Medicine and Health Sciences Commons^™

Strategies For Enriching Variant Coverage In Candidate Disease Loci On A Multiethnic Genotyping Array, Stephanie Bien, Genevieve L. Wojcik, Niha Zubair, Christopher Gignoux, Alicia R. Martin, Lisa W. Martin, Page Study Investigators

Medicine Faculty Publications

Investigating genetic architecture of complex traits in ancestrally diverse populations is imperative to understand the etiology of disease. However, the current paucity of genetic research in people of African and Latin American ancestry, Hispanic and indigenous peoples in the United States is likely to exacerbate existing health disparities for many common diseases. The Population Architecture using Genomics and Epidemiology, Phase II (PAGE II), Study was initiated in 2013 by the National Human Genome Research Institute to expand our understanding of complex trait loci in ethnically diverse and well characterized study populations. To meet this goal, the Multi-Ethnic Genotyping Array (MEGA) …

Leukocyte Telomere Length In Relation To 17 Biomarkers Of Cardiovascular Disease Risk: A Cross-Sectional Study Of Us Adults, David Rehkopf, Belinda L. Needham, Jue Lin, Elizabeth Blackburn, Ami R. Zota, Janet Wojcicki, Elissa Epel

Environmental and Occupational Health Faculty Publications

Background

Leukocyte telomere length (LTL) is a putative biological marker of immune system age, and there are demonstrated associations between LTL and cardiovascular disease. This may be due in part to the relationship of LTL with other biomarkers associated with cardiovascular disease risk. However, the strength of associations between LTL and adiposity, metabolic, proinflammatory, and cardiovascular biomarkers has not been systematically evaluated in a United States nationally representative population.

Methods and Findings

We examined associations between LTL and 17 cardiovascular biomarkers, including lipoproteins, blood sugar, circulatory pressure, proinflammatory markers, kidney function, and adiposity measures, in adults ages 20 to 84 …

Dna Methylation-Based Measures Of Biological Age: Meta-Analysis Predicting Time To Death., B. Chen, R. Marioni, E. Colicino, M. Peters, C. Ward-Caviness, Cara L. Carty, +Several Additional Authors

Clinical Research and Leadership Faculty Publications

Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were …

Expanding The Phenotype Associated With Naa10-Related N-Terminal Acetylation Deficiency., Chloé Saunier, Svein Isungset Støve, Bernt Popp, Bénédicte Gérard, Marina Blenski, Nicholas Ahmew, +Several Additional Authors

Pediatrics Faculty Publications

N-terminal acetylation is a common protein modification in eukaryotes associated with numerous cellular processes. Inherited mutations in NAA10, encoding the catalytic subunit of the major N-terminal acetylation complex NatA have been associated with diverse, syndromic X-linked recessive disorders, whereas de novo missense mutations have been reported in one male and one female individual with severe intellectual disability but otherwise unspecific phenotypes. Thus, the full genetic and clinical spectrum of NAA10 deficiency is yet to be delineated. We identified three different novel and one known missense mutation in NAA10, de novo in 11 females, and due to maternal germ …

The Clinical, Biochemical And Genetic Features Associated With Rmnd1-Related Mitochondrial Disease., Yi Shiau Ng, Charlotte L Alston, Daria Diodato, Andrew A Morris, Nicole Ulrick, Stanislav Kmoch, +Several Additional Authors

Neurology Faculty Publications

BACKGROUND: Mutations in the RMND1 (Required for Meiotic Nuclear Division protein 1) gene have recently been linked to infantile onset mitochondrial disease characterised by multiple mitochondrial respiratory chain defects.

METHODS: We summarised the clinical, biochemical and molecular genetic investigation of an international cohort of affected individuals with RMND1 mutations. In addition, we reviewed all the previously published cases to determine the genotype-phenotype correlates and performed survival analysis to identify prognostic factors.

RESULTS: We identified 14 new cases from 11 pedigrees that harbour recessive RMND1 mutations, including 6 novel variants: c.533C>A, p.(Thr178Lys); c.565C>T, p.(Gln189*); c.631G>A, p.(Val211Met); c.1303C>T, …

Adgrl3 (Lphn3) Variants Are Associated With A Refined Phenotype Of Adhd In The Mta Study, Maria T. Acosta, James Swanson, Annamarie Stehli, Brooke Molina, The Mta Team

Neurology Faculty Publications

Background

ADHD is the most common neuropsychiatric condition affecting individuals of all ages. Long-term outcomes of affected individuals and association with severe comorbidities as SUD or conduct disorders are the main concern. Genetic associations have been extensively described. Multiple studies show that intronic variants harbored in the ADGRL3 (LPHN3) gene are associated with ADHD, especially associated with poor outcomes.

