pathogenic variants differs greatly among human populations, but historically, research about monogenic diseases has focused mainly on people with European ancestry. By comparison, less is known about pathogenic DNA variants in

    更新日期:2020-08-06
  • Fostering Responsible Research on Ancient DNA.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-06
    Jennifer K Wagner,Chip Colwell,Katrina G Claw,Anne C Stone,Deborah A Bolnick,John Hawks,Kyle B Brothers,Nanibaa' A Garrison

    Anticipating and addressing the social implications of scientific work is a fundamental responsibility of all scientists. However, expectations for ethically sound practices can evolve over time as the implications of science come to be better understood. Contemporary researchers who work with ancient human remains, including those who conduct ancient DNA research, face precisely this challenge as

    更新日期:2020-08-06
  • Regional Variation of Splicing QTLs in Human Brain.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-25
    Yida Zhang,Harry Taegyun Yang,Kathryn Kadash-Edmondson,Yang Pan,Zhicheng Pan,Beverly L Davidson,Yi Xing

    A major question in human genetics is how sequence variants of broadly expressed genes produce tissue- and cell type-specific molecular phenotypes. Genetic variation of alternative splicing is a prevalent source of transcriptomic and proteomic diversity in human populations. We investigated splicing quantitative trait loci (sQTLs) in 1,209 samples from 13 human brain regions, using RNA sequencing (RNA-seq)

    更新日期:2020-08-06
  • A Platelet Function Modulator of Thrombin Activation Is Causally Linked to Cardiovascular Disease and Affects PAR4 Receptor Signaling.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-09
    Benjamin A T Rodriguez,Arunoday Bhan,Andrew Beswick,Peter C Elwood,Teemu J Niiranen,Veikko Salomaa,,David-Alexandre Trégouët,Pierre-Emmanuel Morange,Mete Civelek,Yoav Ben-Shlomo,Thorsten Schlaeger,Ming-Huei Chen,Andrew D Johnson

    Dual antiplatelet therapy reduces ischemic events in cardiovascular disease, but it increases bleeding risk. Thrombin receptors PAR1 and PAR4 are drug targets, but the role of thrombin in platelet aggregation remains largely unexplored in large populations. We performed a genome-wide association study (GWAS) of platelet aggregation in response to full-length thrombin, followed by clinical association

    更新日期:2020-08-06
  • A Fast and Accurate Method for Genome-Wide Time-to-Event Data Analysis and Its Application to UK Biobank.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-25
    Wenjian Bi,Lars G Fritsche,Bhramar Mukherjee,Sehee Kim,Seunggeun Lee

    With increasing biobanking efforts connecting electronic health records and national registries to germline genetics, the time-to-event data analysis has attracted increasing attention in the genetics studies of human diseases. In time-to-event data analysis, the Cox proportional hazards (PH) regression model is one of the most used approaches. However, existing methods and tools are not scalable when

    更新日期:2020-08-06
  • The Genetic Landscape and Epidemiology of Phenylketonuria.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-14
    Alicia Hillert,Yair Anikster,Amaya Belanger-Quintana,Alberto Burlina,Barbara K Burton,Carla Carducci,Ana E Chiesa,John Christodoulou,Maja Đorđević,Lourdes R Desviat,Aviva Eliyahu,Roeland A F Evers,Lena Fajkusova,François Feillet,Pedro E Bonfim-Freitas,Maria Giżewska,Polina Gundorova,Daniela Karall,Katya Kneller,Sergey I Kutsev,Vincenzo Leuzzi,Harvey L Levy,Uta Lichter-Konecki,Ania C Muntau,Fares Namour

    Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]–1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed

    更新日期:2020-08-06
  • Characterization of Exome Variants and Their Metabolic Impact in 6,716 American Indians from the Southwest US.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-07
    Hye In Kim,Bin Ye,Nehal Gosalia,,Çiğdem Köroğlu,Robert L Hanson,Wen-Chi Hsueh,William C Knowler,Leslie J Baier,Clifton Bogardus,Alan R Shuldiner,Cristopher V Van Hout

    Applying exome sequencing to populations with unique genetic architecture has the potential to reveal novel genes and variants associated with traits and diseases. We sequenced and analyzed the exomes of 6,716 individuals from a Southwestern American Indian (SWAI) population with well-characterized metabolic traits. We found that the SWAI population has distinct allelic architecture compared to populations

    更新日期:2020-08-06
  • Genetic Consequences of the Transatlantic Slave Trade in the Americas.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-23
    Steven J Micheletti,Kasia Bryc,Samantha G Ancona Esselmann,William A Freyman,Meghan E Moreno,G David Poznik,Anjali J Shastri,,Sandra Beleza,Joanna L Mountain

