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phenome-wide association study

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https://www.readbyqxmd.com/read/30092202/an-atlas-of-genetic-variation-linking-pathogen-induced-cellular-traits-to-human-disease
#1
Liuyang Wang, Kelly J Pittman, Jeffrey R Barker, Raul E Salinas, Ian B Stanaway, Graham D Williams, Robert J Carroll, Tom Balmat, Andy Ingham, Anusha M Gopalakrishnan, Kyle D Gibbs, Alejandro L Antonia, Joseph Heitman, Soo Chan Lee, Gail P Jarvik, Joshua C Denny, Stacy M Horner, Mark R DeLong, Raphael H Valdivia, David R Crosslin, Dennis C Ko
Pathogens have been a strong driving force for natural selection. Therefore, understanding how human genetic differences impact infection-related cellular traits can mechanistically link genetic variation to disease susceptibility. Here we report the Hi-HOST Phenome Project (H2P2): a catalog of cellular genome-wide association studies (GWAS) comprising 79 infection-related phenotypes in response to 8 pathogens in 528 lymphoblastoid cell lines. Seventeen loci surpass genome-wide significance for infection-associated phenotypes ranging from pathogen replication to cytokine production...
August 8, 2018: Cell Host & Microbe
https://www.readbyqxmd.com/read/30090940/association-of-interleukin-6-receptor-variant-with-cardiovascular-disease-effects-of-interleukin-6-receptor-blocking-therapy-a-phenome-wide-association-study
#2
Tianxi Cai, Yichi Zhang, Yuk-Lam Ho, Nicholas Link, Jiehuan Sun, Jie Huang, Tianrun A Cai, Scott Damrauer, Yuri Ahuja, Jacqueline Honerlaw, Jie Huang, Lauren Costa, Petra Schubert, Chuan Hong, David Gagnon, Yan V Sun, J Michael Gaziano, Peter Wilson, Kelly Cho, Philip Tsao, Christopher J O'Donnell, Katherine P Liao
Importance: Electronic health record (EHR) biobanks containing clinical and genomic data on large numbers of individuals have great potential to inform drug discovery. Individuals with interleukin 6 receptor (IL6R) single-nucleotide polymorphisms (SNPs) who are not receiving IL6R blocking therapy have biomarker profiles similar to those treated with IL6R blockers. This gene-drug pair provides an example to test whether associations of IL6R SNPs with a broad range of phenotypes can inform which diseases may benefit from treatment with IL6R blockade...
August 8, 2018: JAMA Cardiology
https://www.readbyqxmd.com/read/29997226/large-scale-phenome-wide-association-study-of-pcsk9-variants-demonstrates-protection-against-ischemic-stroke
#3
Abhiram S Rao, Daniel Lindholm, Manuel A Rivas, Joshua W Knowles, Stephen B Montgomery, Erik Ingelsson
BACKGROUND: PCSK9 inhibition is a potent new therapy for hypercholesterolemia and cardiovascular disease. Although short-term clinical trial results have not demonstrated major adverse effects, long-term data will not be available for some time. Genetic studies in large biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes. METHODS: We tested the association of the PCSK9 missense variant rs11591147 with predefined phenotypes and phenome-wide, in 337 536 individuals of British ancestry in the UK Biobank, with independent discovery and replication...
July 2018: Circulation. Genomic and precision medicine
https://www.readbyqxmd.com/read/29994486/natural-language-processing-for-ehr-based-computational-phenotyping
#4
Zexian Zeng, Yu Deng, Xiaoyu Li, Tristan Naumann, Yuan Luo
This article reviews recent advances in applying natural language processing (NLP) to Electronic Health Records (EHRs) for computational phenotyping. NLP-based computational phenotyping has numerous applications including diagnosis categorization, novel phenotype discovery, clinical trial screening, pharmacogenomics, drug-drug interaction (DDI) and adverse drug event (ADE) detection, as well as genome-wide and phenome-wide association studies. Significant progress has been made in algorithm development and resource construction for computational phenotyping...
June 25, 2018: IEEE/ACM Transactions on Computational Biology and Bioinformatics
https://www.readbyqxmd.com/read/29926116/identification-of-novel-high-impact-recessively-inherited-type-2-diabetes-risk-variants-in-the-greenlandic-population
#5
Niels Grarup, Ida Moltke, Mette K Andersen, Peter Bjerregaard, Christina V L Larsen, Inger K Dahl-Petersen, Emil Jørsboe, Hemant K Tiwari, Scarlett E Hopkins, Howard W Wiener, Bert B Boyer, Allan Linneberg, Oluf Pedersen, Marit E Jørgensen, Anders Albrechtsen, Torben Hansen
AIMS/HYPOTHESIS: In a recent study using a standard additive genetic model, we identified a TBC1D4 loss-of-function variant with a large recessive impact on risk of type 2 diabetes in Greenlanders. The aim of the current study was to identify additional genetic variation underlying type 2 diabetes using a recessive genetic model, thereby increasing the power to detect variants with recessive effects. METHODS: We investigated three cohorts of Greenlanders (B99, n = 1401; IHIT, n = 3115; and BBH, n = 547), which were genotyped using Illumina MetaboChip...