Methods

In this study, we evaluated this association in the Multimodal Treatment Study of children with ADHD (MTA), initiated as a 14-month randomized clinical trial of 579 children diagnosed with DSM-IV ADHD-Combined Type (ADHD-C), that transitioned to a 16-year prospective observational …

Separate F-Type Plasmids Have Shaped The Evolution Of The H30 Subclone Of Escherichia Coli Sequence Type 131., Timothy J Johnson, Jessica L Danzeisen, Bonnie Youmans, Kyle Case, Katharine Llop, Jeannette Munoz-Aguayo, Cristian Flores-Figueroa, Maliha Aziz, Nicole Stoesser, Evgeni Sokurenko, Lance B. Price, James R Johnson

Environmental and Occupational Health Faculty Publications

The extraintestinal pathogenic Escherichia coli (ExPEC) H30 subclone of sequence type 131 (ST131-H30) has emerged abruptly as a dominant lineage of ExPEC responsible for human disease. The ST131-H30 lineage has been well described phylogenetically, yet its plasmid complement is not fully understood. Here, single-molecule, real-time sequencing was used to generate the complete plasmid sequences of ST131-H30 isolates and those belonging to other ST131 clades. Comparative analyses revealed separate F-type plasmids that have shaped the evolution of the main fluoroquinolone-resistant ST131-H30 clades. Specifically, an F1:A2:B20 plasmid is strongly associated with the H …

Identification Of Genes That Are Essential To Restrict Genome Duplication To Once Per Cell Division., Alex Vassilev, Chrissie Y. Lee, Boris Vassilev, Wenge Zhu, Pinar Ormanoglu, Scott E. Martin, Melvin L. Depamphilis

Biochemistry and Molecular Medicine Faculty Publications

Nuclear genome duplication is normally restricted to once per cell division, but aberrant events that allow excess DNA replication (EDR) promote genomic instability and aneuploidy, both of which are characteristics of cancer development. Here we provide the first comprehensive identification of genes that are essential to restrict genome duplication to once per cell division. An siRNA library of 21,584 human genes was screened for those that prevent EDR in cancer cells with undetectable chromosomal instability. Candidates were validated by testing multiple siRNAs and chemical inhibitors on both TP53+ and TP53- cells to reveal the relevance of this ubiquitous tumor suppressor …

A Conserved Dna Repeat Promotes Selection Of A Diverse Repertoire Of Trypanosoma Brucei Surface Antigens From The Genomic Archive., Galadriel Hovel-Miner, Monica R. Mugnier, Benjamin Goldwater, George A. M. Cross, F. Nina Papavasiliou

Microbiology, Immunology, and Tropical Medicine Faculty Publications

African trypanosomes are mammalian pathogens that must regularly change their protein coat to survive in the host bloodstream. Chronic trypanosome infections are potentiated by their ability to access a deep genomic repertoire of Variant Surface Glycoprotein (VSG) genes and switch from the expression of one VSG to another. Switching VSG expression is largely based in DNA recombination events that result in chromosome translocations between an acceptor site, which houses the actively transcribed VSG, and a donor gene, drawn from an archive of more than 2,000 silent VSGs. One element implicated in these duplicative gene conversion events is a DNA repeat …

Comparison Of Two Commercial Dna Extraction Kits For The Analysis Of Nasopharyngeal Bacterial Communities, Marcos Pérez-Losada, Keith Crandall, Robert J. Freishtat

Pediatrics Faculty Publications

Characterization of microbial communities via next-generation sequencing (NGS) requires an extraction ofmicrobial DNA. Methodological differences in DNA extraction protocols may bias results and complicate inter-study comparisons. Here we compare the effect of two commonly used commercial kits (Norgen and Qiagen)for the extraction of total DNA on estimatingnasopharyngeal microbiome diversity. The nasopharynxis a reservoir for pathogens associated with respiratory illnesses and a key player in understandingairway microbial dynamics.
Total DNA from nasal washes corresponding to 30 asthmatic children was extracted using theQiagenQIAamp DNA and NorgenRNA/DNA Purification kits and analyzed via IlluminaMiSeq16S rRNA V4 ampliconsequencing. The Norgen samples included more sequence reads …

