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  • Associations between indicators of socioeconomic position and DNA methylation: A systematic review
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-22
    Janine Cerutti; Alexandre A. Lussier; Yiwen Zhu; Jiaxuan Liu; Erin C. Dunn

    Socioeconomic position (SEP) is a major determinant of health across the life course. Yet, little is known about the biological mechanisms explaining this relationship. One possible explanation is through an epigenetic process called DNA methylation (DNAm), wherein the socioeconomic environment causes no alteration in the DNA sequence but modifies gene activity, gene expression, and therefore long-term

    更新日期:2021-01-22
  • Weighted burden analysis in 200,000 exome-sequenced subjects characterises rare variant effects on risk of type 2 diabetes
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-21
    David Curtis

    Type 2 diabetes (T2D) is a disease for which both common genetic variants and environmental factors influence risk. A few genes have been identified in which very rare variants have large effects on risk and here we carry out a weighted burden analysis of rare variants in a sample of over 200,000 exome-sequenced participants in the UK Biobank project, of whom over 13,000 have T2D. Variant weights were

    更新日期:2021-01-22
  • Leveraging fine-mapping and non-European training data to improve trans-ethnic polygenic risk scores
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-20
    Omer Weissbrod; Masahiro Kanai; Huwenbo Shi; Steven Gazal; Wouter Peyrot; Amit Khera; Yukinori Okada; The Biobank Japan Project; Alicia Martin; Hilary Finucane; Alkes L. Price

    Polygenic risk scores (PRS) based on European training data suffer reduced accuracy in non-European target populations, exacerbating health disparities. This loss of accuracy predominantly stems from LD differences, MAF differences (including population-specific SNPs), and/or causal effect size differences. Here, we propose PolyPred, a method that improves trans-ethnic polygenic prediction by combining

    更新日期:2021-01-21
  • RPE65-related retinal dystrophy: mutational and phenotypic spectrum in 44 affected patients.
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-20
    Rosario Lopez-Rodriguez; Esther Lantero; Fiona Blanco-Kelly; Almudena Avila-Fernandez; Inmaculada Martin-Merida; Marta del Pozo-Valero; Irene Perea-Romero; Olga Zurita; Belen Jimenez-Rolando; Saoud Tahsin Swafiri; Rosa Riveiro-Alvarez; Maria Jose Trujillo-Tiebas; Ester Carreno Salas; Blanca Garcia-Sandoval; Marta Corton; Carmen Ayuso

    Background: Biallelic pathogenic RPE65 variants are related to a spectrum of clinically overlapping inherited retinal dystrophies (IRD). Most affected individuals show a severe progression, with a 50% of patients legally blind by 20 years of age. A better knowledge of the mutational spectrum and the phenotype−genotype correlation in RPE65−related IRD is needed. Methods: Forty−four affected subjects

    更新日期:2021-01-21
  • Validating quantitative PCR assays for cell-free DNA detection without DNA extraction: Exercise induced kinetics in systemic lupus erythematosus patients
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-20
    Elmo WI Neuberger; Alexandra Brahmer; Tobias Ehlert; Katrin Kluge; Keito FA Philippi; Simone C Boedecker; Julia Weinmann-Menke; Perikles Simon

    Circulating cell−free DNA (cfDNA) has been investigated as a screening tool for many diseases. To avoid expensive and time−consuming DNA isolation, direct quantification PCR assays can be established. However, rigorous validation is required to provide reliable data in the clinical and non−clinical context. Considering International Organization for Standardization, as well as bioanalytical method

    更新日期:2021-01-21
  • Kleine Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci.
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-16
    Aditya Ambati; Ryan Hillary; Smaranda Leu-Semenescu; Hanna M Ollila; Ling Lin; Eileen B Leary; Andrea N Goldstein-Piekarski; Yu-Shu Huang; Fang Han; Yakov Sivan; Michel Lecendreux; Pauline Dodet; Makoto Honda; Natan Gadoth; Sona Nevsimalova; Fabio Pizza; Takashi Kanbayashi; Rosa Peraita-Adrados; Guy Leschziner; Rosa Hasan; Francesca Canellas; Kazuhiko Kume; Makrina Daniilidou; Patrice Bourgin; David

    Kleine-Levin Syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide

    更新日期:2021-01-18
  • A global overview of genetically interpretable comorbidities among common diseases in UK Biobank
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-15
    Guiying Dong; Jianfeng Feng; Fengzhu Sun; Jingqi Chen; Xinmging Zhao

    Abstract Background: Comorbidities greatly increase global health burdens, but the landscapes of their genetic factors have not been systematically investigated. Methods: We used the hospital inpatient data of 385,335 patients in UK Biobank to investigate the comorbid relations among 439 common diseases. Post-GWAS analyses were performed to identify comorbidity shared genetic risks at the genomic loci

    更新日期:2021-01-16
  • Application of Optical Genome Mapping For Comprehensive Assessment of Chromosomal Structural Variants for Clinical Evaluation of Myelodysplastic Syndromes
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-15
    Hui Yang; Guillermo Garcia-Manero; Diana Rush; Guillermo Montalban-Bravo; Saradhi Mallampati; L. Jeffrey Medeiros; Brynn Levy; Rajyalakshmi Luthra; Rashmi Kanagal-Shamanna

    Structural chromosomal variants [copy number variants (CNVs): losses/ gains and structural variants (SVs): inversions, balanced and unbalanced fusions/translocations] are important for diagnosis and risk-stratification of myelodysplastic syndromes (MDS). Optical genome mapping (OGM) is a novel single-platform cytogenomic technique that enables high-throughput, accurate and genome-wide detection of