    According to historical records of transatlantic slavery, traders forcibly deported an estimated 12.5 million people from ports along the Atlantic coastline of Africa between the 16th and 19th centuries, with global impacts reaching to the present day, more than a century and a half after slavery’s abolition. Such records have fueled a broad understanding of the forced migration from Africa to the

    更新日期:2020-08-06
  • Human iPSC Modeling Reveals Mutation-Specific Responses to Gene Therapy in a Genotypically Diverse Dominant Maculopathy.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-23
    Divya Sinha,Benjamin Steyer,Pawan K Shahi,Katherine P Mueller,Rasa Valiauga,Kimberly L Edwards,Cole Bacig,Stephanie S Steltzer,Sandhya Srinivasan,Amr Abdeen,Evan Cory,Viswesh Periyasamy,Alireza Fotuhi Siahpirani,Edwin M Stone,Budd A Tucker,Sushmita Roy,Bikash R Pattnaik,Krishanu Saha,David M Gamm

    Dominantly inherited disorders are not typically considered to be therapeutic candidates for gene augmentation. Here, we utilized induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) to test the potential of gene augmentation to treat Best disease, a dominant macular dystrophy caused by over 200 missense mutations in BEST1. Gene augmentation in iPSC-RPE fully restored BEST1 calcium-activated

    更新日期:2020-08-06
  • Mutations in MYLPF Cause a Novel Segmental Amyoplasia that Manifests as Distal Arthrogryposis.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-23
    Jessica X Chong,Jared C Talbot,Emily M Teets,Samantha Previs,Brit L Martin,Kathryn M Shively,Colby T Marvin,Arthur S Aylsworth,Reem Saadeh-Haddad,Ulrich A Schatz,Francesca Inzana,Tawfeg Ben-Omran,Fatima Almusafri,Mariam Al-Mulla,Kati J Buckingham,Tamar Harel,Hagar Mor-Shaked,Periyasamy Radhakrishnan,Katta M Girisha,Shalini S Nayak,Anju Shukla,Klaus Dieterich,Julien Faure,John Rendu,Yline Capri,Xenia

    We identified ten persons in six consanguineous families with distal arthrogryposis (DA) who had congenital contractures, scoliosis, and short stature. Exome sequencing revealed that each affected person was homozygous for one of two different rare variants (c.470G>T [p.Cys157Phe] or c.469T>C [p.Cys157Arg]) affecting the same residue of myosin light chain, phosphorylatable, fast skeletal muscle (MYLPF)

    更新日期:2020-08-06
  • De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-31
    Andreea Manole,Stephanie Efthymiou,Emer O'Connor,Marisa I Mendes,Matthew Jennings,Reza Maroofian,Indran Davagnanam,Kshitij Mankad,Maria Rodriguez Lopez,Vincenzo Salpietro,Ricardo Harripaul,Lauren Badalato,Jagdeep Walia,Christopher S Francklyn,Alkyoni Athanasiou-Fragkouli,Roisin Sullivan,Sonal Desai,Kristin Baranano,Faisal Zafar,Nuzhat Rana,Muhammed Ilyas,Alejandro Horga,Majdi Kara,Francesca Mattioli

    Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1)

    更新日期:2020-08-06
  • Large Copy-Number Variants in UK Biobank Caused by Clonal Hematopoiesis May Confound Penetrance Estimates.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-22
    Marcus Tuke,Jessica Tyrrell,Katherine S Ruth,Robin N Beaumont,Andrew R Wood,Anna Murray,Timothy M Frayling,Michael N Weedon,Caroline F Wright

    Large copy-number variants (CNVs) are strongly associated with both developmental delay and cancer, but the type of disease depends strongly on when and where the mutation occurred, i.e., germline versus somatic. We used microarray data from UK Biobank to investigate the prevalence and penetrance of large autosomal CNVs and chromosomal aneuploidies using a standard CNV detection algorithm not designed

    更新日期:2020-08-06
  • Bi-allelic DNAH8 Variants Lead to Multiple Morphological Abnormalities of the Sperm Flagella and Primary Male Infertility.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-02
    Chunyu Liu,Haruhiko Miyata,Yang Gao,Yanwei Sha,Shuyan Tang,Zoulan Xu,Marjorie Whitfield,Catherine Patrat,Huan Wu,Emmanuel Dulioust,Shixiong Tian,Keisuke Shimada,Jiangshan Cong,Taichi Noda,Hang Li,Akane Morohoshi,Caroline Cazin,Zine-Eddine Kherraf,Christophe Arnoult,Li Jin,Xiaojin He,Pierre F Ray,Yunxia Cao,Aminata Touré,Feng Zhang,Masahito Ikawa

