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  • Lack of evidence for genetic association of saposins A, B, C and D with Parkinson disease
    medRxiv. Genet. Genom. Med. Pub Date : 2020-06-01
    Yuri Ludwig Sosero; Sara Bandres Ciga; Sharon Hassin; Roy N. Alcalay; Ziv Gan-Or

    The PSAP gene encodes prosaposin, which is later cleaved into four active saposins: saposin A, B, C and D. Mutations in these enzymes have been linked to specific lysosomal storage disorders. Recently, a genetic association between mutations in saposin D and Parkinson disease (PD) has been reported. To further examine whether variants in saposin D or the other saposins could be associated with Parkinson

  • The landscape of host genetic factors involved in infection to common viruses and SARS-CoV-2
    medRxiv. Genet. Genom. Med. Pub Date : 2020-06-01
    Linda Kachuri; Stephen S Francis; Maike Morrison; Yohan Bossé Taylor B Cavazos; Sara R Rashkin; Elad Ziv; John S Witte

    Introduction: Humans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and informs public health interventions. Methods: We conducted a comprehensive study linking germline genetic variation and gene expression with antibody response to 28 antigens

  • Novel ultra-Rare exonic variants identified in a founder population implicate cadherins in schizophrenia
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-30
    Todd Lencz; Jin Yu; Raiyan Rashid Kahn; Shai Carmi; Max Lam; Danny Ben-Avraham; Nir Barzilai; Susan Bressman; Ariel Darvasi; Judy H. Cho; Lorraine N. Clark; Zeynep H. Gümüş; Joseph Vijai; Robert J. Klein; Steven Lipkin; Kenneth Offit; Harry Ostrer; Laurie J. Ozelius; Inga Peter; Anil K. Malhotra; Gil Atzmon; Itsik Pe'er

    IMPORTANCE: Schizophrenia is a serious mental illness with high heritability. While common genetic variants account for a portion of the heritability, identification of rare variants associated with the disorder has proven challenging. OBJECTIVE: To identify genes and gene sets associated with schizophrenia in a founder population (Ashkenazi Jewish), and to determine the relative power of this population

  • Alpha globin gene deletions in amelioration of clinical severity in beta haemoglobinopathy subjects with the β0/β+ genotype
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-30
    Dipankar Saha; Prosanto Kumar Chowdhury; Amrita Panja; Debashis Pal; Sharmistha Chakraborty; Kaustav Nayek; Gispati Chakraborty; Prashant Sharma; Reena Das; Surupa Basu; Raghunath Chatterjee; ANUPAM BASU

    Abstract Thalassemia is the commonest inherited hemoglobinopathy worldwide. Variation of clinical symptoms entail differences in disease-onset and transfusion requirements. Our objective was to investigate the role of alpha gene deletions in modulating the clinical heterogeneity of thalassemia syndromes. A total of 214 individuals with diagnosed beta-thalassemia major/intermedia were included in the

  • Whole exome sequencing identifies genes associated with non-obstructive azoospermia
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-29
    Hongguo Zhang; Hui Huang; Xinyue Zhang; Wei Li; Yuting Jiang; Jia Li; Leilei Li; Jing Zhao; Jing He; Mucheng Chen; Ruixue Wang; Jing Wu; Zhiyu Peng; Ruizhi Liu

    Background: Genetic etiology is the main cause of non-obstructive azoospermia, but little is known about the landscape of the disease causative genes. Objective: To identify the association of non-obstructive azoospermia and the putative causative genetic factors. Design, setting, and participants: A single-center perspective case-control study of 133 patients, with clinicopathologic non-obstructive

  • ACE2 variants underlie interindividual variability and susceptibility to COVID-19 in Italian population
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-29
    Alessandra Renieri; Elisa Benetti; Rossella Tita; Ottavia Spiga; Andrea Ciolfi; Giovanni Birolo; Alessandro Bruselles; Gabriella Doddato; Annarita Giliberti; Cterina Marconi; Francesco Musacchia; Tommaso Pippucci; Annalaura Torella; Alfonso Trezza; Floriana Valentino; Mrgherita Baldassarri; Alfredo Brusco; Rosanna Asselta; Bruttini Mirella; Simone Furini; Marco Seri; Vincenzo Nigro; Giuseppe Matullo;

    In December 2019, an initial cluster of interstitial bilateral pneumonia emerged in Wuhan, China. A human-to-human transmission was assumed and a previously unrecognized entity, termed coronavirus-disease-19 (COVID-19) due to a novel coronavirus (SARS-CoV-2) was described. The infection has rapidly spread out all over the world and Italy has been the first European country experiencing the endemic

  • ACE2 polymorphisms as potential players in COVID-19 outcome
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-29
    Andre Salim Khayat; Paulo Pimentel de Assumpcao; Bruna Claudia Meireles Khayat; Taissa Maira Thomaz Araujo; Jessica Almeida Batista-Gomes; Luciana Carvalho Imbiriba; Geraldo Ishak; Paula Barauna de Assumpcao; Fabiano Cordeiro Moreira; Rommel Rodriguez Burbano; Andre Mauricio Ribeiro-dos-Santos; Andrea Kelly Ribeiro-dos-Santos; Ney Pereira Carneiro dos Santos; Sidney Emmanuel Batista dos Santos

    The clinical condition COVID-19, caused by SARS-CoV-2, was declared a pandemic by the WHO in March 2020. Currently, there are more than 5 million cases worldwide, and the pandemic has increased exponentially in many countries, with different incidences and death rates among regions/ethnicities and, intriguingly, between sexes. In addition to the many factors that can influence these discrepancies,