    更新日期:2021-01-16
  • Integrative Omics Reveal Novel Protein Targets For Chronic Obstructive Pulmonary Disease Biomarker Discovery
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-15
    Ana I Hernandez Cordero; Stephen Milne; Chen Xi Yang; Xuan Li; Henry Shi; Don D Sin; Ma'en Obeidat

    Background: Large genome-wide association studies (GWAS) and other genetic studies have revealed genetic loci that are associated with chronic obstructive pulmonary disease (COPD). However, the proteins responsible for COPD pathogenesis remain elusive. We used integrative-omics by combining genetics of lung function and COPD with genetics of proteome to identify proteins underlying lung function variation

    更新日期:2021-01-16
  • A Viral Fragmentation Signature for SARS-CoV-2 in Clinical Samples Correlating with Contagiousness
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-15
    Yukti Choudhury; Chae Yin Cher; Zi Yi Wan; Chao Xie; Jing Shan Lim; Ramandeep Kaur Virk; Min Han Tan; Alvin Kuo Jing Teo; Li Yang Hsu

    The viral load of SARS-CoV-2 in clinical samples as measured by the primary diagnostic tool of RT-PCR is an imperfect readout for infection potential as most targeted assays designed for sensitivity, indiscriminately detect short and long RNA fragments, although infectivity is embodied only in the whole virus and its intact genome. Here, we used next-generation sequencing (NGS) to characterize 155

    更新日期:2021-01-16
  • Fine mapping of the HLA locus in Parkinson's disease in Europeans
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-14
    Eric Yu; Aditya Ambati; Maren Stolp Andersen; Lynne Krohn; Mehrdad A Estiar; Prabhjyot Saini; Konstantin Senkevich; Yuri L Sosero; Ashwin Ashok Kumar Sreelatha; Jennifer A Ruskey; Farnaz Asayesh; Dan Spiegelman; Mathias Toft; Marte K Viken; Manu Sharma; Cornelis Blauwendraat; Lasse Pihlstrøm; Emmanuel Mignot; Ziv Gan-Or

    Abstract Objective: To fine map the association between human leukocyte antigen (HLA) genes and Parkinson's disease (PD) that was discovered using genome-wide association studies (GWASs). Methods: We performed a thorough analysis of the HLA locus in 13,770 PD patients, 20,214 proxy-cases and 490,861 controls of European origin. We used GWAS data to impute HLA types and performed multiple regression

    更新日期:2021-01-16
  • High Throughput Screening for Expanded CTG repeats in Myotonic Dystrophy Type 1 Using Melt Curve Analysis
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-13
    Russell J Butterfield; Carina Imburgia; Katie Mayne; Tara Newcomb; Diane M Dunn; Brett Duval; Marcia L Feldkamp; Nicholas E Johnson; Robert B Weiss

    Background: Myotonic dystrophy type 1 (DM1) is caused by CTG repeat expansions in the DMPK gene and is the most common form of muscular dystrophy. Patients can have long delays from onset to diagnosis, since clinical signs and symptoms are often non-specific and overlapping with other disorders. Clinical genetic testing by Southern blot or triplet-primed PCR (TP-PCR) is technically challenging and

    更新日期:2021-01-13
  • Exploration of interethnic variation in the ibuprofen metabolizing enzyme CYP2C9: a cautionary guide for treatment of COVID-19 symptoms
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-12
    Ammar Ali Almarzooq

    Coronavirus disease 2019 (COVID-19), is a rapidly spreading infectious illness that causes a debilitating respiratory syndrome. Supportive therapy remains the standard for mild-to-moderate cases, including treatment with non-steroidal anti-inflammatory drugs (NSAIDs) e.g. ibuprofen, however such medications may increase COVID-19 complications when used in patients with acute viral respiratory infections

    更新日期:2021-01-12
  • Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-11
    Xin Hu; Marcos Roberto Estecio; Runzhe Chen; Alexandre Reuben; Linghua Wang; Fujumoto Junya; Lisha Ying; Fukuoka Junya; Chi-Wan Chow; Nicholas McGranahan; Hoa Pham; Godoy Myrna; Carter Brett; Behrens Carmen; Jianhua Zhang; Ara A Vaporciyan; John Victor Heymach; Ignacio Ivan Wistuba; Yue Lu; Harvey I. Pass; Humam Kadara; Paul A Scheet; Jack J Lee; Andrew Futreal; Dan Su; Jean-Pierre Issa; Jianjun Zhang

    The evolution of DNA methylome and methylation intra-tumor heterogeneity (ITH) during early carcinogenesis of lung adenocarcinoma has not been systematically studied. We perform reduced representation bisulfite sequencing of invasive lung adenocarcinoma and its precursors, atypical adenomatous hyperplasia, adenocarcinoma in situ and minimally invasive adenocarcinoma. We observe gradual increase of

    更新日期:2021-01-12
  • A multi-task convolutional deep learning method for HLA allelic imputation and its application to trans-ethnic MHC fine-mapping of type 1 diabetes
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-10
    Tatsuhiko Naito; Ken Suzuki; Jun Hirata; Yoichiro Kamatani; Koichi Matsuda; Tatsushi Toda; Yukinori Okada

    Conventional HLA imputation methods drop their performance for infrequent alleles, which is one of the factors that reduce the reliability of trans-ethnic MHC fine-mapping due to inter-ethnic heterogeneity in allele frequency spectra. We developed DEEP*HLA, a deep learning method for imputing HLA genotypes. Through validation using the Japanese and European HLA reference panels (n = 1,118 and 5,122)

