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phenome-wide association study

J Dylan Weissenkampen, Yu Jiang, Scott Eckert, Bibo Jiang, Bingshan Li, Dajiang J Liu
With the advent of Next Generation Sequencing (NGS) technologies, whole genome and whole exome DNA sequencing has become affordable for routine genetic studies. Coupled with improved genotyping arrays and genotype imputation methodologies, it is increasingly feasible to obtain rare genetic variant information in large datasets. Such datasets allow researchers to gain a more complete understanding of the genetic architecture of complex traits caused by rare variants. State-of-the-art statistical methods for the statistical genetics analysis of sequence-based association, including efficient algorithms for association analysis in biobank-scale datasets, gene-association tests, meta-analysis, fine mapping methods that integrate functional genomic dataset, and phenome-wide association studies (PheWAS), are reviewed here...
March 8, 2019: Current Protocols in Human Genetics
Nick Shrine, Anna L Guyatt, A Mesut Erzurumluoglu, Victoria E Jackson, Brian D Hobbs, Carl A Melbourne, Chiara Batini, Katherine A Fawcett, Kijoung Song, Phuwanat Sakornsakolpat, Xingnan Li, Ruth Boxall, Nicola F Reeve, Ma'en Obeidat, Jing Hua Zhao, Matthias Wielscher, Stefan Weiss, Katherine A Kentistou, James P Cook, Benjamin B Sun, Jian Zhou, Jennie Hui, Stefan Karrasch, Medea Imboden, Sarah E Harris, Jonathan Marten, Stefan Enroth, Shona M Kerr, Ida Surakka, Veronique Vitart, Terho Lehtimäki, Richard J Allen, Per S Bakke, Terri H Beaty, Eugene R Bleecker, Yohan Bossé, Corry-Anke Brandsma, Zhengming Chen, James D Crapo, John Danesh, Dawn L DeMeo, Frank Dudbridge, Ralf Ewert, Christian Gieger, Amund Gulsvik, Anna L Hansell, Ke Hao, Joshua D Hoffman, John E Hokanson, Georg Homuth, Peter K Joshi, Philippe Joubert, Claudia Langenberg, Xuan Li, Liming Li, Kuang Lin, Lars Lind, Nicholas Locantore, Jian'an Luan, Anubha Mahajan, Joseph C Maranville, Alison Murray, David C Nickle, Richard Packer, Margaret M Parker, Megan L Paynton, David J Porteous, Dmitry Prokopenko, Dandi Qiao, Rajesh Rawal, Heiko Runz, Ian Sayers, Don D Sin, Blair H Smith, María Soler Artigas, David Sparrow, Ruth Tal-Singer, Paul R H J Timmers, Maarten Van den Berge, John C Whittaker, Prescott G Woodruff, Laura M Yerges-Armstrong, Olga G Troyanskaya, Olli T Raitakari, Mika Kähönen, Ozren Polašek, Ulf Gyllensten, Igor Rudan, Ian J Deary, Nicole M Probst-Hensch, Holger Schulz, Alan L James, James F Wilson, Beate Stubbe, Eleftheria Zeggini, Marjo-Riitta Jarvelin, Nick Wareham, Edwin K Silverman, Caroline Hayward, Andrew P Morris, Adam S Butterworth, Robert A Scott, Robin G Walters, Deborah A Meyers, Michael H Cho, David P Strachan, Ian P Hall, Martin D Tobin, Louise V Wain
Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants...
March 2019: Nature Genetics
Rounak Dey, Jonas B Nielsen, Lars G Fritsche, Wei Zhou, Huanhuan Zhu, Cristen J Willer, Seunggeun Lee
With the availability of large-scale biobanks, genome-wide scale phenome-wide association studies are being instrumental in discovering novel genetic variants associated with clinical phenotypes. As increasing number of such association results from different biobanks become available, methods to meta-analyse those association results is of great interest. Because the binary phenotypes in biobank-based studies are mostly unbalanced in their case-control ratios, very few methods can provide well-calibrated tests for associations...
February 22, 2019: Genetic Epidemiology
William Pitchers, Jessica Nye, Eladio J Márquez, Alycia Kowalski, Ian Dworkin, David Houle
Due to the complexity of genotype-phenotype relationships, simultaneous analyses of genomic associations with multiple traits will be more powerful and informative than a series of univariate analyses. In most cases, however, studies of genotype-phenotype relationships have been analyzed only one trait at a time. Here, we report the results of a fully integrated multivariate genome-wide association analysis of the shape of the Drosophila melanogaster wing in the Drosophila Genetic Reference Panel. Genotypic effects on wing shape were highly correlated between two different labs...