  • Clinical population genetic analysis of variants in the SARS-CoV-2 receptor ACE2
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-29
    Amin Ardeshirdavani; Pooya Zakeri; Amirhosein Mehrtash; Sayed Mostafa Hosseini; Guangdi Li; Hanifeh Mirtavoos-Mahyari; Mohamad javad Soltanpour; Mahmoud Tavallaie; Yves Moreau

    Purpose: SARS-CoV-2 infects cells via the human Angiotensin-converting enzyme 2 (ACE2) protein. The genetic variation of ACE2 function and expression across populations is still poorly understood. This study aims at better understanding the genetic basis of COVID-19 outcomes by studying association between genetic variation in ACE2 and disease severity in the Iranian population. Methods: We analyzed

  • RNA sequencing identifies a cryptic exon caused by a deep intronic variant in NDUFB10 resulting in isolated Complex I deficiency.
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-26
    Guy Helman; Alison G. Compton; Daniella H. Hock; Marzena Walkiewicz; Gemma R. Brett; Lynn Pais; Tiong Y. Tan; Ricardo De Paoli-Iseppi; Michael B. Clark; John Christodoulou; Susan M. White; David R. Thorburn; David A. Stroud; Zornitza Stark; Cas Simons

    The diagnosis of mitochondrial disorders remains a challenging and often unmet need. We sought to investigate a sibling pair with suspected mitochondrial disease and a clinical presentation notable for global developmental delay, poor growth, sensorineural hearing loss, and brain MRI abnormalities, both with early death. Following uninformative exome and genome sequencing of the family quartet, RNA

  • No evidence for allelic association between Covid-19 and ACE2 genetic variants by direct exome sequencing in 99 SARS-CoV-2 positive patients
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-26
    Antonio Novelli; Michela Biancolella; Paola Borgiani; Dario Cocciadiferro; Vito Luigi Colona; Maria Rosaria D'Apice; Paola Rogliani; Salvatore Zaffina; Francesca Leonardis; Andrea Campana; Massimiliano Raponi; Massimo Andreoni; Sandro Grelli; Giuseppe Novelli

    Background: Coronaviruses (CoV) are a large family of viruses that are common in people and many animal species. Animal coronaviruses rarely infect humans with the exceptions of the Middle East Respiratory Syndrome (MERS-CoV), the Severe acute respiratory syndrome coronavirus (SARS-CoV), and now SARS-CoV-2, which is the cause of the ongoing pandemic of coronavirus disease 2019 (COVID-19). Many studies

  • Higher maternal adiposity reduces offspring birth weight if associated with a metabolically favourable profile
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-25
    William David Thompson; Robin N Beaumont; Alan Kuang; Nicole Warrington; Yingjie Ji; Jess N Tyrrell; Andrew R Wood; Denise Scholtens; Bridget A Knight; David M Evans; Bill L Lowe; Gillian Santorelli; Rafaq Azad; Dan Mason; Andrew T Hattersley; Timothy M Frayling; Hanieh Yaghootkar; Maria Carolina Borges; Debbie Lawlor; Rachel M Freathy

    Aims/Hypothesis Higher maternal BMI during pregnancy results in higher offspring birth weight, but it is not known whether this is solely the result of adverse metabolic consequences of higher maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors. We aimed

  • Clinical and molecular characterization of COVID-19 hospitalized patients
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-25
    Elisa Benetti; Annarita Giliberti; Arianna Emiliozzi; Floriana Velentino; Laura Bergantini; Chiara Fallerini; Federico Anedda; Sara Amitrano; Edoardo Conticini; Rossella Tita; Miriana DAlessandro; Francesca Fava; Simona Marcantonio; Margherita Baldassarri; Mirella Bruttini; Maria Antonietta Mazzei; Francesca Montagnani; Marco Mandala; Elena Bargagli; Simone Furini; COVID-19 MULTICENTER STUDY; Alessandra

    Clinical and molecular characterization by Whole Exome Sequencing (WES) is reported in 35 COVID-19 patients attending the University Hospital in Siena, Italy, from April 7 to May 7, 2020. Eighty percent of patients required respiratory assistance, half of them being on mechanical ventilation. Fiftyone percent had hepatic involvement and hyposmia was ascertained in 3 patients. Searching for common genes

  • Machine Learning for Interpretation of DNA Variants of Maturity-Onset Diabetes of the Young Genes Based on ACMG Criteria
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-23
    Yichuan Liu; Huiqi Qu; Adam S Wenocur; Jingchun Qu; Xiao Chang; Joseph Glessner; Patrick Sleiman; Lifeng Tian; Hakon Hakonarson

    Background: Maturity-onset diabetes of the young (MODY) is a group of dominantly inherited monogenic diabetes, with HNF4A-MODY, GCK-MODY and HNF1A-MODY being the three most common genes responsible. Molecular diagnosis of MODY is important for precise treatment. While a DNA variant causing MODY can be assessed by the criteria of the American College of Medical Genetics and Genomics (ACMG) guidelines

  • The Polygenic Score Catalog: an open database for reproducibility and systematic evaluation
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-23
    Samuel A Lambert; Laurent Gil; Simon Jupp; Scott C Ritchie; Yu Xu; Annalisa Buniello; Gad Abraham; Michael Chapman; Helen Parkinson; John Danesh; Jacqueline A MacArthur; Michael Inouye

    Polygenic [risk] scores (PGS) can enhance prediction and understanding of common diseases and traits. However, the reproducibility of PGS and their subsequent applications in biological and clinical research have been hindered by several factors, including: inadequate and incomplete reporting of PGS development, heterogeneity in evaluation techniques, and inconsistent access to, and distribution of