    更新日期:2021-01-10
  • Polygenic Risk Scores for Alzheimer's Disease and Mild Cognitive Impairment in Hispanics/Latinos in the U.S: The Study of Latinos - Investigation of Neurocognitive Aging
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-09
    Tamar Sofer; Nuzulul Kurniansyah; Einat Granot-Hershkovitz; Matthew O Goodman; Wassim Tarraf; Iris Broce; Richard B Lipton; Martha Daviglus; Melissa Lamar; Sylvia Wassertheil-Smoller; Jianwen Cai; Charles S DeCarli; Hector M Gonzalez; Myriam Fornage

    Introduction: Polygenic Risk Score (PRS) are powerful summaries of genetic risk alleles that can potentially be used to predict disease outcomes and guide treatment decisions. Hispanics/Latinos suffer from higher rates of Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) compared to non-Hispanic Whites, yet the strongest known genetic risk factor for AD, APOE-ϵ4 allele, has weak association

    更新日期:2021-01-10
  • BinomiRare: A carriers-only test for association of rare genetic variants with a binary outcome for mixed models and any case-control proportion
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-09
    Tamar Sofer; Jiwon Lee; Nuzulul Kurniansyah; Deepti Jain; Cecelia A Laurie; Stephanie M Gogarten; Matthew Conomos; Ben Heavner; Yao Hu; Charles Kooperberg; Jeffrey Haessler; Ramachandran S Vasan; L. Adrienne Cupples; Brandon J Coombes; Amanda Seyerle; Sina A Gharib; Han Chen; Jeffrey R O'Connell; Man Zhang; Daniel Gottlieb; Bruce M Psaty; W.T. Longstreth; Jerome I Rotter; Kent D Taylor; Steve S Rich;

    Whole genome and exome sequencing studies have become increasingly available and are being used to identify rare genetic variants associated with health and disease outcomes. Investigators routinely use mixed models to account for genetic relatedness or other clustering variables (e.g. family or household) when testing genetic associations. However, no existing tests of the association of a rare variant

    更新日期:2021-01-10
  • Inter-population differences of allele frequency and regulome tagging are associated with the heterogeneity of loci identified by cross-ancestry genome-wide association studies
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-09
    Antonella De Lillo; Salvatore D'antona; Gita A Pathak; Frank Wendt; Flavio De Angelis; Maria Fuciarelli; Renato Polimanti

    To investigate cross-ancestry genetics of complex traits, we conducted a phenome-wide analysis of loci with heterogeneous effects across African, Admixed-American, Central/South Asian, East Asian, European, and Middle Eastern participants of UK Biobank (N=441,331). Testing 843 phenotypes, we identified 82 independent genomic regions mapping variants showing genome-wide significant (GWS) associations

    更新日期:2021-01-10
  • Association between resting-state functional brain connectivity and gene expression is altered in autism spectrum disorder
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-08
    Stefano Berto; Alex Treacher; Emre Caglayan; Danni Luo; Jillian R. Haney; Michael J. Gandal; Daniel H. Geschwind; Albert Montillo; Genevieve Konopka

    Gene expression covaries with brain activity as measured by resting state functional MRI. However, it is unclear how genomic differences driven by disease state can affect this relationship. Here, we integrate brain gene expression datasets of neurotypical controls and autistic (ASD) patients with regionally matched brain activity measurements from fMRI datasets. We identify genes linked with brain

    更新日期:2021-01-08
  • Quality Control Metrics for Whole Blood Transcriptome Analysis in the Parkinson′s Progression Markers Initiative (PPMI)
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-08
    Elizabeth Hutchins; David W. Craig; Ivo Violich; Eric Alsop; Bradford Casey; Samantha Hutten; Alyssa Reimer; Timothy G. Whitsett; Karen L. Crawford; Arthur W. Toga; Shawn Levy; Madison Robison; Nripesh Prasad; J. Raphael Gibbs; Mark R Cookson; Parkinson's Progression Markers Initiative; Kendall Van Keuren-Jensen

    The Michael J. Fox Foundation's Parkinson's Progression Markers Initiative (PPMI) is an observational study to comprehensively evaluate Parkinson's disease (PD) patients using imaging, biologic sampling, clinical and behavioral assessments to identify biomarkers of PD progression. As part of this study, we obtained 4,756 whole blood samples from 1,570 subjects at baseline, 0.5, 1, 2, and 3 years from

    更新日期:2021-01-08
  • Prioritization of putatively detrimental variants in euploid miscarriages
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-08
    Silvia Buonaiuto; Imma Di Biase; Valentina Aleotti; Amin Ravaei; Adriano De Marino; Gianluca Damaggio; Marco Chierici; Madhuri Pulijala; Palmira D'Ambrosio; Gabriella Esposito; Qasim Ayub; Cesare Furlanello; Pantaleo Greco; Antonio Capalbo; Michele Rubini; Sebastiano Di Biase; Vincenza Colonna

    STUDY QUESTION: Can small genetic variants detected in the whole genome sequencing of spontaneously aborted euploid embryos give insight into possible causes of pregnancy loss? SUMMARY ANSWER: By filtering and prioritizing genetic variants it is possible to identify genomic variants putatively responsible for miscarriage. WHAT IS KNOWN ALREADY: Miscarriage is often caused to chromosomal aneuploidies

    更新日期:2021-01-08
  • Implementing genomic screening in diverse populations
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-06
    Noura S Abul-Husn; Emily R Soper; Giovanna T Braganza; Jessica E Rodriguez; Natasha Zeid; Sinead Cullina; Dean Bobo; Arden Moscati; Amanda Merkelson; Ruth J F Loos; Judy H Cho; Gillian M Belbin; Sabrina A Suckiel; Eimear E Kenny