February 21, 2019: Genetics
Jacob E Choby, Andrew J Monteith, Lauren E Himmel, Paris Margaritis, Jana K Shirey-Rice, Andrea Pruijssers, Rebecca N Jerome, Jill Pulley, Eric P Skaar
Coagulation and inflammation are interconnected, suggesting coagulation plays a key role in the inflammatory response to pathogens. A Phenome-Wide Association Study (PheWAS) was used to identify clinical phenotypes of patients with a polymorphism in coagulation Factor X. Patients with this SNP were more likely to be hospitalized with hemostatic and infection-related disorders, suggesting Factor X contributes to the immune response to infection. To investigate this, we modeled infections by human pathogens in a mouse model of Factor X deficiency...
February 19, 2019: Infection and Immunity
Maya S Safarova, Benjamin A Satterfield, Xiao Fan, Erin E Austin, Zhan Ye, Lisa Bastarache, Neil Zheng, Marylyn D Ritchie, Kenneth M Borthwick, Marc S Williams, Eric B Larson, Aaron Scrol, Gail P Jarvik, David R Crosslin, Kathleen Leppig, Laura J Rasmussen-Torvik, Sarah A Pendergrass, Amy C Sturm, Bahram Namjou, Amy Sanghavi Shah, Robert J Carroll, Wendy K Chung, Wei-Qi Wei, QiPing Feng, C Michael Stein, Dan M Roden, Teri A Manolio, Daniel J Schaid, Joshua C Denny, Scott J Hebbring, Mariza de Andrade, Iftikhar J Kullo
We conducted an electronic health record (EHR)-based phenome-wide association study (PheWAS) to discover pleiotropic effects of variants in three lipoprotein metabolism genes PCSK9 , APOB , and LDLR . Using high-density genotype data, we tested the associations of variants in the three genes with 1232 EHR-derived binary phecodes in 51,700 European-ancestry (EA) individuals and 585 phecodes in 10,276 African-ancestry (AA) individuals; 457 PCSK9 , 730 APOB , and 720 LDLR variants were filtered by imputation quality ( r 2  > 0...
2019: NPJ Genomic Medicine
Juan Zhao, QiPing Feng, Patrick Wu, Jeremy L Warner, Joshua C Denny, Wei-Qi Wei
Genome-wide and phenome-wide association studies are commonly used to identify important relationships between genetic variants and phenotypes. Most studies have treated diseases as independent variables and suffered from the burden of multiple adjustment due to the large number of genetic variants and disease phenotypes. In this study, we used topic modeling via non-negative matrix factorization (NMF) for identifying associations between disease phenotypes and genetic variants. Topic modeling is an unsupervised machine learning approach that can be used to learn patterns from electronic health record data...
2019: PloS One
Louise A C Millard, Neil M Davies, Kate Tilling, Tom R Gaunt, George Davey Smith
Mendelian randomization (MR) has been used to estimate the causal effect of body mass index (BMI) on particular traits thought to be affected by BMI. However, BMI may also be a modifiable, causal risk factor for outcomes where there is no prior reason to suggest that a causal effect exists. We performed a MR phenome-wide association study (MR-pheWAS) to search for the causal effects of BMI in UK Biobank (n = 334 968), using the PHESANT open-source phenome scan tool. A subset of identified associations were followed up with a formal two-stage instrumental variable analysis in UK Biobank, to estimate the causal effect of BMI on these phenotypes...
February 1, 2019: PLoS Genetics
Jun Hirata, Kazuyoshi Hosomichi, Saori Sakaue, Masahiro Kanai, Hirofumi Nakaoka, Kazuyoshi Ishigaki, Ken Suzuki, Masato Akiyama, Toshihiro Kishikawa, Kotaro Ogawa, Tatsuo Masuda, Kenichi Yamamoto, Makoto Hirata, Koichi Matsuda, Yukihide Momozawa, Ituro Inoue, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada
To perform detailed fine-mapping of the major-histocompatibility-complex region, we conducted next-generation sequencing (NGS)-based typing of the 33 human leukocyte antigen (HLA) genes in 1,120 individuals of Japanese ancestry, providing a high-resolution allele catalog and linkage-disequilibrium structure of both classical and nonclassical HLA genes. Together with population-specific deep-whole-genome-sequencing data (n = 1,276), we conducted NGS-based HLA, single-nucleotide-variant and indel imputation of large-scale genome-wide-association-study data from 166,190 Japanese individuals...
