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genetic variant

Ulrike Bechtold, John N Ferguson, Philip M Mullineaux
The emergence of Arabidopsis as a model species and the availability of genetic and genomic resources have resulted in the identification and detailed characterisation of abiotic stress signalling pathways. However, this has led only to limited success in engineering abiotic stress tolerance in crops. This is because there needs to be a deeper understanding in how to combine resistances to a range of stresses with growth and productivity. The natural variation and genomic resources of Arabidopsis thaliana (Arabidopsis) is a great asset to understand the mechanisms of multiple stress tolerances...
March 17, 2018: Journal of Experimental Botany
Patrick J Short, Jeremy F McRae, Giuseppe Gallone, Alejandro Sifrim, Hyejung Won, Daniel H Geschwind, Caroline F Wright, Helen V Firth, David R FitzPatrick, Jeffrey C Barrett, Matthew E Hurles
We previously estimated that 42% of patients with severe developmental disorders carry pathogenic de novo mutations in coding sequences. The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders...
March 21, 2018: Nature
Noura S Abul-Husn, Xiping Cheng, Alexander H Li, Yurong Xin, Claudia Schurmann, Panayiotis Stevis, Yashu Liu, Julia Kozlitina, Stefan Stender, G Craig Wood, Ann N Stepanchick, Matthew D Still, Shane McCarthy, Colm O'Dushlaine, Jonathan S Packer, Suganthi Balasubramanian, Nehal Gosalia, David Esopi, Sun Y Kim, Semanti Mukherjee, Alexander E Lopez, Erin D Fuller, John Penn, Xin Chu, Jonathan Z Luo, Uyenlinh L Mirshahi, David J Carey, Christopher D Still, Michael D Feldman, Aeron Small, Scott M Damrauer, Daniel J Rader, Brian Zambrowicz, William Olson, Andrew J Murphy, Ingrid B Borecki, Alan R Shuldiner, Jeffrey G Reid, John D Overton, George D Yancopoulos, Helen H Hobbs, Jonathan C Cohen, Omri Gottesman, Tanya M Teslovich, Aris Baras, Tooraj Mirshahi, Jesper Gromada, Frederick E Dewey
BACKGROUND: Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. METHODS: We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples...
March 22, 2018: New England Journal of Medicine
Nicole Selleski, Lucas Malta Almeida, Fernanda Coutinho de Almeida, Claudia Beatriz Pratesi, Yanna Karla de Medeiros Nóbrega, Lenora Gandolfi
BACKGROUND: Celiac disease is an autoimmune enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. Almost all celiac patients carry immune recognition genes coding for HLA-DQ2.5 and DQ8 heterodimers. Over the last few years, great importance has been given to HLA-DQ2.2 as probable predisposing variant, although controversies still exist regarding its relevance. OBJECTIVE: The aim of our study was to determine the possible existence of an association between HLA-DQ2...
January 2018: Arquivos de Gastroenterologia
Kwondo Kim, Jaehoon Jung, Kelsey Caetano-Anollés, Samsun Sung, DongAhn Yoo, Bong-Hwan Choi, Hyung-Chul Kim, Jin-Young Jeong, Yong-Min Cho, Eung-Woo Park, Tae-Jeong Choi, Byoungho Park, Dajeong Lim, Heebal Kim
Artificial selection has been demonstrated to have a rapid and significant effect on the phenotype and genome of an organism. However, most previous studies on artificial selection have focused solely on genomic sequences modified by artificial selection or genomic sequences associated with a specific trait. In this study, we generated whole genome sequencing data of 126 cattle under artificial selection, and 24,973,862 single nucleotide variants to investigate the relationship among artificial selection, genomic sequences and trait...
2018: PloS One
Nicola Silvestris, Oronzo Brunetti, Rosamaria Pinto, Daniela Petriella, Antonella Argentiero, Livia Fucci, Stefania Tommasi, Katia Danza, Simona De Summa
OBJECTIVES: Adenosquamous cancer of pancreas (ASCP) is a rare variant of pancreatic adenocarcinoma (PDAC). It is characterized by poor prognosis and lacks of literature data supporting the choice of systemic therapies. The role of immunotherapy for this malignancy is still unknown. In this study, we evaluated any differences between immune-related genes of PDAC and its adenosquamous variant with the aim to characterize these histothistotypes and eventually identify potential biomarkers useful for an immune-therapy approach in ASCP...