    Background: Population-based genomic screening has the predicted ability to reduce morbidity and mortality associated with medically actionable conditions. However, much research is needed to develop standards for genomic screening, and to understand the perspectives of people offered this new testing modality. This is particularly true for non-European ancestry populations who are vastly underrepresented

    更新日期:2021-01-06
  • Prognostic significance of circRNAs expression in breast carcinoma patients: A meta-analysis
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-04
    Zhou zi zhen; Li xian cai; Liu de wu

    Objective: The aim of our study was to systematically evaluate the prognostic effects of various circrnas and to explore the prognostic value of circRNA in breast cancer patients. Methods: A systematical search was conducted on PubMed, Scopus, EMBASE, and the Cochrane Library databases. Eligible studies reporting on the association among circRNAs and prognostic values of breast cancer patients were

    更新日期:2021-01-05
  • Whole Genome Sequence Association Analysis of Fasting Glucose and Fasting Insulin Levels in Diverse Cohorts from the NHLBI TOPMed Program
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-04
    Daniel DiCorpo; Sheila M Gaynor; Emily M Russell; Kenneth E Westerman; Laura M Raffield; Timothy D Majarian; Peitao Wu; Chloe Sarnowski; Heather M Highland; Anne Jackson; Natalie R Hasbani; Paul S de Vries; Jennifer A Brody; Bertha Hidalgo; Xiuqing Guo; James A Perry; Jeffrey R O'Connell; Samantha Lent; May E Montasser; Brian E Cade; Deepti Jain; Heming Wang; Ricardo D'Oliveira Albanus; Arushi Varshney;

    The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome and exome arrays, resulting in over 100 associated variants. We extended this work with a high-coverage whole genome sequencing (WGS) analysis from fifteen cohorts in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. More than 23,000 non-diabetic individuals from five self-reported

    更新日期:2021-01-05
  • GestaltMatcher: Overcoming the limits of rare disease matching using facial phenotypic descriptors
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-04
    Tzung-Chien Hsieh; Aviram Bar-Haim; Shahida Moosa; Nadja Ehmke; Karen W. Gripp; Jean Tori Pantel; Magdalena Danyel; Martin Atta Mensah; Denise Horn; Nicole Fleischer; Guilherme Bonini; Alexander Schmid; Alexej Knaus; Sugirthan Sivalingam; Tom Kamphans; Frédéric Ebstein; Elke Krüger; Sébastien Küry; Stéphane Bézieau; Axel Schmidt; Sophia Peters; Hartmut Engels; Elisabeth Mangold; Martina Kreiß; Kirsten

    The majority of monogenic disorders cause craniofacial abnormalities with characteristic facial morphology. These disorders can be diagnosed more quickly by using computer-aided next-generation phenotyping tools, such as DeepGestalt. These tools have learned to associate facial phenotypes with the underlying syndrome through training on thousands of patient photographs. However, this "supervised" approach

    更新日期:2021-01-04
  • AMELIE 3: Fully Automated Mendelian Patient Reanalysis at Under 1 Alert per Patient per Year
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-04
    Johannes Birgmeier; Ethan Steinberg; Ethan E. Bodle; Cole A. Deisseroth; Karthik A. Jagadeesh; Jennefer N. Kohler; Devon Bonner; Shruti Marwaha; Julian A. Martinez-Agosto; Stan Nelson; Christina G. Palmer; Joy D. Cogan; Rizwan Hamid; Joan M. Stoler; Joel B. Krier; Jill A. Rosenfeld; Paolo Moretti; David R. Adams; Vandana Shashi; Elizabeth A. Worthey; Christine M. Eng; Euan A. Ashley; Matthew T. Wheeler;

    Background: Many thousands of patients with a suspected Mendelian disease have their exomes/genomes sequenced every year, but only about 30% receive a definitive diagnosis. Since a novel Mendelian gene-disease association is published on average every business day, thousands of undiagnosed patient cases could receive a diagnosis each year if their genomes were regularly compared to the latest literature

    更新日期:2021-01-04
  • Improving Polygenic Prediction in Ancestrally Diverse Populations
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-02
    Yunfeng Ruan; Yen-Chen Anne Feng; Chia-Yen Chen; Max Lam; Stanley Global Asia Initiatives; Akira Sawa; Alicia R. Martin; Shengying Qin; Hailiang Huang; Tian Ge

    Polygenic risk scores (PRS) have attenuated cross-population predictive performance. As existing genome-wide association studies (GWAS) were predominantly conducted in individuals of European descent, the limited transferability of PRS reduces its clinical value in non-European populations and may exacerbate healthcare disparities. Recent efforts to level ancestry imbalance in genomic research have

    更新日期:2021-01-04
  • A genome-wide association study for nonalcoholic fatty liver disease identifies novel genetic loci and trait-relevant candidate genes in the Million Veteran Program.
    medRxiv. Genet. Genom. Med. Pub Date : 2021-01-02
    Marijana Vujkovic; Shweta Ramdas; Kimberly M. Lorenz; Carolin V. Schneider; Joseph Park; Kyung M. Lee; Marina Serper; Rotonya M. Carr; David E. Kaplan; Mary E. Haas; Matthew T. MacLean; Walter R. Witschey; Xiang Zhu; Catherine Tcheandjieu; Rachel L. Kember; Henry R. Kranzler; Anurag Verma; Ayush Giri; Derek M. Klarin; Yan V. Sun; Jie Huang; Jennifer Huffman; Kate Townsend Creasy; Nicholas J. Hand;