  • Examining the bidirectional association between emotion recognition and ASD symptoms using observational and genetic analyses
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-23
    Zoe E Reed; Liam Mahedy; Abigail Jackson; George Davey Smith; Ian Penton-Voak; Angela S Attwood; Marcus R Munafo

    Background: There is mixed evidence for an association between autism spectrum disorder (ASD) and emotion recognition deficits. We sought to assess the bidirectionality of this association using phenotypic and genetic data in a large community sample. Methods: Analyses were conducted in three stages. First, we examined the bidirectional association between ASD symptoms at age 16 years and emotion recognition

  • Full genome viral sequences inform patterns of SARS-CoV-2 spread into and within Israel
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-22
    Danielle Miller; Michael A Martin; Noam Harel; Talia Kustin; Omer Tirosh; Moran Meir; Nadav Sorek; Shiraz Gefen-Halevi; Sharon Amit; Olesya Vorontsov; Dana Wolf; Avi Peretz; Yonat Shemer-Avni; Diana Roif-Kaminsky; Na'ama Kopelman; Amit Huppert; Katia Koelle; Adi Stern

    Full genome sequences are increasingly used to track the geographic spread and transmission dynamics of viral pathogens. Here, with a focus on Israel, we sequenced 212 SARS-CoV-2 sequences and use them to perform a comprehensive analysis to trace the origins and spread of the virus. A phylogenetic analysis including thousands of globally sampled sequences allowed us to infer multiple independent introductions

  • ApoE e2 and aging-related outcomes in 379,000 UK Biobank participants
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-22
    Chia-Ling Kuo; Luke C Pilling; Janice L. Atkins; George A. Kuchel; David Melzer

    The Apolipoprotein E (APOE) e4 allele is associated with reduced longevity and increased Coronary Artery Disease (CAD) and Alzheimer's disease, with e4e4 having markedly larger effect sizes than e3e4. The e2 longevity promoting variant is less studied. We conducted a phenome-wide association study of ApoE e2e3 and e2e2 with aging phenotypes, to assess their potential as targets for anti-aging interventions

  • GWAS of Depression Phenotypes in the Million Veteran Program and Meta-analysis in More than 1.2 Million Participants Yields 178 Independent Risk Loci
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-22
    Daniel F Levey; Murray B Stein; Frank R Wendt; Gita A Pathak; Hang Zhou; Mihaela Aslan; Rachel Quaden; Kelly M Harrington; Gerard Sanacora; Andrew M McIntosh; John Concato; Renato Polimanti; Joel Gelernter; on behalf of the Million Veteran Program

    We report a large meta-analysis of depression using data from the Million Veteran Program (MVP), 23andMe Inc., UK Biobank, and FinnGen; including individuals of European ancestry (n=1,154,267; 340,591 cases) and African ancestry (n=59,600; 25,843 cases). We identified 223 and 233 independent SNPs associated with depression in European ancestry and transancestral analysis, respectively. Genetic correlations

  • Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-21
    Garan Jones; Katerina Trajanoska; Adam J Santanasto; Najada Stringa; Chia-Ling Kuo; Janice L Atkins; Joshua R Lewis; ThuyVy Duong; Shengjun Hong; Mary L Biggs; Jian'an Luan; Chloe Sarnowski; Kathryn L Lunetta; Toshiko Tanaka; Mary K Wojczynski; Ryan Cvejkus; Maria Nethander; Sahar Ghasemi; Jingyun Yang; M. Carola Zillikens; Stefan Walter; Kamil Sicinski; Erika Kague; Cheryl L Ackert-Bicknell; Dan E

    Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identified 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n=48,596 cases, 18.9% of total), including 12 loci

  • ELF4 Expression is Associated with Worse Disease Outcomes and Increased Resistance to Anticancer Agents in Human Cancers
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-20
    Doris Kafita; Victor Daka; Panji Nkhoma; Mildred Zulu; Ephraim Zulu; Rabecca Tembo; Zifa Ngwira; Florence Mwaba; Musalula Sinkala; Sody Munsaka

    The malignant phenotype of tumour cells is fuelled by changes in the expression of various transcription factors, which include some of the well-studied proteins such as p53 and Myc. Despite significant progress made, little is known about several other transcription factors, including ELF4, and how they help shape the oncogenic processes that occur in cancer cells. To this end, we performed a bioinformatics

  • COVID-19 genomic susceptibility: Definition of ACE2 variants relevant to human infection with SARS-CoV-2 in the context of ACMG/AMP Guidance
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-19
    Claire L Shovlin; Marcela P Vizcaychipi

    BACKGROUND: Mortality remains very high and unpredictable in COVID-19, with intense public protection strategies tailored to perceived risk. Genomic studies are in process to identify differences in host susceptibility to infection by the SARS-CoV-2 virus. Open source research publications are accessible to pre-genotyped individuals. Males are more at risk from severe COVID-19. METHODS: To facilitate

  • Analysis of heterozygous PRKN variants and copy number variations in Parkinson's disease
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-18
    Eric Yu; Uladzislau Rudakou; Lynne Krohn; Kheireddin Mufti; Jennifer A Ruskey; Farnaz Asayesh; Mehrdad A Estiar; Dan Spiegelman; Stanley Fahn; Cheryl H Waters; Lior Greenbaum; Alberto J Espay; Yves Dauvilliers; Nicolas Dupré; Guy A Rouleau; Sharon Hassin-Baer; Edward A Fon; Roy N Alcalay; Ziv Gan-Or