June 20, 2018: Diabetologia
https://www.readbyqxmd.com/read/29912272/evaluating-statistical-approaches-to-leverage-large-clinical-datasets-for-uncovering-therapeutic-and-adverse-medication-effects
#6
Leena Choi, Robert J Carroll, Cole Beck, Jonathan D Mosley, Dan M Roden, Joshua C Denny, Sara L Van Driest
Motivation: Phenome-wide association studies (PheWAS) have been used to discover many genotype-phenotype relationships and have the potential to identify therapeutic and adverse drug outcomes using longitudinal data within electronic health records (EHRs). However, the statistical methods for PheWAS applied to longitudinal EHR medication data have not been established. Results: In this study, we developed methods to address two challenges faced with reuse of EHR for this purpose: confounding by indication, and low exposure and event rates...
April 18, 2018: Bioinformatics
https://www.readbyqxmd.com/read/29909275/genetic-regulation-of-plasma-lipid-species-and-their-association-with-metabolic-phenotypes
#7
Pooja Jha, Molly T McDevitt, Emina Halilbasic, Evan G Williams, Pedro M Quiros, Karim Gariani, Maroun B Sleiman, Rahul Gupta, Arne Ulbrich, Adam Jochem, Joshua J Coon, Michael Trauner, David J Pagliarini, Johan Auwerx
The genetic regulation and physiological impact of most lipid species are unexplored. Here, we profiled 129 plasma lipid species across 49 strains of the BXD mouse genetic reference population fed either chow or a high-fat diet. By integrating these data with genomics and phenomics datasets, we elucidated genes by environment (diet) interactions that regulate systemic metabolism. We found quantitative trait loci (QTLs) for ∼94% of the lipids measured. Several QTLs harbored genes associated with blood lipid levels and abnormal lipid metabolism in human genome-wide association studies...
June 27, 2018: Cell Systems
https://www.readbyqxmd.com/read/29888080/learning-opportunities-for-drug-repositioning-via-gwas-and-phewas-findings
#8
Wen Yin, Cheng Gao, Yaomin Xu, Bingshan Li, Douglas M Ruderfer, You Chen
Drug repositioning for available medications can be preferred over traditional drug development, which requires substantially more effort to uncover new insights into medications and diseases. Genome-Wide Association Studies (GWAS) and Phenome-Wide Association Studies (PheWAS) are two complimentary methods for finding novel associations between genes and diseases. We hypothesize that discoveries from these studies could be leveraged to find new targets for existing drugs. Thus, we propose a framework to learn opportunities for inferring such relationships via overlapped genes between disease-associated genes (e...
2018: AMIA Summits on Translational Science Proceedings
https://www.readbyqxmd.com/read/29847655/family-based-genome-wide-association-study-of-south-indian-pedigrees-supports-wnt7b-as-a-central-corneal-thickness-locus
#9
Bao Jian Fan, Xueli Chen, Nisha Sondhi, P Ferdinamarie Sharmila, Nagasamy Soumittra, Sarangapani Sripriya, Srinivasan Sacikala, Rashima Asokan, David S Friedman, Louis R Pasquale, X Raymond Gao, Lingam Vijaya, Jessica Cooke Bailey, Veronique Vitart, Stuart MacGregor, Christopher J Hammond, Chiea Chuen Khor, Jonathan L Haines, Ronnie George, Janey L Wiggs
Purpose: To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. Methods: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. Results: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = -0...
May 1, 2018: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29846171/the-mr-base-platform-supports-systematic-causal-inference-across-the-human-phenome
#10
Gibran Hemani, Jie Zheng, Benjamin Elsworth, Kaitlin H Wade, Valeriia Haberland, Denis Baird, Charles Laurin, Stephen Burgess, Jack Bowden, Ryan Langdon, Vanessa Y Tan, James Yarmolinsky, Hashem A Shihab, Nicholas J Timpson, David M Evans, Caroline Relton, Richard M Martin, George Davey Smith, Tom R Gaunt, Philip C Haycock
Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-sample Mendelian randomization (2SMR) and bypassing the need for individual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base (<ext-link ext-link-type="uri" xlink:href="http://www.mrbase.org">http://www...