January 28, 2019: Nature Genetics
Joe-Elie Salem, M Benjamin Shoemaker, Lisa Bastarache, Christian M Shaffer, Andrew M Glazer, Brett Kroncke, Quinn S Wells, Mingjian Shi, Peter Straub, Gail P Jarvik, Eric B Larson, Digna R Velez Edwards, Todd L Edwards, Lea K Davis, Hakon Hakonarson, Chunhua Weng, David Fasel, Bjorn C Knollmann, Thomas J Wang, Joshua C Denny, Patrick T Ellinor, Dan M Roden, Jonathan D Mosley
Importance: Thyroid hormone levels are tightly regulated through feedback inhibition by thyrotropin, produced by the pituitary gland. Hyperthyroidism is overwhelmingly due to thyroid disorders and is well recognized to contribute to a wide spectrum of cardiovascular morbidity, particularly the increasingly common arrhythmia atrial fibrillation (AF). Objective: To determine the association between genetically determined thyrotropin levels and AF. Design, Setting, and Participants: This phenome-wide association study scanned 1318 phenotypes associated with a polygenic predictor of thyrotropin levels identified by a previously published genome-wide association study that included participants of European ancestry...
January 23, 2019: JAMA Cardiology
Xinyuan Zhang, Anna O Basile, Sarah A Pendergrass, Marylyn D Ritchie
BACKGROUND: The development of sequencing techniques and statistical methods provides great opportunities for identifying the impact of rare genetic variation on complex traits. However, there is a lack of knowledge on the impact of sample size, case numbers, the balance of cases vs controls for both burden and dispersion based rare variant association methods. For example, Phenome-Wide Association Studies may have a wide range of case and control sample sizes across hundreds of diagnoses and traits, and with the application of statistical methods to rare variants, it is important to understand the strengths and limitations of the analyses...
January 22, 2019: BMC Bioinformatics
Ángel Ferrero-Serrano, Sarah M Assmann
The environment imposes critical selective forces on all living organisms, and the sessile nature of plants makes them particularly useful for investigating the relationship between genetic variation and environmental adaptation. In the model plant Arabidopsis thaliana, extensive information on phenotypic and genotypic variation is available, but comparable information on environmental variation within the native range of the species is lacking. Here, we compile 204 geoclimatic variables to describe the local environments of Arabidopsis accessions with known collection sites encompassing a wide geo-environmental range, and fully sequenced genomes from the 1001 Genomes Project...
January 14, 2019: Nature Ecology & Evolution
Alisdair R Fernie, Jose Gutierrez-Marcos
No abstract text is available yet for this article.
January 2019: Plant Journal: for Cell and Molecular Biology
Timothy E Thayer, Shi Huang, Rebecca T Levinson, Eric Farber-Eger, Tufik R Assad, Jessica H Huston, Jonathan D Mosley, Quinn S Wells, Evan L Brittain
RATIONALE: Red cell distribution width (RDW) is a prognostic factor in many diseases, however, its clinical utility remains limited because the relative value of RDW as a biomarker across disease states has not been established. OBJECTIVES: To establish an unbiased RDW-disease hierarchy to guide the clinical use of RDW and to assess its relationship to cardiovascular hemodynamic and structural parameters. METHODS: We performed phenome-wide association studies for RDW in discovery and replication cohorts derived from a de-identified electronic health record in non-anemic individuals...
January 4, 2019: Annals of the American Thoracic Society
Shikha Chaganti, Louise A Mawn, Hakmook Kang, Josephine Egan, Susan M Resnick, Lori L Beason-Held, Bennett A Landman, Thomas Lasko
Composite models that combine medical imaging with electronic medical records (EMR) improve predictive power when compared to traditional models that use imaging alone. The digitization of EMR provides potential access to a wealth of medical information, but presents new challenges in algorithm design and inference. Previous studies, such as PheWAS (Phenome Wide Association Study), have shown that EMR data can be used to investigate the relationship between genotypes and clinical conditions. Here, we introduce PheDAS (Phenome-Disease Association Study) to extend the statistical capabilities of the PheWAS software through a custom python package which creates diagnostic EMR signatures to capture system-wide co-morbidities for a disease population within a given time interval...
December 28, 2018: IEEE Journal of Biomedical and Health Informatics
Anurag Verma, Lisa Bang, Jason E Miller, Yanfei Zhang, Ming Ta Michael Lee, Yu Zhang, Marta Byrska-Bishop, David J Carey, Marylyn D Ritchie, Sarah A Pendergrass, Dokyoon Kim
Phenome-wide association studies (PheWASs) have been a useful tool for testing associations between genetic variations and multiple complex traits or diagnoses. Linking PheWAS-based associations between phenotypes and a variant or a genomic region into a network provides a new way to investigate cross-phenotype associations, and it might broaden the understanding of genetic architecture that exists between diagnoses, genes, and pleiotropy. We created a network of associations from one of the largest PheWASs on electronic health record (EHR)-derived phenotypes across 38,682 unrelated samples from the Geisinger's biobank; the samples were genotyped through the DiscovEHR project...