    Abstract Biallelic PRKN mutation carriers with Parkinson's disease typically have an earlier disease onset, slow disease progression and, often, different neuropathology compared to sporadic patients. However, the role of heterozygous PRKN variants in the risk of Parkinson's disease remains unclear. In the current study we examined the association between heterozygous PRKN variants, including single

  • Meta-analysis of Transcriptomic Data Reveals Pathophysiological Modules Involved with Atrial Fibrillation
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-16
    Rodrigo Haas Bueno; Mariana Recamonde-Mendoza

    Atrial fibrillation (AF) is a complex disease and affects millions of people around the world. The biological mechanisms that are involved with AF are complex and still need to be fully elucidated. Therefore, we performed a meta-analysis of transcriptome data related to AF to explore these mechanisms aiming at more sensitive and reliable results. Public transcriptomic datasets were downloaded, analyzed

  • Causes of variation in epigenetic aging across the lifespan
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-15
    Shuai Li; Tuong Nguyen; Ee Ming Wong; Pierre-Antoine Dugué; Gillian S Dite; Nicola J Armstrong; Jeffrey M Craig; Karen A Mather; Perminder S Sachdev; Richard Saffery; Joohon Sung; Qihua Tan; Anbupalam Thalamuthu; Roger L Milne; Graham G Giles; Melissa C Southey; John L Hopper

    Background DNA methylation-based biological age (DNAm age) is potentially an important biomarker for adult health. Studies in specific age ranges have found widely varying results about its causes of variation. We investigated these causes across the lifespan. Methods We pooled genome-wide DNA methylation data for 4,217 people aged 0-92 years from 1,871 families. DNAm age was calculated using the Horvath

  • De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-15
    Chiara Klöckner; Heinrich Sticht; Pia Zacher; Bernt Popp; Dewi P. Bakker; Katy Barwick; Michaela V. Bonfert; Eva H. Brilstra; Care4Rare Canada Consortium; Wendy K. Chung; Angus J. Clarke; Patrick Devine; Jennifer Friedman; Alyssa Gates; Gabriella Horvath; Jennifer Keller-Ramey; Boris Keren; Manju A. Kurian; Virgina Lee; Kathleen A. Leppig; Johan Lundgren; Marie T. McDonald; Amy McTague; Heather C.

    Purpose This study aims to provide the first comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals. Methods Individuals harboring heterozygous missense or truncating variants in SNAP25 were assembled through a collaboration with international colleagues, matchmaking

    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-15
    Chia-Ling Kuo; Luke C Pilling; Janice L Atkins; Jane AH Masoli; Joao Delgado; George A Kuchel; David Melzer

    The novel respiratory disease COVID-19 produces varying symptoms, with fever, cough, and shortness of breath being common. In older adults, we found that pre-existing dementia is a major risk factor (OR = 3.07, 95% CI: 1.71 to 5.50) for COVID-19 severity in the UK Biobank (UKB). In another UK study of 16,749 patients hospitalized for COVID-19, dementia was among the common comorbidities and was associated

  • A Systems Approach Identifies Key Regulators of HPV-Positive Cervical Cancer
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-14
    Musalula Sinkala; Mildred Zulu; Panji Nkhoma; Doris Kafita; Ephraim Zulu; Rabecca Tembo; Zifa Ngwira; Victor Daka; Sody Munsaka

    Cervical cancer has remained the most prevalent and lethal malignancy among women worldwide and accounted for over 250,000 deaths in 2019. Nearly ninety-five per cent of cervical cancer cases are associated with persistent infection with high-risk Human Papillomavirus (HPV), and seventy per cent of these are associated with viral integration in the host genome. HPV-infection imparts specific changes

  • The relationship between glycaemia, cognitive function, structural brain outcomes and dementia: A Mendelian randomization study in the UK Biobank
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-12
    Victoria Garfield; Aliki-Eleni Farmaki; Ghazaleh Fatemifar; Sophie V Eastwood; Rohini Mathur; Christopher T. Rentsch; Spiros Denaxas; Krishnan T. Bhaskaran; Liam Smeeth; Nish Chaturvedi

    Aims: To investigate the relationship between glycaemia and cognitive function, brain structure and incident dementia using bidirectional Mendelian randomisation (MR). Methods: UK Biobank (n~500,000) individuals, aged 40-69 years at baseline. Our exposures were genetic instruments for type-2 diabetes (163 variants) and HbA1c (52 variants) and our outcomes were reaction time (RT - milliseconds), visual

  • Multi-omics study revealing tissue-dependent putative mechanisms of SARS-CoV-2 drug targets on viral infections and complex diseases
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-11
    Jie Zheng; Yuemiao Zhang; Yi Liu; Denis Baird; Xingzi Liu; Lin Wang; Hong Zhang; George Davey Smith; Tom Gaunt

    Drug target prioritisation for new targets and drug repurposing of existing drugs for COVID-19 treatment are urgently needed for the current pandemic. Here we pooled 353 candidate drug targets of COVID-19 from clinical trial registries and the literature and estimated their putative causal effects in 11 SARS-CoV-2 related tissues on 622 complex human diseases. By constructing a disease atlas of drug

  • Polygenic hazard score is associated with prostate cancer in multi-ethnic populations
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-08
    Minh-Phuong Huynh-Le; Chun Chieh Fan; Roshan Karunamuni; Wesley K Thompson; Maria Elena Martinez; Rosalind A Eeles; Zsofia Kote-Jarai; Kenneth Muir; UKGPCS collaborators; Johanna Schleutker; Nora Pashayan; Jyotsna Batra; APCB (Australian Prostate Cancer BioResource); Henrik Grönberg; David E Neal; Jenny Donovan; Freddie C Hamdy; Richard M Martin; Sune F Nielsen; Børge G Nordestgaard; Fredrik Wiklund;