    Nonalcoholic fatty liver disease (NAFLD) is a prevalent, heritable trait that can progress to cancer and liver failure. Using our recently developed proxy definition for NAFLD based on chronic liver enzyme elevation without other causes of liver disease or alcohol misuse, we performed a multi-ancestry genome-wide association study in the Million Veteran Program with 90,408 NAFLD cases and 128,187 controls

    更新日期:2021-01-04
  • Prevalence of bacterial pathogens and potential role in COVID-19 severity in patients admitted to intensive care units in Brazil
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-28
    Fabiola Marques Carvalho; Leandro Nascimento Lemos; Luciane Prioli Ciapina; Rennan Garcias Moreira; Alexandra Gerber; Ana Paula Guimaraes; Tatiani Fereguetti; Virginia Antunes de Andrade Zambelli; Renata Avila; Tailah Bernardo de Almeida; Jheimson Silva Lima; Shana Priscila Coutinho Barroso; Mauro Martins Teixeira; Renan Pedra Souza; Cynthia Chester Cardoso; Renato Santana Aguiar; Ana Tereza Ribeiro

    Secondary bacterial and fungal infections are associated with respiratory viral infections and invasive mechanical ventilation. In Coronavirus disease 2019 (COVID-19), lung injury by SARS-CoV-2 and impaired immune response can provide a favorable environment for microorganism growth and colonization in hospitalized individuals. Recent studies suggest that secondary bacterial pneumonia is a risk factor

    更新日期:2020-12-29
  • Retrospective analysis of The Two Sister Study using haplotype-based association testing to identify loci associated with early-onset breast cancer
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-28
    James Ray Gilbert; James J Cray; Joseph E Losee; Gregory M Cooper

    Breast cancer is a polygenic disorder and is the leading cause of cancer related mortality among women. Early-onset breast cancer (EOBC) is diagnosed in women prior to 45 years-of-age and is associated with worse clinical outcomes, a more aggressive disease phenotype, and poor prognosis for disease-free survival. While substantial progress has been made in defining the genetics of breast cancer, EOBC

    更新日期:2020-12-28
  • Global approaches to postmortem genetic testing after sudden cardiac death in the young: A survey among healthcare professionals
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-26
    Lieke van den Heuvel; Judy Do; Laura Yeates; Heather MacLeod; Cynthia James; Johan Duflou; Jonathan Skinner; Chris Semsarian; J. Peter van Tintelen; Jodie Ingles

    Purpose: Thorough investigation of sudden cardiac death (SCD) in those aged 1-40 years commonly reveals a heritable cause, yet access to postmortem genetic testing is variable. We explore practices of postmortem genetic testing and attitudes of healthcare professionals worldwide. Methods: A survey was administered among healthcare professionals recruited through professional associations, social media

    更新日期:2020-12-27
  • MHC Haplotyping of SARS-CoV-2 patients: HLA subtypes are not associated with the presence and severity of Covid-19 in the Israeli population
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-26
    shay Ben-shachar; Noam Barda; Sigal SM Manor; Sapir Israeli; Noa Dagan; Shai Carmi; Ran Balicer; Bracha Zisser; Yoram Louzoun

    HLA haplotypes were found to be associated with increased risk for viral infections or disease severity in various diseases, including SARS. Several genetic variants are associated with Covid-19 severity. However, no clear association between HLA and Covid-19 incidence or severity has been reported. We conducted a large scale HLA analysis of Israeli individuals who tested positive for SARS-CoV-2 infection

    更新日期:2020-12-26
  • Genome-wide gene-diet interaction analysis in the UK Biobank identifies novel effects on Hemoglobin A1c
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-26
    Kenneth E Westerman; Jenkai Miao; Daniel I Chasman; Jose C Florez; Han Chen; Alisa K Manning; Joanne B Cole

    Diet is a significant modifiable risk factor for type 2 diabetes (T2D), and its effect on disease risk is under partial genetic control. Identification of specific gene-diet interactions (GDIs) influencing risk biomarkers such as glycated hemoglobin (HbA1c) is a critical step towards developing precision nutrition for T2D prevention, but progress has been slow due to limitations in sample size and

    更新日期:2020-12-26
  • Identification of potential core genes in hepatoblastoma via bioinformatics analysis
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-26
    Basavaraj Mallikarjunayya Vastrad; Chanabasayya Mallikarjunayya Vastrad; Iranna B Kotturshetti

    Hepatoblastoma is the childhood liver cancer. Profound efforts have been made to illuminate the pathology, but the molecular mechanisms of hepatoblastoma are still not well understood. To identify the candidate genes in the carcinogenesis and progression of hepatoblastoma, microarray dataset GSE131329 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs)

    更新日期:2020-12-26
  • Genomic characterization of a novel SARS-CoV-2 lineage from Rio de Janeiro, Brazil
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-26
    Carolina M Voloch; Ronaldo da Silva Francisco Junior; Luiz Gonzaga P de Almeida; Cynthia C Cardoso; Otavio J Brustolini; Alexandra L Gerber; Ana Paula de C Guimaraes; Diana Mariani; Raissa Mirella da Costa; Orlando Costa Ferreira Junior; Covid19-UFRJ Workgroup; LNCC-Workgroup; Adriana Cony Cavalcanti; Thiago Silva Frauches; Claudia Maria Braga de Mello; Rafael de Mello Galiez; Debora Souza Faffe; Terezinha