March 21, 2018: Expert Opinion on Therapeutic Targets
Minseok Kwon, Sangseob Leem, Joon Yoon, Taesung Park
BACKGROUND: With the rapid advancement of array-based genotyping techniques, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with common complex diseases. However, it has been shown that only a small proportion of the genetic etiology of complex diseases could be explained by the genetic factors identified from GWAS. This missing heritability could possibly be explained by gene-gene interaction (epistasis) and rare variants. There has been an exponential growth of gene-gene interaction analysis for common variants in terms of methodological developments and practical applications...
March 19, 2018: BMC Systems Biology
Afaf Elsaid, Rasha Zahran, Rami Elshazli, Ahmed El-Sayed, Marwa Abou Samra, Fatma El-Tarapely, Camelia Abdel-Malak
BACKGROUND: Previous reports demonstrated the role of TP53 gene polymorphisms with CRC risk among several ethnic populations. The purpose of this study is to assess the association of the TP53 Arg72Pro and Pro47Ser variants with CRC risk among Egyptian patients. SUBJECTS AND METHODS: This work was conducted on 120 unrelated CRC Egyptian patients who were compared to 140 healthy controls. DNA was genotyped for these variants using the PCR-RFLP technique. RESULTS: CRC patients observed a significant association of the rare genotype of TP53 Arg72Pro polymorphism compared with healthy controls...
March 21, 2018: Archives of Physiology and Biochemistry
Amanda C Smith, Yoko Ito, Afsana Ahmed, Jeremy A Schwartzentruber, Chandree L Beaulieu, Erika Aberg, Jacek Majewski, Dennis E Bulman, Karina Horsting-Wethly, Diana Vermunt-de Koning, Richard J Rodenburg, Kym M Boycott, Lynette S Penney
Primary CoQ10 deficiency is a clinically and genetically heterogeneous, autosomal recessive disorder resulting from mutations in genes involved in the synthesis of coenzyme Q10 (CoQ10 ). To date, mutations in nine proteins required for the biosynthesis of CoQ10 cause CoQ10 deficiency with varying clinical presentations. In 2009 the first patient with mutations in COQ9 was reported in an infant with a neonatal-onset, primary CoQ10 deficiency with multi-system disease. Here we describe four siblings with a previously undiagnosed lethal disorder characterized by oligohydramnios and intrauterine growth restriction, variable cardiomyopathy, anemia, and renal anomalies...
March 20, 2018: Journal of Inherited Metabolic Disease
Jessica Scott Schwoerer, Nicoletta Drilias, Ashley Kuhl, Sean Mochal, Mei Baker
In the Plain Community, there is an increased frequency of genetic disorders including phenylalanine hydroxylase (PAH) deficiency. Common pathogenic variants have been observed due to founder effect and closed community. This study obtained genotypes of 12 Plain individuals with PAH deficiency, identified through newborn screen or diagnosed by symptomatic presentation, who are receiving medical care at the University of Wisconsin metabolic clinic. Genotype and phenotypic data were evaluated to characterize genotype-phenotype correlations...
June 2018: Molecular Genetics and Metabolism Reports
David M Barris, Shoshana B Weiner, Robert A Dubin, Michael Fremed, Xusheng Zhang, Sajida Piperdi, Wendong Zhang, Shahina Maqbool, Jonathan Gill, Michael Roth, Bang Hoang, David Geller, Richard Gorlick, Daniel A Weiser
Identification and quantification of somatic alterations in plasma-derived, circulating tumor DNA (ctDNA) is gaining traction as a non-invasive and cost effective method of disease monitoring in cancer patients, particularly to evaluate response to treatment and monitor for disease recurrence. To our knowledge, genetic analysis of ctDNA in osteosarcoma has not yet been studied. To determine whether somatic alterations can be detected in ctDNA and perhaps applied to patient management in this disease, we collected germline, tumor, and serial plasma samples from pediatric, adolescent, and young adult patients with osteosarcoma and used targeted Next Generation Sequencing (NGS) to identify somatic single nucleotide variants (SNV), insertions and deletions (INDELS), and structural variants (SV) in 7 genes commonly mutated in osteosarcoma...