    Abstract Objectives: A polygenic hazard score (PHS1)--weighted sum of 54 single-nucleotide polymorphism genotypes--was previously associated with age at prostate cancer (PCa) diagnosis and improved PCa screening accuracy in Europeans. Performance in more diverse populations is unknown. We evaluated PHS association with PCa in multi-ethnic populations. Design: PHS1 was adapted for compatibility with

  • The genetic analysis of a founder Northern American population of European descent identifies FANCI as a candidate familial ovarian cancer risk gene
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-08
    Caitlin T Fierheller; Laure Guitton-Sert; Wejdan M Alenezi; Timothée Revil; Kathleen K Oros; Karine Bedard; Suzanna L Arcand; Corinne Serruya; Supriya Behl; Liliane Meunier; Hubert Fleury; Eleanor Fewings; Deepak N Subramanian; Javad Nadaf; Diane Provencher; William D Foulkes; Zaki El Haffaf; Anne-Marie Mes-Masson; Jacek Majewski; Marc Tischkowitz; Paul A James; Ian G Campbell; Celia M T Greenwood;

    Some familial ovarian cancer (OC) could be due to rare risk alleles in genes that each account for a relatively small proportion of cases not due to BRCA1 and BRCA2, major risk genes in the homologous recombination (HR) DNA repair pathway. We report a new candidate OC risk allele, FANCI c.1813C>T in a Fanconi anemia (FA) gene that plays a role upstream of the HR DNA repair pathway. This variant was

  • Clinical sequencing yield in epilepsy, autism spectrum disorder, and intellectual disability:A systematic review and meta-analysis
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-08
    Arthur Stefanski; Yamile Calle Lopez; Costin Leu; Eduardo Perez Palma; Elia Pestana-Knight; Dennis Lal

    Importance: Clinical genetic sequencing is frequently utilized to diagnose individuals with neurodevelopmental disorders (NDDs). Several reviews have been published regarding clinical genetic testing in various NDD subtypes. However, there is no systematic review and meta-analysis - in accordance with the PRISMA guidelines - which compares the genetic testing yield across neurodevelopmental disorder

  • Whole exome sequencing reveals a wide spectrum of ciliary gene mutations in nonsyndromic biliary atresia
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-08
    Wai-Yee Lam; Man-Ting So; Jacob Shujui Hsu; Patrick Ho-Yu Chung; Diem Ngoc Ngo; Pham Anh Hoa Nguyen; Hannah M Mitchison; Dagan Jenkins; Christopher O'Callaghan; Pak-Chung Sham; Maria-Mercè Garcia-Barceló; Vincent Chi-Hang Lui; Clara Sze-Man Tang; Paul Kwong-Hang Tam

    Biliary atresia (BA) is the most common obstructive cholangiopathy in neonates, often progressing to end-stage cirrhosis. BA pathogenesis is believed to be multifactorial, but the genetic contribution remains poorly defined. We conducted exome sequencing on 89 nonsyndromic BA trios. In 31.5% of the patients, rare and deleterious de novo, homozygous recessive and/or compound heterozygous variants were

  • Improving reporting standards for polygenic scores in risk prediction studies
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-08
    Hannah Wand; Samuel A Lambert; Cecelia Tamburro; Michael A Iacocca; Jack W O'Sullivan; Catherine Sillari; Iftikhar J Kullo; Robb Rowley; Deanna Brockman; Eric Venner; Mark I McCarthy; Antonis C Antoniou; Douglas F Easton; Robert A Hegele; Amit V Khera; Nilanjan Chatterjee; Charles Kooperberg; Karen Edwards; Katherine R Vlessis; Kim Kinnear; John N Danesh; Helen Parkinson; Erin M Ramos; Megan C Roberts;

    Over the past decade, genome-wide association studies have identified genetic variation associated with a wide range of human diseases and traits. These findings are now commonly aggregated into polygenic risk scores, which can bridge the gap between the initial discovery efforts and clinical applications for disease risk estimation. However, there is remarkable heterogeneity in the reporting of these

  • Genome-wide association studies of cognitive and motor progression in Parkinson's disease
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-08
    Manuela MX Tan; Michael A Lawton; Edwin Jabbari; Regina H Reynolds; Hirotaka Iwaki; Cornelis Blauwendraat; Sofia Kanavou; Miriam I Pollard; Leon Hubbard; Naveed Malek; Katherine A Grosset; Sarah L Marrinan; Nin Bajaj; Roger A Barker; David J Burn; Catherine Bresner; Thomas Foltynie; Nicholas W Wood; Caroline H Williams-Gray; John Hardy; Michael A Nalls; Andrew B Singleton; Nigel M Williams; Yoav Ben-Shlomo;

    Background: There are currently no treatments that stop or slow the progression of Parkinson's disease (PD). Case-control genome-wide association studies (GWASs) have identified variants associated with disease risk, but not progression. Objective: To identify genetic variants associated with PD progression in GWASs. Methods: We analysed three large, longitudinal cohorts: Tracking Parkinson's, Oxford