    In this study, we report the sequencing of 180 new viral genomes obtained from different municipalities of the state of Rio de Janeiro from April to December 2020. We identified a novel lineage of SARS-CoV-2, originated from B.1.1.28, distinguished by five single-nucleotide variants (SNVs): C100U, C28253U, G28628U, G28975U, and C29754U. The SNV G23012A (E484K), in the receptor-binding domain of Spike

    更新日期:2020-12-26
  • Common genetic associations between age-related diseases
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-24
    Handan Melike Donertas; Daniel K Fabian; Matias Fuentealba Valenzuela; Linda Partridge; Janet M Thornton

    Age is a common risk factor in many diseases, but the molecular basis for this relationship is elusive. In this study we identified 4 disease clusters from 116 diseases in the UK Biobank data, defined by their age-of-onset profiles, and found that diseases with the same onset profile are genetically more similar, suggesting a common etiology. This similarity was not explained by disease categories

    更新日期:2020-12-24
  • HLA-C* 04:01 is a Genetic Risk Allele for Severe Course of COVID-19
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-24
    January Weiner; Phillip Suwalski; Manuel Holtgrewe; Charlotte Thibeault; Melina Mueller; Dimitri Patriki; Claudia Quedenau; Ulrike Krueger; Elisa Theresa Helbig; Lena Lippert; Paula Stubbemann; Luis Miguel Real; Juan Macias Sanchez; Juan A. Pineda; Marta Fernandez-Fuertes; Xiaomin Wang; Zehra Karadeniz; Jacopo Saccomanno; Jan-Moritz Doehn; Ralf-Harto Hubner; Bernd Hinzmann; Mauricio Salvo; Anja Blueher;

    Background Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing demand to identify predictors of severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors. We sought to evaluate this hypothesis by conducting an

    更新日期:2020-12-24
  • A Neanderthal OAS1 Isoform Protects Against COVID-19 Susceptibility and Severity: Results from Mendelian Randomization and Case-Control Studies
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-24
    Sirui Zhou; Guillaume Butler-Laporte; Tomoko Nakanishi; David Morrison; Jonathan Afilalo; Marc Afilalo; Laetitia Laurent; Maik Pietzner; Nicola Kerrison; Kaiqiong Zhao; Elsa Brunet-Ratnasingham; Danielle Henry; Nofar Kimchi; Zaman Afrasiabi; Nardin Rezk; Meriem Bouab; Charlotte Guzman; Louis Petitjean; Xiaoqing Xue; Chris Tselios; Branka Vulesevic; Olumide Adeleye; Tala Abdullah; Noor Almamlouk; Yiheng

    Proteins detectable in peripheral blood may influence COVID-19 susceptibility or severity. However, understanding which circulating proteins are etiologically involved is difficult because their levels may be influenced by COVID-19 itself and are also subject to confounding factors. To identify circulating proteins influencing COVID-19 susceptibility and severity we undertook a large-scale two-sample

    更新日期:2020-12-24
  • Coronavirus GenBrowser for monitoring adaptive evolution and transmission of SARS-CoV-2
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-24
    Dalang Yu; Xiao Yang; Bixia Tang; Yi-Hsuan Pan; Jianing Yang; Junwei Zhu; Guangya Duan; Zi-Qian Hao; Hailong Mu; Long Dai; Wangjie Hu; Language translation team; Xiao Su; Guo-Qing Zhang; Wenming Zhao; Haipeng Li

    COVID-19 has widely spread across the world, and much research is being conducted on the causative virus SARS-CoV-2. To help control the infection, we developed the Coronavirus GenBrowser (CGB) to monitor the pandemic. CGB allows visualization and analysis of the latest viral genomic data. Distributed genome alignments and an evolutionary tree built on the existing subtree are implemented for easy

    更新日期:2020-12-24
  • THE SEARCH FOR AN ASSOCIATION OF HLA ALLELES AND COVID-19 RELATED MORTALITY IN THE RUSSIAN POPULATION
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-24
    Valery Cheranev; Irina Bulusheva; Valery I. Vechorko; Dmitriy Korostin; Denis V. Rebrikov

    HLA genes play a pivotal role in an immune response via the presentation of pathogen peptides in a complex on the surface of cells of a host organism. Here, we studied the association of class I and class II genes with the severity of COVID-19 infection and HLA allele variants. We performed high-resolution sequencing of class I and class II HLA genes using the sample population of 147 patients who

    更新日期:2020-12-24
  • Identification of potential key genes and pathway linked with sporadic Creutzfeldt-Jakob disease based on integrated bioinformatics analyses
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-24
    Basavaraj Mallikarjunayya Vastrad; Chanabasayya Mallikarjunayya Vastrad; Iranna B Kotturshetti

    Sporadic Creutzfeldt-Jakob disease (sCJD) is neurodegenerative disease also called prion disease linked with poor prognosis. The aim of the current study was to illuminate the underlying molecular mechanisms of sCJD. The mRNA microarray dataset GSE124571 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened. Pathway and GO enrichment analyses

    更新日期:2020-12-24
  • Identification of Key Genes and Signaling Pathways Associated with the Progression of Glioblastoma multiform
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-23
    Basavaraj Mallikarjunayya Vastrad; Chanabasayya Mallikarjunayya Vastrad; Iranna B Kotturshetti

    Genomic features have been gradually regarded as part of the basics to the clinical diagnosis, prognosis and treatment for glioblastoma multform (GBM). However, the molecular modifications taking place during the advancement of GBM remain unclear. Therefore, recognition of potential important genes and pathways in the gastric cancer progression is important to clinical practices. In the present study