February 27, 2018: Oncotarget
Weijing Wang, Dongfeng Zhang, Chunsheng Xu, Yili Wu, Haiping Duan, Shuxia Li, Qihua Tan
Serum uric acid (SUA), as the end product of purine metabolism, has proven emerging roles in human disorders. Here based on a sample of 379 middle and old-aged Chinese twin pairs, we aimed to explore the magnitude of genetic impact on SUA variation by performing sex-limitation twin modeling analyses and further detect specific genetic variants related to SUA by conducting a genome-wide association study. Monozygotic (MZ) twin correlation for SUA level (rMZ = 0.56) was larger than for dizygotic (DZ) twin correlation (rDZ = 0...
2018: Frontiers in Endocrinology
Azmeraw T Amare, Klaus Oliver Schubert, Fasil Tekola-Ayele, Yi-Hsiang Hsu, Katrin Sangkuhl, Gregory Jenkins, Ryan M Whaley, Poulami Barman, Anthony Batzler, Russ B Altman, Volker Arolt, Jürgen Brockmöller, Chia-Hui Chen, Katharina Domschke, Daniel K Hall-Flavin, Chen-Jee Hong, Ari Illi, Yuan Ji, Olli Kampman, Toshihiko Kinoshita, Esa Leinonen, Ying-Jay Liou, Taisei Mushiroda, Shinpei Nonen, Michelle K Skime, Liewei Wang, Masaki Kato, Yu-Li Liu, Verayuth Praphanphoj, Julia C Stingl, William V Bobo, Shih-Jen Tsai, Michiaki Kubo, Teri E Klein, Richard M Weinshilboum, Joanna M Biernacka, Bernhard T Baune
Studies reported a strong genetic correlation between the Big Five personality traits and major depressive disorder (MDD). Moreover, personality traits are thought to be associated with response to antidepressants treatment that might partly be mediated by genetic factors. In this study, we examined whether polygenic scores (PGSs) derived from the Big Five personality traits predict treatment response and remission in patients with MDD who were prescribed selective serotonin reuptake inhibitors (SSRIs). In addition, we performed meta-analyses of genome-wide association studies (GWASs) on these traits to identify genetic variants underpinning the cross-trait polygenic association...
2018: Frontiers in Psychiatry
Yingze Zhang, Inna Belfer, Mehdi Nouraie, Qilu Zeng, Ruchika Goel, Yanxia Chu, Inna Krasiy, Lakshmanan Krishnamurti
Background: Vaso-occlusive pain episodes (VOEs) are the hallmark of sickle cell disease (SCD), and our current understanding of disease biology, treatment, and psychological covariates does not adequately explain the variability of pain in SCD. Functional variants in catechol- O -methyltransferase ( COMT ) gene contribute to variability in pain perception, but their impact on pain perception in African American SCD patients is not well known. Methods: We studied COMT single-nucleotide polymorphisms (SNPs) rs6269, rs4633, rs4818, rs4680, and rs165599 to determine their relationship to patient self-reported pain, the number of acute VOEs, and their impact on daily life and health care utilization in 438 hemoglobin SS patients who participated in the walk-PHaSST study...
2018: Journal of Pain Research
Eleni Zengini, Konstantinos Hatzikotoulas, Ioanna Tachmazidou, Julia Steinberg, Fernando P Hartwig, Lorraine Southam, Sophie Hackinger, Cindy G Boer, Unnur Styrkarsdottir, Arthur Gilly, Daniel Suveges, Britt Killian, Thorvaldur Ingvarsson, Helgi Jonsson, George C Babis, Andrew McCaskie, Andre G Uitterlinden, Joyce B J van Meurs, Unnur Thorsteinsdottir, Kari Stefansson, George Davey Smith, Jeremy M Wilkinson, Eleftheria Zeggini
Osteoarthritis is a common complex disease imposing a large public-health burden. Here, we performed a genome-wide association study for osteoarthritis, using data across 16.5 million variants from the UK Biobank resource. After performing replication and meta-analysis in up to 30,727 cases and 297,191 controls, we identified nine new osteoarthritis loci, in all of which the most likely causal variant was noncoding. For three loci, we detected association with biologically relevant radiographic endophenotypes, and in five signals we identified genes that were differentially expressed in degraded compared with intact articular cartilage from patients with osteoarthritis...