  • Genetic architectures of proximal and distal colorectal cancer are partly distinct
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-06
    Jeroen R Huyghe; Tabitha A Harrison; Stephanie A Bien; Heather Hampel; Jane C Figueiredo; Stephanie L Schmit; David V Conti; Sai Chen; Conghui Qu; Yi Lin; Richard Barfield; John A Baron; Amanda J Cross; Brenda Diergaarde; David Duggan; Sophia Harlid; Liher Imaz; Hyun Min Kang; David M Levine; Vittorio Perduca; Aurora Perez-Cornago; Lori C Sakoda; Fredrick R Schumacher; Martha L Slattery; Amanda E Toland;

    Objective An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of

  • Differential Levels of Telomeric Oxidized Bases and TERRA Transcripts in Childhood Autism
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-06
    Mohammad Eftekhar; Yasin Panahi; Fahimeh Salasar Moghaddam; Mohammad Reza Eskandari; Hamid Pezeshk; Mehrdad Pedram

    The underlying molecular mechanisms responsible for the etiology of autism and its sex-biased prevalence remain largely elusive. Abnormally shortened telomeres have recently been associated with autism. We have previously shown that children with non-syndromic autism exhibit a sexually dimorphic pattern of relative telomere length (RTL). Only male children with autism have significantly shorter RTLs

  • Coding variants in ACE2 and TMPRSS2 are not major drivers of COVID-19 severity in UK Biobank subjects.
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-02
    David Curtis

    There is wide individual variation in response to infection with SARS-CoV-2 and this may be influenced by ethnicity. It is plausible that coding variants in the ACE2 and TMPRSS2 genes might contribute to this variation. Exome sequence data was obtained for 49,953 UK Biobank subjects of whom 74 had tested positive for SARS-CoV-2 and could be presumed to have severe disease because mildly affected subjects

  • Clinical-grade whole genome sequencing of colorectal cancer and 3-prime transcriptome analysis demonstrate targetable alterations in the majority of patients.
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-01
    Agata Stodolna; Miao He; Mahesh Vasipalli; Zoya Kingsbury; Jennifer Becq; Joanne D Stockton; Mark P Dilworth; Jonathan D James; Toju Sillo; Daniel Blakeway; Stephen T Ward; Tariq Ismail; Mark T Ross; Andrew D Beggs

    Introduction: Clinical grade whole genome sequencing (cWGS) has the potential to become standard of care within the clinic because of its breadth of coverage and lack of bias towards certain regions of the genome. Colorectal cancer presents a difficult treatment paradigm, with over 40% of patients presenting at diagnosis with metastatic disease. We hypothesised that cWGS coupled with 3-prime transcriptome

  • A Novel Gene ZNF862 Causes Hereditary Gingival Fibromatosis
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-01
    Juan Wu; Dongna Chen; Hui Huang; Ning Luo; Huishuang Chen; Junjie Zhao; Yanyan Wang; Yang Ren; Teng Zhai; Weibin Sun; Houxuan Li; Wei Li

    Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis which is featured as a localized or generalized overgrowth of gingivae. HGF is genetically heterogeneous and usually be transmitted as an autosomal-dominant inheritance pattern, also can be as autosomal-recessive or occur sporadically. Currently only two genes (SOS1 and REST), as well as four loci (2p22

  • Sexual Dimorphism in Telomere Length in Childhood Autism
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-01
    Yasin Panahi; Fahimeh Salasar Moghaddam; Khadijeh Babaei; Mohammad Eftekhar; Reza Shervin Badv; Mohammad Reza Eskandari; Mohammad Vafaee-Shahi; Hamid Pezeshk; Mehrdad Pedram

    Autism spectrum disorders (ASD) are lifelong heterogeneous set of neurodevelopmental conditions with strikingly profound male prevalence. Differences in sex biology and hormones are thought to play key roles in ASD prevalence and outcome, but the underlying molecular mechanisms responsible for ASD sex-differential risk are not well understood. Two recent studies reported a significant association between

  • Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants
    medRxiv. Genet. Genom. Med. Pub Date : 2020-05-01
    Cristina Fortuno; Kristy Lee; Magali Olivier; Tina Pesaran; Phuong L. Mai; Kelvin C. de Andrade; Laura D. Attardi; Stephanie Crowley; D. Gareth Evans; Bing-Jian Feng; Ann Katherine Major Foreman; Megan N. Frone; Robert Huether; Paul A. James; Kelly McGoldrick; Jessica Mester; Bryce A. Seifert; Thomas P. Slavin; Leora Witkowski; Liying Zhang; Sharon E. Plon; Amanda B. Spurdle; Sharon A. Savage

    Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome (LFS), an autosomal dominant cancer predisposition disorder associated with high risk of malignancy, including early onset breast cancers, sarcomas, adrenocortical carcinomas and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants has been shown to decrease mortality; therefore

  • Deciphering the causal relationship between blood metabolites and Alzheimers Disease: a Mendelian Randomization study
    medRxiv. Genet. Genom. Med. Pub Date : 2020-04-30
    Jodie Lord; Bradley Jermy; Rebecca Green; Andrew Wong; Jin Xu; Cristina Legido-Quigley; Richard Dobson; Marcus Richards; Petra Proitsi

    There are currently no disease modifying treatments for Alzheimers Disease (AD). Epidemiological studies have highlighted blood metabolites as potential biomarkers, but possible confounding and reverse causation prevent causal conclusions. Here, we investigated whether nineteen metabolites previously associated with midlife cognitive function, are on the causal pathway to AD. Summary statistics from