Teaching Internal Medicine Residents About Genetics: One Topic At A Time - Breast Cancer, Maria Henry, Andrew Nance, Charles Macri

GW Research Days 2016 - 2020

Background: Currently, the field of medicine is experiencing rapid changes in genetics and genomics information. While medical school curricula all include some genetics education, the content may vary from one school to another, leaving Internal Medicine (IM) residents with different skills and knowledge. In an IM residency where residents come from different medical schools, presenting an organized genetics curriculum may have value. Patients expect their physicians to be knowledgeable and current about their specific disease, including the genetic components and expect that they can inform them about terminology, inheritance, diagnostic testing, risks and benefits of testing. Physicians will need …

Single Nucleotide Polymorphisms In Cldn14 And Smoc1 Affecting Bone Mineral Density Influence Other Musculoskeletal Traits, Christopher Payette, Courtney Sprouse, Cara Goerlich, Heather A. Gordish-Dressman, Thomas Lynch, Heather Flynn, Leticia M. Ryan, Eric P. Hoffman, Monica J. Hubal, Paul D. Thompson, Theodore J. Angelopoulos, Paul M. Gordon, Niall M. Moyna, Linda S. Pescatello, Paul S. Visich, Robert F. Zoeller, Laura L. Tosi

GW Research Days 2016 - 2020

Background: A recent genome-wide association study (GWAS) identified novel genes influencing bone mineral density (BMD). This three stage GWAS identified two novel loci: rs227425 in the SPARC-Related Modular Calcium Binding 1 gene (SMOC1) was significantly associated with BMD and rs170183 in the claudin 14 (CLDN14) gene was significantly associated with BMD in females.

Objective: The purpose of this study was to determine if two novel single nucleotide polymorphisms (SNPs) known to affect BMD are associated with other musculoskeletal traits.

Methods/Design :The Bone Health Cohort consists of 150 African-American participants enrolled at Children’s National Health System as part of …

Dnah6 And Its Interactions With Pcd Genes In Heterotaxy And Primary Ciliary Dyskinesia., You Li, Hisato Yagi, Ezenwa Obi Onuoha, Rama Rao Damerla, Richard Francis, Yoshiyuki Furutani, Iman Sami, Linda Leatherbury, +13 Additional Authors

Pediatrics Faculty Publications

Heterotaxy, a birth defect involving left-right patterning defects, and primary ciliary dyskinesia (PCD), a sinopulmonary disease with dyskinetic/immotile cilia in the airway are seemingly disparate diseases. However, they have an overlapping genetic etiology involving mutations in cilia genes, a reflection of the common requirement for motile cilia in left-right patterning and airway clearance. While PCD is a monogenic recessive disorder, heterotaxy has a more complex, largely non-monogenic etiology. In this study, we show mutations in the novel dynein gene DNAH6 can cause heterotaxy and ciliary dysfunction similar to PCD. We provide the first evidence that trans-heterozygous interactions between DNAH6 and …

Complete Genome Sequence Of A Ctx-M-15-Producing Escherichia Coli Strain From The H30rx Subclone Of Sequence Type 131 From A Patient With Recurrent Urinary Tract Infections, Closely Related To A Lethal Urosepsis Isolate From The Patient's Sister., Timothy J. Johnson, Maliha Aziz, Cindy M. Liu, Evgeni Sokurenko, Dagmara I. Kisiela, Sandip Paul, Paal S. Andersen, James R. Johnson, Lance B. Price

Environmental and Occupational Health Faculty Publications

We report here the complete genome sequence, including five plasmid sequences, of Escherichia coli sequence type 131 (ST131) strain JJ1887. The strain was isolated in 2007 in the United States from a patient with recurrent cystitis, whose caregiver sister died from urosepsis caused by a nearly identical strain.