    Sperm malformation is a direct factor for male infertility. Multiple morphological abnormalities of the flagella (MMAF), a severe form of asthenoteratozoospermia, are characterized by immotile spermatozoa with malformed and/or absent flagella in the ejaculate. Previous studies indicated genetic heterogeneity in MMAF. To further define genetic factors underlying MMAF, we performed whole-exome sequencing

    更新日期:2020-08-06
  • Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-15
    Margot J Wyrwoll,Şehime G Temel,Liina Nagirnaja,Manon S Oud,Alexandra M Lopes,Godfried W van der Heijden,James S Heald,Nadja Rotte,Joachim Wistuba,Marius Wöste,Susanne Ledig,Henrike Krenz,Roos M Smits,Filipa Carvalho,João Gonçalves,Daniela Fietz,Burcu Türkgenç,Mahmut C Ergören,Murat Çetinkaya,Murad Başar,Semra Kahraman,Kevin McEleny,Miguel J Xavier,Helen Turner,Adrian Pilatz,Albrecht Röpke,Martin Dugas

    Male infertility affects ∼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift

    更新日期:2020-08-06
  • De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-20
    Maria J Guillen Sacoto,Iva A Tchasovnikarova,Erin Torti,Cara Forster,E Hallie Andrew,Irina Anselm,Kristin W Baranano,Lauren C Briere,Julie S Cohen,William J Craigen,Cheryl Cytrynbaum,Nina Ekhilevitch,Matthew J Elrick,Ali Fatemi,Jamie L Fraser,Renata C Gallagher,Andrea Guerin,Devon Haynes,Frances A High,Cara N Inglese,Courtney Kiss,Mary Kay Koenig,Joel Krier,Kristin Lindstrom,Michael Marble,Hannah Meddaugh

    MORC2 encodes an ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous variants in MORC2 have been reported in individuals with autosomal-dominant Charcot-Marie-Tooth disease type 2Z and spinal muscular atrophy, and the onset of symptoms ranges from infancy to the second decade of life. Here, we present a cohort of 20 individuals referred for exome

    更新日期:2020-08-06
  • Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-23
    Ralf A Husain,Mona Grimmel,Matias Wagner,J Christopher Hennings,Christian Marx,René G Feichtinger,Abdelkrim Saadi,Kevin Rostásy,Florentine Radelfahr,Andrea Bevot,Marion Döbler-Neumann,Hans Hartmann,Laurence Colleaux,Isabell Cordts,Xenia Kobeleva,Hossein Darvish,Somayeh Bakhtiari,Michael C Kruer,Arnaud Besse,Andy Cheuk-Him Ng,Diana Chiang,Francois Bolduc,Abbas Tafakhori,Shrikant Mane,Saghar Ghasemi

    We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with

    更新日期:2020-08-06
  • This Month in The Journal.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-06
    Sarah Ratzel,Sara B Cullinan

    更新日期:2020-08-06
  • Genomic Analyses Reveal Mutational Signatures and Frequently Altered Genes in Esophageal Squamous Cell Carcinoma.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-06
    Ling Zhang,Yong Zhou,Caixia Cheng,Heyang Cui,Le Cheng,Pengzhou Kong,Jiaqian Wang,Yin Li,Wenliang Chen,Bin Song,Fang Wang,Zhiwu Jia,Lin Li,Yaoping Li,Bin Yang,Jing Liu,Ruyi Shi,Yanghui Bi,Yanyan Zhang,Juan Wang,Zhenxiang Zhao,Xiaoling Hu,Jie Yang,Hongyi Li,Zhibo Gao,Gang Chen,Xuanlin Huang,Xukui Yang,Shengqing Wan,Chao Chen,Bin Li,Yongkai Tan,Longyun Chen,Minghui He,Sha Xie,Xiangchun Li,Xuehan Zhuang

    更新日期:2020-08-06
  • Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-08-06
    Tim Van Damme,Thatjana Gardeitchik,Miski Mohamed,Sergio Guerrero-Castillo,Peter Freisinger,Brecht Guillemyn,Ariana Kariminejad,Daisy Dalloyaux,Sanne van Kraaij,Dirk J Lefeber,Delfien Syx,Wouter Steyaert,Riet De Rycke,Alexander Hoischen,Erik-Jan Kamsteeg,Sunnie Y Wong,Monique van Scherpenzeel,Payman Jamali,Ulrich Brandt,Leo Nijtmans,G Christoph Korenke,Brian H Y Chung,Christopher C Y Mak,Ingrid Hausser