May 30, 2018: ELife
https://www.readbyqxmd.com/read/29788308/pheprob-probabilistic-phenotyping-using-diagnosis-codes-to-improve-power-for-genetic-association-studies
#11
Jennifer A Sinnott, Fiona Cai, Sheng Yu, Boris P Hejblum, Chuan Hong, Isaac S Kohane, Katherine P Liao
Objective: Standard approaches for large scale phenotypic screens using electronic health record (EHR) data apply thresholds, such as ≥2 diagnosis codes, to define subjects as having a phenotype. However, the variation in the accuracy of diagnosis codes can impair the power of such screens. Our objective was to develop and evaluate an approach which converts diagnosis codes into a probability of a phenotype (PheProb). We hypothesized that this alternate approach for defining phenotypes would improve power for genetic association studies...
May 17, 2018: Journal of the American Medical Informatics Association: JAMIA
https://www.readbyqxmd.com/read/29779563/association-of-polygenic-risk-scores-for-multiple-cancers-in-a-phenome-wide-study-results-from-the-michigan-genomics-initiative
#12
Lars G Fritsche, Stephen B Gruber, Zhenke Wu, Ellen M Schmidt, Matthew Zawistowski, Stephanie E Moser, Victoria M Blanc, Chad M Brummett, Sachin Kheterpal, Gonçalo R Abecasis, Bhramar Mukherjee
Health systems are stewards of patient electronic health record (EHR) data with extraordinarily rich depth and breadth, reflecting thousands of diagnoses and exposures. Measures of genomic variation integrated with EHRs offer a potential strategy to accurately stratify patients for risk profiling and discover new relationships between diagnoses and genomes. The objective of this study was to evaluate whether polygenic risk scores (PRS) for common cancers are associated with multiple phenotypes in a phenome-wide association study (PheWAS) conducted in 28,260 unrelated, genotyped patients of recent European ancestry who consented to participate in the Michigan Genomics Initiative, a longitudinal biorepository effort within Michigan Medicine...
June 7, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29774543/human-monocyte-transcriptional-profiling-identifies-il-18-receptor-accessory-protein-and-lactoferrin-as-novel-immune-targets-in-hypertension
#13
Matthew R Alexander, Allison E Norlander, Fernando Elijovich, Ravi V Atreya, Amadou Gaye, Juan S Gnecco, Cheryl L Laffer, Cristi L Galindo, Meena S Madhur
BACKGROUND AND PURPOSE: Monocytes play a critical role in hypertension. The purpose of our study was to use an unbiased approach to determine whether hypertensive individuals on conventional therapy exhibit an altered monocyte gene expression profile and to perform validation studies of selected genes to identify novel therapeutic targets for hypertension. EXPERIMENTAL APPROACH: Next generation RNA sequencing identified differentially expressed genes in a small discovery cohort of normotensive and hypertensive individuals...
May 18, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29771313/evaluating-the-potential-role-of-pleiotropy-in-mendelian-randomization-studies
#14
Gibran Hemani, Jack Bowden, George Davey Smith
Pleiotropy, the phenomenon of a single genetic variant influencing multiple traits, is likely widespread in the human genome. If pleiotropy arises because the single nucleotide polymorphism (SNP) influences one trait, which in turn influences another ('vertical pleiotropy'), then Mendelian randomization (MR) can be used to estimate the causal influence between the traits. Of prime focus among the many limitations to MR is the unprovable assumption that apparent pleiotropic associations are mediated by the exposure (i...
August 1, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29746339/comorbidities-in-childhood-celiac-disease-a-phenome-wide-association-study-using-the-electronic-health-record
#15
Ariana Prinzbach, Soheil Moosavinasab, Steve Rust, Brendan Boyle, John A Barnard, Yungui Huang, Simon Lin
OBJECTIVES: Celiac disease (CD) is associated with a variety of extraintestinal autoimmune and inflammatory findings that manifest clinically as symptoms and comorbidities. Understanding these comorbidities may improve identification of the disease and prevent sequelae. In this study, we use an unbiased electronic health record (EHR)-based Phenome Wide Association Study (PheWAS) method to confirm known comorbidities, discover novel associations and enhance characterization of the clinical presentation of CD in children...