  • Linkage analysis identifies an isolated strabismus locus at 14q12 overlapping with FOXG1 syndrome region
    medRxiv. Genet. Genom. Med. Pub Date : 2020-04-30
    Xin (Cynthia) Ye; Nicole M Roslin; Andrew D. Paterson; Christopher Lyons; Victor Pegado; Phillip Andrew Richmond; Casper Shyr; Oriol Fornes; Xiaohua Han; Michelle Higginson; Colin Ross; Deborah Giaschi; Cheryl Y Gregory-Evans; Millan Patel; Wyeth W Wasserman

    Strabismus is a common condition, affecting 1-4% of individuals. Isolated strabismus has been studied in families with Mendelian inheritance patterns. Despite the identification of multiple loci via linkage analyses, no specific genes have been identified from these studies. The current study is based on a seven-generation family with isolated strabismus inherited in an autosomal dominant manner. A

  • Copy number signature analyses in prostate cancer reveal distinct etiologies and clinical outcomes
    medRxiv. Genet. Genom. Med. Pub Date : 2020-04-29
    Shixiang Wang; Huimin Li; Minfang Song; Zaoke He; Tao Wu; Xuan Wang; Ziyu Tao; Kai Wu; Xue-Song Liu

    Genome alteration signatures reflect recurring patterns caused by distinct endogenous or exogenous mutational events during the evolution of cancer. Signatures of single base substitution (SBS) have been extensively studied in different types of cancer, however, signatures of cancer genome copy number alteration (CNA) are still elusive in most cancer types, especially in prostate cancer (PC), which

  • Genomics of Indian SARS-CoV-2: Implications in genetic diversity, possible origin and spread of virus
    medRxiv. Genet. Genom. Med. Pub Date : 2020-04-29
    Kumaravel Somasundaram; Mainak Mondal; Ankita Lawarde

    World Health Organization (WHO) declared COVID-19 as a pandemic disease on March 11, 2020. Comparison of genome sequences from diverse locations allows us to identify the genetic diversity among viruses which would help in ascertaining viral virulence, disease pathogenicity, origin and spread of the SARS-CoV-2 between countries. The aim of this study is to ascertain the genetic diversity among Indian

  • Regional differences in reported Covid-19 cases show genetic correlations with higher socio-economic status and better health, potentially confounding studies on the genetics of disease susceptibility
    medRxiv. Genet. Genom. Med. Pub Date : 2020-04-28
    Abdel Abdellaoui

    Background: In March 2020, England showed a rapid increase in Covid-19 cases. Susceptibility for infectious diseases like Covid-19 is likely to be partly genetic. Mapping the genetic susceptibility for Covid-19 outcomes may reveal biological mechanisms that could potentially aid in drug or vaccine developments. However, as the disease spreads unevenly across the country, regional allele frequency differences

  • Synaptic processes and immune-related pathways implicated in Tourette Syndrome
    medRxiv. Genet. Genom. Med. Pub Date : 2020-04-27
    Fotis Tsetsos; Dongmei Yu; Jae Hoon Sul; Alden Y Huang; Cornelia Illmann; Lisa Osiecki; Sabrina Darrow; Matthew E Hirschtritt; Erica Greenberg; Kirsten R Muller-Vahl; Manfred Stuhrmann; Yves Dion; Guy Rouleau; Harald Aschauer; Mara Stamenkovic; Monika Schlögelhofer; Paul Sandor; Cathy L Barr; Marco Grados; Harvey S Singer; Markus M Nöthen; Johannes Hebebrand; Anke Hinney; Robert A King; Thomas V Fernandez;

    Tourette Syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with Tourette Syndrome (TS) and 7682 ancestry-matched controls and investigated associations of TS

  • Clinical utility of genetic and genomic testing in the precision diagnosis and management of pediatric patients with kidney and urinary tract diseases
    medRxiv. Genet. Genom. Med. Pub Date : 2020-04-26
    Nasim Bekheirnia; Kevin E Glinton; Linda Rossetti; joshua Manor; Wuyan Chen; Dolores J Lamb; Michael C Braun; Mir Reza Bekheirnia

    As genetic and genomic testing increasingly integrates into the practice of nephrology, our understanding of the basis of many kidney disorders has exponentially increased. Given this, we recently initiated a Renal Genetics Clinic (RGC) at our large, urban childrens hospital for patients with either a personal or strong family history of renal disorders. Genetic testing was performed in Clinical Laboratory

  • Lack of association between genetic variants at ACE2 and TMPRSS2 genes involved in SARS-CoV-2 infection and human quantitative phenotypes
    medRxiv. Genet. Genom. Med. Pub Date : 2020-04-25
    Esteban Lopera; Adriaan van der Graaf; Pauline Lanting; Marije van der Geest; Lifelines Cohort Study; Jingyuan Fu; Morris Swertz; Lude Franke; Cisca Wijmenga; Patrick Deelen; Alexandra Zhernakova; Serena Sanna

    Coronavirus disease 2019 (COVID-19) shows a wide variation in expression and severity of symptoms, from very mild or no symptomes, to flu-like symptoms, and in more severe cases, to pneumonia, acute respiratory distress syndrome and even death. Large differences in outcome have also been observed between males and females. The causes for this variability are likely to be multifactorial, and to include

  • Association between DNA Methylation Levels in Brain Tissue and Late-Life Depression in Community-Based Participants
    medRxiv. Genet. Genom. Med. Pub Date : 2020-04-24
    Anke Huels; Chloe Robins; Karen N Conneely; Philip L De Jager; David A Bennett; Michael P Epstein; Thomas S Wingo; Aliza P Wingo

    Objective: Major depressive disorder (MDD) arises from a combination of genetic and environmental risk factors and DNA methylation is one of the molecular mechanisms through which these factors can manifest. However, little is known about the epigenetic signature of MDD in brain tissue. This study aimed to investigate associations between brain tissue-based DNA methylation and late-life MDD. Methods:

  • Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency
    medRxiv. Genet. Genom. Med. Pub Date : 2020-04-24
    Denisa Hathazi; Helen Griffin; Matt J Jennings; Michele Giunta; Christopher Powell; Sarah F Pearce; Benjamin Munro; Wei Wei; Veronika Boczonadi; Joanna Poulton; Angela Pyle; Claudia Calabrese; Aurora Gomez-Duran; Ulrike Schara; Robert S Pitceathly; Michael G Hanna; Kairit Joost; Ana Cotta; Julia Filardi Paim; Monica Machado Navarro; Jennifer Duff; Andre Mattmann; Kristine Chapman; Serenella Servidei;

    Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6 months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation, however only ∼1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found

  • Immune defects and cardiovascular risk in X chromosome monosomy mosaicism mediated by loss of chromosome Y. A risk factor for SARS-CoV-2 vulnerability in elderly men?
    medRxiv. Genet. Genom. Med. Pub Date : 2020-04-24
    Luis A Perez-Jurado; Alejandro Caceres; Tonu Esko; Juan R Gonzalez

    The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) has an estimated overall case fatality ratio of 1.38% in China, being 53% higher in males and increasing exponentially with age. Mosaicism for X chromosome monosomy (XCM) shows a similar increase in aging population mostly driven by loss of chromosome Y in males (LOY), and is associated with a raise

  • Little Evidence of Modified Genetic Effect of rs16969968 on Heavy Smoking Based on Age of Onset of Smoking
    medRxiv. Genet. Genom. Med. Pub Date : 2020-04-24
    Christine Adjangba; Richard Border; Pamela N Romero Villela; Marissa A Ehringer; Luke McLean Evans

    Importance: Tobacco smoking is the leading cause of preventable death globally. Smoking quantity, measured in cigarettes per day (CPD), is influenced both by the age of onset of regular smoking (AOS) and by genetic factors, including a strong association with the non-synonymous single nucleotide polymorphism rs16969968. A previous study reported an interaction between these two factors, whereby individuals

  • Self-reported symptoms of covid-19 including symptoms most predictive of SARS-CoV-2 infection, are heritable
    medRxiv. Genet. Genom. Med. Pub Date : 2020-04-24
    Frances MK Williams; Maxim Freydin; Massimo Mangino; Simon Couvreur; Alessia Visconti; Ruth CE Bowyer; Caroline I Le Roy; Mario Falchi; Carole Sudre; Richard Davies; Christopher Hammond; Cristina Menni; Claire Steves; Tim Spector

    Susceptibility to infection such as SARS-CoV-2 may be influenced by host genotype. TwinsUK volunteers (n=2633) completing the C-19 Covid symptom tracker app allowed classical twin studies of covid-19 symptoms including predicted covid-19, a symptom-based algorithm predicting true infection derived in app users tested for SARS-CoV-2. We found heritability for fever = 41 (95% confidence intervals 12-70)%;

  • Clinical genetics lacks standard definitions and protocols for the collection and use of diversity measures
    medRxiv. Genet. Genom. Med. Pub Date : 2020-04-23
    Alice B Popejoy; Kristy R Crooks; S. Malia Fullerton; Lucia A Hindorff; Gillian W Hooker; Barbara A Koenig; Natalie Pino; Erin M Ramos; Deborah I Ritter; Hannah Wand; Matt W Wright; Michael Yudell; James Y Zou; Sharon E Plon; Carlos D Bustamante; Kelly E Ormond; Clinical Genome Resource (ClinGen) Ancestry and Diversity Working Group

    Genetics researchers and clinical professionals rely on diversity measures such as race, ethnicity, and ancestry (REA) to stratify study participants and patients for a variety of applications in research and precision medicine. However, there are no comprehensive, widely accepted standards or guidelines for collecting and using such data in either setting. Two NIH-funded research consortia, the Clinical

  • African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer
    medRxiv. Genet. Genom. Med. Pub Date : 2020-04-23
    Roshan Karunamuni; Minh-Phuong Huynh-Le; Chun Fan; Wesley Thompson; Rosalind Eeles; Zsofia Kote-Jarai; Kenneth Muir; UKGPCS collaborators; Artitaya Lophatananon; Catherine Tangen; Phyllis Goodman; Ian Thompson; William Blot; Wei Zheng; Adam Kibel; Bettina Drake; Olivier Cussenot; Geraldine Cancel-Tassin; Florence Menegaux; Therese Truong; Jong Park; Hui-Yi Lin; Jeannette Bensen; Elizabeth Fontham;

    Introduction: Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46), showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify SNPs that might improve performance in this population. Material and Methods: Anonymized genotypic data were obtained from the PRACTICAL consortium

  • Influence of blood pressure on pneumonia risk: Epidemiological association and Mendelian randomisation in the UK Biobank
    medRxiv. Genet. Genom. Med. Pub Date : 2020-04-23
    Seyedeh Maryam Zekavat; Michael Honigberg; James Pirruccello; Puja Kohli; Elizabeth W. Karlson; Christopher Newton-Cheh; Hongyu Zhao; Pradeep Natarajan

    Objectives: To determine whether elevated blood pressure influences risk for respiratory infection. Design: Prospective, population-based epidemiological and Mendelian randomisation studies. Setting: UK Biobank. Participants: 377,143 self-identified British descent (54% women; median age 58 years) participants in the UK Biobank. Main outcome measures: First incident pneumonia over an average of 8 follow-up

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