    更新日期:2020-08-06
  • Management of Secondary Genomic Findings.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-07-02
    Alexander E Katz,Robert L Nussbaum,Benjamin D Solomon,Heidi L Rehm,Marc S Williams,Leslie G Biesecker

    Secondary genomic findings are increasingly being returned to individuals as opportunistic screening results. A secondary finding offers the chance to identify and mitigate disease that may otherwise be unrecognized in an individual. As a form of screening, secondary findings must be considered differently from sequencing results in a diagnostic setting. For these reasons, clinicians should employ

    更新日期:2020-07-02
  • Bi-allelic Missense Pathogenic Variants in TRIP13 Cause Female Infertility Characterized by Oocyte Maturation Arrest.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-29
    Zhihua Zhang,Bin Li,Jing Fu,Rong Li,Feiyang Diao,Caihong Li,Biaobang Chen,Jing Du,Zhou Zhou,Jian Mu,Zheng Yan,Ling Wu,Shuai Liu,Wenjing Wang,Lin Zhao,Jie Dong,Lin He,Xiaozhen Liang,Yanping Kuang,Xiaoxi Sun,Qing Sang,Lei Wang

    Normal oocyte meiosis is a prerequisite for successful human reproduction, and abnormalities in the process will result in infertility. In 2016, we identified mutations in TUBB8 as responsible for human oocyte meiotic arrest. However, the underlying genetic factors for most affected individuals remain unknown. TRIP13, encoding an AAA-ATPase, is a key component of the spindle assembly checkpoint, and

    更新日期:2020-07-02
  • Homozygous Mutations in BTG4 Cause Zygotic Cleavage Failure and Female Infertility.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-04
    Wei Zheng,Zhou Zhou,Qianqian Sha,Xiangli Niu,Xiaoxi Sun,Juanzi Shi,Lei Zhao,Shuoping Zhang,Jing Dai,Sufen Cai,Fei Meng,Liang Hu,Fei Gong,Xiaoran Li,Jing Fu,Rong Shi,Guangxiu Lu,Biaobang Chen,Hengyu Fan,Lei Wang,Ge Lin,Qing Sang

    Zygotic cleavage failure (ZCF) is a unique early embryonic phenotype resulting in female infertility and recurrent failure of in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI). With this phenotype, morphologically normal oocytes can be retrieved and successfully fertilized, but they fail to undergo cleavage. Until now, whether this phenotype has a Mendelian inheritance pattern

    更新日期:2020-07-02
  • Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-03
    Huijun Wang,Aytaj Humbatova,Yuanxiang Liu,Wen Qin,Mingyang Lee,Nicole Cesarato,Fanny Kortüm,Sheetal Kumar,Maria Teresa Romano,Shangzhi Dai,Ran Mo,Sugirthan Sivalingam,Susanne Motameny,Yuan Wu,Xiaopeng Wang,Xinwu Niu,Songmei Geng,Dorothea Bornholdt,Peter M Kroisel,Gianluca Tadini,Scott D Walter,Fabian Hauck,Katta M Girisha,Anne-Marie Calza,Armand Bottani,Janine Altmüller,Andreas Buness,Shuxia Yang,Xiujuan

    IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant

    更新日期:2020-07-02
  • Non-parametric Polygenic Risk Prediction via Partitioned GWAS Summary Statistics.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-05-28
    Sung Chun,Maxim Imakaev,Daniel Hui,Nikolaos A Patsopoulos,Benjamin M Neale,Sekar Kathiresan,Nathan O Stitziel,Shamil R Sunyaev

    In complex trait genetics, the ability to predict phenotype from genotype is the ultimate measure of our understanding of genetic architecture underlying the heritability of a trait. A complete understanding of the genetic basis of a trait should allow for predictive methods with accuracies approaching the trait’s heritability. The highly polygenic nature of quantitative traits and most common phenotypes

    更新日期:2020-07-02
  • Evidence of Polygenic Adaptation in Sardinia at Height-Associated Loci Ascertained from the Biobank Japan.
    Am. J. Hum. Genet. (IF 10.502) Pub Date : 2020-06-12
    Minhui Chen,Carlo Sidore,Masato Akiyama,Kazuyoshi Ishigaki,Yoichiro Kamatani,David Schlessinger,Francesco Cucca,Yukinori Okada,Charleston W K Chiang

    Adult height is one of the earliest putative examples of polygenic adaptation in humans. However, this conclusion was recently challenged because residual uncorrected stratification from large-scale consortium studies was considered responsible for the previously noted genetic difference. It thus remains an open question whether height loci exhibit signals of polygenic adaptation in any human population

    更新日期:2020-07-02