Importance Of Hereditary And Selected Environmental Risk Factors In The Etiology Of Inflammatory Breast Cancer: A Case-Comparison Study., Roxana Moslehi, Elizabeth Freedman, Nur Zeinomar, Carmela Veneroso, Paul H. Levine

Epidemiology Faculty Publications

BACKGROUND: To assess the importance of heredity in the etiology of inflammatory breast cancer (IBC), we compared IBC patients to several carefully chosen comparison groups with respect to the prevalence of first-degree family history of breast cancer.

METHODS: IBC cases (n = 141) were compared to non-inflammatory breast cancer cases (n = 178) ascertained through George Washington University (GWU) with respect to the prevalence of first-degree family history of breast cancer and selected environmental/lifestyle risk factors for breast cancer. Similar comparisons were conducted with subjects from three case-control studies: breast cancer cases (n = 1145) and unaffected controls (n = …

Mutational Profiles Reveal An Aberrant Tgf-Β-Cea Regulated Pathway In Colon Adenomas., Jian Chen, Gottumukkala S Raju, Wilma Jogunoori, Shoujun Gu, Lopa Mishra, + 27 More

Surgery Faculty Publications

Mutational processes and signatures that drive early tumorigenesis are centrally important for early cancer prevention. Yet, to date, biomarkers and risk factors for polyps (adenomas) that inordinately and rapidly develop into colon cancer remain poorly defined. Here, we describe surprisingly high mutational profiles through whole-genome sequence (WGS) analysis in 2 of 4 pairs of benign colorectal adenoma tissue samples. Unsupervised hierarchical clustered transcriptomic analysis of a further 7 pairs of adenomas reveals distinct mutational signatures regardless of adenoma size. Transitional single nucleotide substitutions of C:G>T:A predominate in the adenoma mutational spectrum. Strikingly, we observe mutations in the TGF-β pathway …

Mirnas As Potential Biomarkers In Early Breast Cancer Detection Following Mammography, Sidney W. Fu, Woojin Lee, Caitrin M. Coffey, Alexa Lea, Xiaoling Wu, Xiaohui Tan, Yan-Gao Man, Rachel F. Brem

Medicine Faculty Publications

Breast cancer is the most common cancer among American women, except for skin cancers. About 12 % women in the United States will develop invasive breast cancer during their lifetime. Currently one of the most accepted model/theories is that ductal breast cancer (most common type of breast cancer) follows a linear progression: from normal breast epithelial cells to ductal hyperplasia to atypical ductal hyperplasia (ADH) to ductal carcinoma in situ (DCIS), and finally to invasive ductal carcinoma (IDC). Distinguishing pure ADH diagnosis from DCIS and/or IDC on mammography, and even combined with follow-up core needle biopsy (CNB) is still a …

A Point Mutation In Dna Polymerase Β (Polb) Gene Is Associated With Increased Progesterone Receptor (Pr) Expression And Intraperitoneal Metastasis In Gastric Cancer, Xiaohui Tan, Xiaoling Wu, Shuyang Ren, Hongyi Wang, Weaam Alshenawy, Wenmei Li, Jiantao Cui, Guangbin Luo, Robert S. Siegel, Sidney W. Fu, Youyong Lu

Medicine Faculty Publications

Increased expression of progesterone receptor (PR) has been reported in gastric cancer (GC). We have previously identified a functional T889C point mutation in DNA polymerase beta (POLB), a DNA repair gene in GC. To provide a detailed analysis of molecular changes associated with the mutation, human cDNA microarrays focusing on 18 signal transduction pathways were used to analyze differential gene expression profiles between GC tissues with T889C mutant in POLB gene and those with wild type. Among the differentially expressed genes, notably, PR was one of the significantly up-regulated genes in T889C mutant POLB tissues, which were subsequently confirmed in …

Discovery Of Metabolic Biomarkers For Duchenne Muscular Dystrophy Within A Natural History Study., Simina M. Boca, Maki Nishida, Michael Harris, Shruti Rao, Amrita Cheema, Kirandeep Gill, Haeri Seol, Lauren P. Morgenroth, Erik Henricson, Craig M. Mcdonald, Jean K. Mah, Paula R. Clemens, Eric P. Hoffman, Yetrib Hathout, Subha Madhavan