May 9, 2018: Journal of Pediatric Gastroenterology and Nutrition
https://www.readbyqxmd.com/read/29703846/-lpa-variants-are-associated-with-residual-cardiovascular-risk-in-patients-receiving-statins
#16
Wei-Qi Wei, Xiaohui Li, Qiping Feng, Michiaki Kubo, Iftikhar J Kullo, Peggy L Peissig, Elizabeth W Karlson, Gail P Jarvik, Ming Ta Michael Lee, Ning Shang, Eric A Larson, Todd Edwards, Christian Shaffer, Jonathan D Mosley, Shiro Maeda, Momoko Horikoshi, Marylyn Ritchie, Marc S Williams, Eric B Larson, David R Crosslin, Sarah T Bland, Jennifer A Pacheco, Laura J Rasmussen-Torvik, David Cronkite, George Hripcsak, Nancy J Cox, Russell A Wilke, C Michael Stein, Jerome I Rotter, Yukihide Momozawa, Dan M Roden, Ronald M Krauss, Joshua C Denny
Background -Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with HMG-CoA reductase inhibitors (statins) decreases circulating levels of low-density lipoprotein cholesterol (LDL-C) and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. Methods -We performed a two-stage genome-wide association study (GWAS) of CHD events during statin therapy. We first identified 3,099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7,681 controls without CHD events during comparable intensity and duration of statin therapy from four sites in the Electronic Medical Records and Genomics (eMERGE) Network...
April 27, 2018: Circulation
https://www.readbyqxmd.com/read/29691392/medical-relevance-of-protein-truncating-variants-across-337-205-individuals-in-the-uk-biobank-study
#17
Christopher DeBoever, Yosuke Tanigawa, Malene E Lindholm, Greg McInnes, Adam Lavertu, Erik Ingelsson, Chris Chang, Euan A Ashley, Carlos D Bustamante, Mark J Daly, Manuel A Rivas
Protein-truncating variants can have profound effects on gene function and are critical for clinical genome interpretation and generating therapeutic hypotheses, but their relevance to medical phenotypes has not been systematically assessed. Here, we characterize the effect of 18,228 protein-truncating variants across 135 phenotypes from the UK Biobank and find 27 associations between medical phenotypes and protein-truncating variants in genes outside the major histocompatibility complex. We perform phenome-wide analyses and directly measure the effect in homozygous carriers, commonly referred to as "human knockouts," across medical phenotypes for genes implicated as being protective against disease or associated with at least one phenotype in our study...
April 24, 2018: Nature Communications
https://www.readbyqxmd.com/read/29675560/patterns-of-differential-gene-expression-in-a-cellular-model-of-human-islet-development-and-relationship-to-type-2-diabetes-predisposition
#18
Marta Perez-Alcantara, Christian Honoré, Agata Wesolowska-Andersen, Anna L Gloyn, Mark I McCarthy, Mattias Hansson, Nicola L Beer, Martijn van de Bunt
AIMS/HYPOTHESIS: Most type 2 diabetes-associated genetic variants identified via genome-wide association studies (GWASs) appear to act via the pancreatic islet. Observed defects in insulin secretion could result from an impact of these variants on islet development and/or the function of mature islets. Most functional studies have focused on the latter, given limitations regarding access to human fetal islet tissue. Capitalising upon advances in in vitro differentiation, we characterised the transcriptomes of human induced pluripotent stem cell (iPSC) lines differentiated along the pancreatic endocrine lineage, and explored the contribution of altered islet development to the pathogenesis of type 2 diabetes...
July 2018: Diabetologia
https://www.readbyqxmd.com/read/29659871/rare-variants-in-the-gene-alpl-that-cause-hypophosphatasia-are-strongly-associated-with-ovarian-and-uterine-disorders
#19
Kathryn M Dahir, Daniel R Tilden, Jeremy L Warner, Lisa Bastarache, Derek K Smith, Aliya Gifford, Andrea H Ramirez, Jill S Simmons, Margo M Black, John H Newman, Josh C Denny
Context: Mutations in alkaline phosphatase (AlkP), liver/bone/kidney (ALPL), which encodes tissue-nonspecific isozyme AlkP, cause hypophosphatasia (HPP). HPP is suspected by a low-serum AlkP. We hypothesized that some patients with bone or dental disease have undiagnosed HPP, caused by ALPL variants. Objective: Our objective was to discover the prevalence of these gene variants in the Vanderbilt University DNA Biobank (BioVU) and to assess phenotypic associations...
June 1, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29623448/recent-genetics-and-epigenetics-approaches-to-ptsd
#20
REVIEW
Nikolaos P Daskalakis, Chuda M Rijal, Christopher King, Laura M Huckins, Kerry J Ressler
PURPOSE OF REVIEW: Following a life-threatening traumatic exposure, about 10% of those exposed are at considerable risk for developing posttraumatic stress disorder (PTSD), a severe and disabling syndrome characterized by uncontrollable intrusive memories, nightmares, avoidance behaviors, and hyperarousal in addition to impaired cognition and negative emotion symptoms. This review will explore recent genetic and epigenetic approaches to PTSD that explain some of the differential risk following trauma exposure...
April 5, 2018: Current Psychiatry Reports
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