March 20, 2018: Nature Genetics
Kiatichai Faksri, Eryu Xia, Rick Twee-Hee Ong, Jun Hao Tan, Ditthawat Nonghanphithak, Nampueng Makhao, Nongnard Thamnongdee, Arirat Thanormchat, Arisa Phurattanakornkul, Somcharn Rattanarangsee, Chate Ratanajaraya, Prapat Suriyaphol, Therdsak Prammananan, Yik-Ying Teo, Angkana Chaiprasert
Tuberculous meningitis (TBM) is a severe form of tuberculosis with a high mortality rate. The factors associated with TBM pathogenesis are still unclear. Using comparative whole-genome sequence analysis we compared Mycobacterium tuberculosis (Mtb) isolates from cerebrospinal fluid of TBM cases (n = 73) with those from sputum of pulmonary tuberculosis (PulTB) patients (n = 220) from Thailand. The aim of this study was to seek genetic variants of Mtb associated with TBM. Regardless of Mtb lineage, we found 242 variants that were common to all TBM isolates...
March 20, 2018: Scientific Reports
Freja Herborg, Thorvald F Andreassen, Frida Berlin, Claus J Loland, Ulrik Gether
Genetic factors are known to significantly contribute to the etiology of psychiatric diseases such as attention deficit hyperactivity disorder (ADHD) and autism spectrum and bipolar disorders, but the underlying molecular processes remain largely elusive. The dopamine transporter (DAT) has received continuous attention as a potential risk factor for psychiatric disease, as it is critical for dopamine homeostasis and serves as principal target for ADHD medications. Constrain metrics for the DAT-encoding gene solute carrier family 6 member 3 (SLC6A3) indicate that missense mutations are under strong negative selection, pointing to pathophysiological outcomes when DAT function is compromised...
March 20, 2018: Journal of Biological Chemistry
Maryam Dendana, Wael Bahia, Ramzi R Finan, Mariam Al-Mutawa, Wassim Y Almawi
BACKGROUND: This study addresses whether the association of adiponectin gene (ADIPOQ) variants with idiopathic recurrent pregnancy loss (RPL) is influenced by obesity. METHODS: Retrospective case-control study performed in outpatient obstetrics/gynecology clinics. Study subjects comprised 308 women with RPL, defined as ≥ 3 consecutive miscarriages of unknown etiology, and 310 control women. ADIPOQ genotyping was done by allele exclusion method on real-time PCR...
March 20, 2018: Journal of Translational Medicine
Ross W Paterson, Catherine F Slattery, Teresa Poole, Jennifer M Nicholas, Nadia K Magdalinou, Jamie Toombs, Miles D Chapman, Michael P Lunn, Amanda J Heslegrave, Martha S Foiani, Philip S J Weston, Ashvini Keshavan, Jonathan D Rohrer, Martin N Rossor, Jason D Warren, Catherine J Mummery, Kaj Blennow, Nick C Fox, Henrik Zetterberg, Jonathan M Schott
BACKGROUND: Cerebrospinal fluid (CSF) biomarkers are increasingly being used to support a diagnosis of Alzheimer's disease (AD). Their clinical utility for differentiating AD from non-AD neurodegenerative dementias, such as dementia with Lewy bodies (DLB) or frontotemporal dementia (FTD), is less well established. We aimed to determine the diagnostic utility of an extended panel of CSF biomarkers to differentiate AD from a range of other neurodegenerative dementias. METHODS: We used immunoassays to measure conventional CSF markers of amyloid and tau pathology (amyloid beta (Aβ)1-42, total tau (T-tau), and phosphorylated tau (P-tau)) as well as amyloid processing (AβX-38, AβX-40, AβX-42, soluble amyloid precursor protein (sAPP)α, and sAPPβ), large fibre axonal degeneration (neurofilament light chain (NFL)), and neuroinflammation (YKL-40) in 245 patients with a variety of dementias and 30 controls...
March 20, 2018: Alzheimer's Research & Therapy
Shehu S Awandu, Jaishree Raman, Takalani I Makhanthisa, Philip Kruger, John Frean, Teun Bousema, Jandeli Niemand, Lyn-Marie Birkholtz
BACKGROUND: Primaquine (PQ) is recommended as an addition to standard malaria treatments in pre-elimination settings due to its pronounced activity against mature Plasmodium falciparum gametocytes, the parasite stage responsible for onward transmission to mosquitoes. However, PQ may trigger haemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. Additional human genetic factors, including polymorphisms in the human cytochrome P450 2D6 (CYP2D6) complex, may negatively influence the efficacy of PQ...
March 20, 2018: Malaria Journal
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