Pediatrics Faculty Publications

Serum metabolite profiling in Duchenne muscular dystrophy (DMD) may enable discovery of valuable molecular markers for disease progression and treatment response. Serum samples from 51 DMD patients from a natural history study and 22 age-matched healthy volunteers were profiled using liquid chromatography coupled to mass spectrometry (LC-MS) for discovery of novel circulating serum metabolites associated with DMD. Fourteen metabolites were found significantly altered (1% false discovery rate) in their levels between DMD patients and healthy controls while adjusting for age and study site and allowing for an interaction between disease status and age. Increased metabolites included arginine, creatine and unknown …

Molecular And Behavioral Profiling Of Dbx1-Derived Neurons In The Arcuate, Lateral And Ventromedial Hypothalamic Nuclei., Katie Sokolowski, Tuyen Tran, Shigeyuki Esumi, Yasmin Kamal, Livio Oboti, Julieta Lischinsky, Meredith Goodrich, Andrew Lam, Margaret Carter, Yasushi Nakagawa, Joshua G. Corbin

Pediatrics Faculty Publications

BACKGROUND: Neurons in the hypothalamus function to regulate the state of the animal during both learned and innate behaviors, and alterations in hypothalamic development may contribute to pathological conditions such as anxiety, depression or obesity. Despite many studies of hypothalamic development and function, the link between embryonic development and innate behaviors remains unexplored. Here, focusing on the embryonically expressed homeodomain-containing gene Developing Brain Homeobox 1 (Dbx1), we explored the relationship between embryonic lineage, post-natal neuronal identity and lineage-specific responses to innate cues. We found that Dbx1 is widely expressed across multiple developing hypothalamic subdomains. Using standard and inducible fate-mapping to …

The Clinical Outcome Study For Dysferlinopathy, Elizabeth Harris, Catherine Bladen, Anna Mayhew, Meredith James, Karen Bettinson, Avital Cnaan, The Jain Cos Consortium

Pediatrics Faculty Publications

Objective: To describe the baseline clinical and functional characteristics of an international cohort of 193 patients with dysferlinopathy.

Methods: The Clinical Outcome Study for dysferlinopathy (COS) is an international multicenter study of this disease, evaluating patients with genetically confirmed dysferlinopathy over 3 years. We present a cross-sectional analysis of 193 patients derived from their baseline clinical and functional assessments.

Results: There is a high degree of variability in disease onset, pattern of weakness, and rate of progression. No factor, such as mutation class, protein expression, or age at onset, accounted for this variability. Among patients with clinical diagnoses of Miyoshi …

Incidence Of X And Y Chromosomal Aneuploidy In A Large Child Bearing Population., Carole Samango-Sprouse, Eser Kırkızlar, Megan P Hall, Patrick Lawson, Zachary Demko, Susan M Zneimer, Kirsten J Curnow, Susan Gross, Andrea Gropman

Pediatrics Faculty Publications

BACKGROUND: X&Y chromosomal aneuploidies are among the most common human whole-chromosomal copy number changes, but the population-based incidence and prevalence in the child-bearing population is unclear.

METHODS: This retrospective analysis of prospectively collected data leveraged a routine non-invasive prenatal test (NIPT) using parental genotyping to estimate the population-based incidence of X&Y chromosome variations in this population referred for NIPT (generally due to advanced maternal age).

RESULTS: From 141,916 women and 29,336 men, 119 X&Y chromosomal abnormalities (prevalence: 1 in 1,439) were identified. Maternal findings include: 43 cases of 45,X (40 mosaic); 30 cases of 47,XXX (12 mosaic); 3 cases of …

Variant Discovery And Fine Mapping Of Genetic Loci Associated With Blood Pressure Traits In Hispanics And African Americans., Nora Franceschini, Cara L. Carty, Yingchang Lu, Ran Tao, Yun Ju Sung, Ani Manichaikul, +20 Additional Authors

Clinical Research and Leadership Faculty Publications

Despite the substantial burden of hypertension in US minority populations, few genetic studies of blood pressure have been conducted in Hispanics and African Americans, and it is unclear whether many of the established loci identified in European-descent populations contribute to blood pressure variation in non-European descent populations. Using the Metabochip array, we sought to characterize the genetic architecture of previously identified blood pressure loci, and identify novel cardiometabolic variants related to systolic and diastolic blood pressure in a multi-ethnic US population including Hispanics (n = 19,706) and African Americans (n = 18,744). Several known blood pressure loci replicated in African …