December 13, 2018: American Journal of Human Genetics
Ayush Giri, Jacklyn N Hellwege, Jacob M Keaton, Jihwan Park, Chengxiang Qiu, Helen R Warren, Eric S Torstenson, Csaba P Kovesdy, Yan V Sun, Otis D Wilson, Cassianne Robinson-Cohen, Christianne L Roumie, Cecilia P Chung, Kelly A Birdwell, Scott M Damrauer, Scott L DuVall, Derek Klarin, Kelly Cho, Yu Wang, Evangelos Evangelou, Claudia P Cabrera, Louise V Wain, Rojesh Shrestha, Brian S Mautz, Elvis A Akwo, Muralidharan Sargurupremraj, Stéphanie Debette, Michael Boehnke, Laura J Scott, Jian'an Luan, Jing-Hua Zhao, Sara M Willems, Sébastien Thériault, Nabi Shah, Christopher Oldmeadow, Peter Almgren, Ruifang Li-Gao, Niek Verweij, Thibaud S Boutin, Massimo Mangino, Ioanna Ntalla, Elena Feofanova, Praveen Surendran, James P Cook, Savita Karthikeyan, Najim Lahrouchi, Chunyu Liu, Nuno Sepúlveda, Tom G Richardson, Aldi Kraja, Philippe Amouyel, Martin Farrall, Neil R Poulter, Markku Laakso, Eleftheria Zeggini, Peter Sever, Robert A Scott, Claudia Langenberg, Nicholas J Wareham, David Conen, Colin Neil Alexander Palmer, John Attia, Daniel I Chasman, Paul M Ridker, Olle Melander, Dennis Owen Mook-Kanamori, Pim van der Harst, Francesco Cucca, David Schlessinger, Caroline Hayward, Tim D Spector, Marjo-Riitta Jarvelin, Branwen J Hennig, Nicholas J Timpson, Wei-Qi Wei, Joshua C Smith, Yaomin Xu, Michael E Matheny, Edward E Siew, Cecilia Lindgren, Karl-Heinz Herzig, George Dedoussis, Joshua C Denny, Bruce M Psaty, Joanna M M Howson, Patricia B Munroe, Christopher Newton-Cheh, Mark J Caulfield, Paul Elliott, J Michael Gaziano, John Concato, Peter W F Wilson, Philip S Tsao, Digna R Velez Edwards, Katalin Susztak, Christopher J O'Donnell, Adriana M Hung, Todd L Edwards
In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells...
January 2019: Nature Genetics
Arthur Gilly, Lorraine Southam, Daniel Suveges, Karoline Kuchenbaecker, Rachel Moore, Giorgio E M Melloni, Konstantinos Hatzikotoulas, Aliki-Eleni Farmaki, Graham Ritchie, Jeremy Schwartzentruber, Petr Danecek, Britt Kilian, Martin O Pollard, Xiangyu Ge, Emmanouil Tsafantakis, George Dedoussis, Eleftheria Zeggini
Motivation: Very low depth sequencing has been proposed as a cost-effective approach to capture low-frequency and rare variation in complex trait association studies. However, a full characterisation of the genotype quality and association power for very low depth sequencing designs is still lacking. Results: We perform cohort-wide whole genome sequencing (WGS) at low depth in 1,239 individuals (990 at 1x depth and 249 at 4x depth) from an isolated population, and establish a robust pipeline for calling and imputing very low depth WGS genotypes from standard bioinformatics tools...
December 21, 2018: Bioinformatics
Bo-Min Lv, Xin-Yu Tong, Yuan Quan, Meng-Yuan Liu, Qing-Ye Zhang, Yun-Feng Song, Hong-Yu Zhang
Japanese encephalitis is a zoonotic disease caused by the Japanese encephalitis virus (JEV). It is mainly epidemic in Asia with an estimated 69,000 cases occurring per year. However, no approved agents are available for the treatment of JEV infection, and existing vaccines cannot control various types of JEV strains. Drug repurposing is a new concept for finding new indication of existing drugs, and, recently, the concept has been used to discover new antiviral agents. Identifying host proteins involved in the progress of JEV infection and using these proteins as targets are the center of drug repurposing for JEV infection...
December 18, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Oliver Tills, John I Spicer, Andrew Grimmer, Simone Marini, Vun Wen Jie, Ellen Tully, Simon D Rundle
Phenomics has the potential to facilitate significant advances in biology but requires the development of high-throughput technologies capable of generating and analysing high-dimensional data. There are significant challenges associated with building such technologies, not least those required for investigating dynamic processes such as embryonic development, during which high rates of temporal, spatial, and functional change are inherently difficult to capture. Here, we present EmbryoPhenomics, an accessible high-throughput platform for phenomics in aquatic embryos comprising an Open-source Video Microscope (OpenVIM) that produces high-resolution videos of multiple embryos under tightly controlled environmental conditions...
December 2018: PLoS Biology
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