    更新日期:2020-12-24
  • Identification and Interaction Analysis of Molecular Markers in Pancreatic Ductal Adenocarcinoma by Integrated Bioinformatics Analysis and Molecular Docking Experiments
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-23
    Basavaraj Mallikarjunayya Vastrad; Chanabasayya Mallikarjunayya Vastrad; Anandkumar Revanasiddappa Tengli

    The current investigation aimed to mine therapeutic molecular targets that play an key part in the advancement of pancreatic ductal adenocarcinoma (PDAC). The expression profiling by high throughput sequencing dataset profile GSE133684 dataset was downloaded from the Gene Expression Omnibus (GEO) database. Limma package of R was used to identify differentially expressed genes (DEGs). Functional enrichment

    更新日期:2020-12-24
  • Long-range PCR-based NGS applications to diagnose Mendelian retinal diseases
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-22
    Jordi Maggi; Samuel Koller; Luzy Bähr; Silke Feil; Fatma Kivrak-Pfiffner; James V. M. Hanson; Alessandro Maspoli; Christina Gerth-Kahlert; Wolfgang Berger

    Purpose: To develop a flexible, cost-efficient next-generation sequencing (NGS) protocol for genetic testing. Methods: Long-range polymerase chain reaction (LR PCR) amplicons of up to 20 kb in size were designed to amplify entire genomic regions for a panel (n=35) of loci associated with retinal diseases (RDs). Amplicons were pooled and sequenced by NGS. The analysis was applied to 227 probands diagnosed

    更新日期:2020-12-23
  • An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-22
    Liuyang Wang; Thomas J Balmat; Alejandro L Antonia; Florica J Constantine; Ricardo Henao; Thomas W Burke; Andy Ingham; Micah T McClain; Ephraim L Tsalik; Emily R Ko; Geoffrey Ginsburg; Mark DeLong; Xiling Shen; Christopher W Woods; Elizabeth R Hauser; Dennis C Ko

    While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility. Here, we

    更新日期:2020-12-22
  • Failure to replicate the association of rare loss-of-function variants in type I IFN immunity genes with severe COVID-19
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-21
    Gundula Povysil; Guillaume Butler-Laporte; Ning Shang; Chen Weng; Atlas Khan; Manal Alaamery; Tomoko Nakanishi; Sirui Zhou; Vincenzo Forgetta; Robert Eveleigh; Mathieu Bourgey; Naveed Aziz; Steven Jones; Bartha Knoppers; Stephen Scherer; Lisa Strug; Pierre Lepage; Jiannis Ragoussis; Guillaume Bourque; Jahad Alghamdi; Nora Aljawini; Nour Albes; Hani M. Al-Afghani; Bader Alghamdi; Mansour Almutair; Ebrahim

    A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,934 COVID-19 cases (713 with severe and 1,221 with mild disease) and 15,251 ancestry-matched population controls across four independent COVID-19 biobanks

    更新日期:2020-12-21
  • Common variants at 21q22.3 locus influence MX1 gene expression and susceptibility to severe COVID-19
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-20
    Immacolata Andolfo; Roberta Russo; Alessandro Vito Lasorsa; Sueva Cantalupo; Barbara Eleni Rosato; Ferdinando Bonfiglio; Giulia Frisso; Pasquale Abete; Gian Marco Cassese; Giuseppe Servillo; Gabriella Esposito; Ivan Gentile; Carmelo Piscopo; Romolo Villani; Giuseppe Fiorentino; Pellegrino Cerino; Carlo Buonerba; Biancamaria Pierri; Massimo Zollo; Achille Iolascon; Mario Capasso

    The COVID-19 disease, caused by the SARS-Cov-2, presents a heterogeneous clinical spectrum. The risk factors do not fully explain the wide spectrum of disease manifestations, so it is possible that genetic factors could account for novel insights into its pathogenesis. In our previous study, we hypothesized that common variants on chromosome 21, near TMPRSS2 and MX1 genes, may be genetic risk factors

    更新日期:2020-12-21
  • Genetic correlations between COVID-19 and a variety of diseases and other medically relevant traits
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-20
    Xiao Chang; Yun Li; Kenny Nguyen; Huiqi Qu; Yichuan Liu; Joseph Glessner; Patrick Sleiman; Hakon Hakonarson

    We analyzed GWAS results released by COVID-19 Host Genetics Initiative, UK biobank and GWAS Catalog to explore the genetic overlap between COVID-19 and a broad spectrum of traits and diseases. We validate previously reported medical conditions and risk factors based on epidemiological studies, including but not limited to hypertension, type 2 diabetes and obesity. We also report novel traits associated

    更新日期:2020-12-21
  • Whole Genome Rare-Variant Association Study of HIV-1 Progression in a Southern African Population
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-18
    Prisca K. Thami; Wonderful T. Choga; Delesa Damena Mulisa; Collet Dandara; Andrey K. Shevchenko; Melvin M. Leteane; Vlad Novitsky; Stephen J. O'Brien; Myron Essex; Simani Gaseitsiwe; Emile R. Chimusa

    Despite the high burden of HIV-1 in Botswana, the population of Botswana is significantly underrepresentation in host genetics studies of HIV-1. Furthermore, the bulk of previous genomics studies evaluated common human genetic variations, however, there is increasing evidence of the influence of rare variants in the outcome of diseases which may be uncovered by comprehensive complete and deep genome

    更新日期:2020-12-20
  • Systematic review reveals multiple sexually antagonistic polymorphisms affecting human disease and complex traits
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-18
    Jon A Harper; Tim Janicke; Edward H Morrow

    Sex differences in human disease risk and incidence are widely documented but their origins are poorly understood. An evolutionary model for differential disease risk between the sexes posits that alleles that are a risk factor (deleterious) in one sex may actually be protective (beneficial) in the opposite sex, and as such these sexually antagonistic (SA) alleles may be maintained in the population

    更新日期:2020-12-20
  • Whats in a diagnosis? A genetic decomposition of major depression.
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-17
    Bradley Scott Jermy; Kylie Patricia Glanville; Jonathan RI Coleman; Cathryn Lewis; Evangelos Vassos

    Determining a diagnosis of major depressive disorder (MDD) is complex, involving consideration and rating of a variety of different components. These include number of symptoms over an agreed threshold, symptom duration, functional impairment, persistence of symptoms within an episode, and symptom recurrence. While these components are generally accepted amongst physicians, it is unknown whether they

    更新日期:2020-12-17
  • Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-16
    Emma C Johnson; Manav Kapoor; Alexander S Hatoum; Hang Zhou; Renato Polimanti; Frank R Wendt; Raymond K Walters; Dongbing Lai; Rachel L Kember; Sarah Hartz; Jacquelyn L Meyers; Roseann E Peterson; Stephan Ripke; Tim B Bigdeli; Ayman H Fanous; Carlos N Pato; Michele T Pato; Alison M Goate; Henry R Kranzler; Michael C O'Donovan; James TR Walters; Joel Gelernter; Howard J Edenberg; Arpana Agrawal

    Background: Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and recent genome-wide association studies (GWAS) have identified significant genetic correlations between them. Methods: We used the largest published GWAS for AUD (total cases = 77,822) and SCZ (total cases = 46,827) to systematically identify genetic variants that influence both disorders (in either the same or opposite

    更新日期:2020-12-17
  • Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-16
    Joao Fadista; Luke M. Kraven; Juha Karjalainen; Shea J. Andrews; Frank Geller; The COVID-19 Host Genetics Initiative; J Kenneth Baillie; Louise V. Wain; R. Gisli Jenkins; Bjarke Feenstra

    Background. Idiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19

    更新日期:2020-12-16
  • Genome-wide association studies of LRRK2 modifiers of Parkinson's disease
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-16
    Dongbing Lai; Babak Alipanahi; Pierre Fontanillas; Tae-Hwi Schwantes-An; Jan Aasly; Roy N. Alcalay; Gary W. Beecham; Daniela Berg; Susan Bressman; Alexis Brice; Kathrin Brockman; Lorraine Clark; Mark Cookson; Sayantan Das; Vivianna Van Deerlin; Matthew Farrer; Joanne Trinh; Thomas Gasser; Stefano Goldwurm; Emil Gustavsson; Christine Klein; Anthony E. Lang; William J. Langston; Jeanne Latourelle; Timothy

    Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. Methods: We performed the first genome-wide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models

    更新日期:2020-12-16
  • Common genetic variants identify therapeutic targets for COVID-19 and individuals at high risk of severe disease
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-16
    Julie E. Horowitz; Jack A. Kosmicki; Amy Damask; Deepika Sharma; Genevieve H. L. Roberts; Anne A. E. Justice; Nilanjana Banerjee; Marie V. Coignet; Ashish Yadav; Joseph B. Leader; Anthony Marcketta; Danny S. Park; Rouel Lanche; Evan Maxwell; Spencer C. Knight; Xiaodong Bai; Harenda Guturu; Dylan Sun; Asher Baltzell; Fabricio S. P. Kury; Joshua D. Backman; Ahna R. Girshick; Colm O'Dushlaine; Shannon

    The need to identify and effectively treat COVID-19 cases at highest risk for severe disease is critical. We identified seven common genetic variants (three novel) that modulate COVID-19 susceptibility and severity, implicating IFNAR2, CCHCR1, TCF19, SLC6A20 and the hyaluronan pathway as potential therapeutic targets. A high genetic burden was strongly associated with increased risk of hospitalization

    更新日期:2020-12-16
  • An Evidence-based Assessment of Genes in Dilated Cardiomyopathy
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-15
    Elizabeth Jordan; Laiken Peterson; Tomohiko Ai; Babken Asatryan; Lucas Bronicki; Emily Brown; Rudy Celeghin; Matthew Edwards; Judy Fan; Jodie Ingles; Cynthia A James; Olga Jarinova; Renee Johnson; Daniel P Judge; Najim Lahrouchi; Ronald Lekanne Deprez; R Thomas Lumbers; Francesco Mazzarotto; Argelia Medeiros Domingo; Rebecca Miller; Ana Morales; Brittney Murray; Stacey Peters; Kalliopi Pilichou; Alexandros

    Background: The cardiomyopathies are classically categorized as hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular (ARVC), and each have a signature genetic theme. HCM and ARVC are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning more than 10 gene ontologies have been implicated in DCM, representing a complex

    更新日期:2020-12-16
  • A Framework for Automated Gene Selection in Genomic Screening
    medRxiv. Genet. Genom. Med. Pub Date : 2020-12-15
    Lorena Lazo de la Vega; Wanfeng Yu; Kalotina Machini; Christina Austin-Tse; Limin Hao; Carrie L Blout Zawatsky; Heather Mason-Suares; Robert C Green; Heidi L Rehm; Matthew S Lebo

    An efficient framework to identify disease-causing genes is needed to evaluate genomic data for both individuals with an unknown disease etiology and those undergoing genomic screening. Here, we propose a framework for gene selection used in genomic analyses, including screening applications limited to genes with strong or established evidence levels and diagnostic applications that includes genes