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phenome-wide association study

Dorothée Diogo, Chao Tian, Christopher S Franklin, Mervi Alanne-Kinnunen, Michael March, Chris C A Spencer, Ciara Vangjeli, Michael E Weale, Hannele Mattsson, Elina Kilpeläinen, Patrick M A Sleiman, Dermot F Reilly, Joshua McElwee, Joseph C Maranville, Arnaub K Chatterjee, Aman Bhandari, Khanh-Dung H Nguyen, Karol Estrada, Mary-Pat Reeve, Janna Hutz, Nan Bing, Sally John, Daniel G MacArthur, Veikko Salomaa, Samuli Ripatti, Hakon Hakonarson, Mark J Daly, Aarno Palotie, David A Hinds, Peter Donnelly, Caroline S Fox, Aaron G Day-Williams, Robert M Plenge, Heiko Runz
Phenome-wide association studies (PheWAS) have been proposed as a possible aid in drug development through elucidating mechanisms of action, identifying alternative indications, or predicting adverse drug events (ADEs). Here, we select 25 single nucleotide polymorphisms (SNPs) linked through genome-wide association studies (GWAS) to 19 candidate drug targets for common disease indications. We interrogate these SNPs by PheWAS in four large cohorts with extensive health information (23andMe, UK Biobank, FINRISK, CHOP) for association with 1683 binary endpoints in up to 697,815 individuals and conduct meta-analyses for 145 mapped disease endpoints...
October 16, 2018: Nature Communications
Linda M Polfus, Laura M Raffield, Marsha M Wheeler, Russell P Tracy, Leslie A Lange, Guillaume Lettre, Amanda Miller, Adolfo Correa, Russell P Bowler, Joshua C Bis, Shabnam Salimi, Nancy Swords Jenny, Nathan Pankratz, Biqi Wang, Michael H Preuss, Lisheng Zhou, Arden Moscati, Girish N Nadkarni, Ruth J F Loos, Xue Zhong, Bingshan Li, Jill M Johnsen, Deborah A Nickerson, Alex P Reiner, Paul L Auer, Nhlbi Trans-Omics For Precision Medicine Consortium
E-selectin mediates the rolling of circulating leukocytes during inflammatory processes. Previous genome-wide association studies (GWAS) in European and Asian individuals have identified the ABO locus associated with E-selectin levels. Using Trans-Omics for Precision Medicine (TOPMed) whole-genome sequencing (WGS) data in 2,249 African Americans (AAs) from the Jackson Heart Study (JHS), we examined genome-wide associations with soluble E-selectin levels. In addition to replicating known signals at ABO, we identified a novel association of a common loss-of-function, missense variant in FUT6 (rs17855739,p...
October 10, 2018: Human Molecular Genetics
Navneet Kumar Dubey, Dina Nur Anggraini Ningrum, Rajni Dubey, Yue-Hua Deng, Yu-Chuan Li, Peter D Wang, Joseph R Wang, Shabbir Syed-Abdul, Win-Ping Deng
Recent years have witnessed an increased prevalence of knee osteoarthritis (KOA) among diabetes mellitus (DM) patients-conditions which might share common risk factors such as obesity and advanced aging. Therefore, we conducted dry-to-wet lab research approaches to assess the correlation of type 1 DM (T1DM) and type 2 DM (T2DM) with KOA among all age and genders of Taiwanese population. The strength of association (odds ratio: OR) was analyzed using a phenome-wide association study portal. Populations of 37,353 T1DM and 1,218,254 T2DM were included...
October 3, 2018: International Journal of Molecular Sciences
Derek Klarin, Scott M Damrauer, Kelly Cho, Yan V Sun, Tanya M Teslovich, Jacqueline Honerlaw, David R Gagnon, Scott L DuVall, Jin Li, Gina M Peloso, Mark Chaffin, Aeron M Small, Jie Huang, Hua Tang, Julie A Lynch, Yuk-Lam Ho, Dajiang J Liu, Connor A Emdin, Alexander H Li, Jennifer E Huffman, Jennifer S Lee, Pradeep Natarajan, Rajiv Chowdhury, Danish Saleheen, Marijana Vujkovic, Aris Baras, Saiju Pyarajan, Emanuele Di Angelantonio, Benjamin M Neale, Aliya Naheed, Amit V Khera, John Danesh, Kyong-Mi Chang, Gonçalo Abecasis, Cristen Willer, Frederick E Dewey, David J Carey, John Concato, J Michael Gaziano, Christopher J O'Donnell, Philip S Tsao, Sekar Kathiresan, Daniel J Rader, Peter W F Wilson, Themistocles L Assimes
The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n > 600,000)...
October 1, 2018: Nature Genetics
Rachel F Fordyce, Nicole E Soltis, Céline Caseys, Raoni Gwinner, Jason A Corwin, Susanna Atwell, Daniel Copeland, Julie Feusier, Anushriya Subedy, Robert Eshbaugh, Daniel J Kliebenstein
Plant resistance to generalist pathogens with broad host ranges, such as Botrytis cinerea, is typically quantitative and highly polygenic. Recent studies have begun to elucidate the molecular genetic basis of plant-pathogen interactions using commonly measured traits, including lesion size and/or pathogen biomass. However, with the advent of digital imaging and high-throughput phenomics, there are a large number of additional traits available to study quantitative resistance. In this study, we used high-throughput digital imaging analysis to investigate previously poorly characterized visual traits of plant-pathogen interactions related to disease resistance using the Arabidopsis/Botrytis pathosystem...
September 28, 2018: Plant Physiology
Jennifer E Spindel, Jeffery Dahlberg, Matthew Colgan, Joy Hollingsworth, Julie Sievert, Scott H Staggenborg, Robert Hutmacher, Christer Jansson, John P Vogel
BACKGROUND: Sorghum bicolor is the fifth most commonly grown cereal worldwide and is remarkable for its drought and abiotic stress tolerance. For these reasons and the large size of biomass varieties, it has been proposed as a bioenergy crop. However, little is known about the genes underlying sorghum's abiotic stress tolerance and biomass yield. RESULTS: To uncover the genetic basis of drought tolerance in sorghum at a genome-wide level, we undertook a high-density phenomics genome wide association study (GWAS) in which 648 diverse sorghum lines were phenotyped at two locations in California once per week by drone over the course of a growing season...
September 17, 2018: BMC Genomics
Seth D Rhoades, Lisa Bastarache, Joshua C Denny, Jacob J Hughey
The electronic health record (EHR) contains rich histories of clinical care, but has not traditionally been mined for information related to sleep habits. Here, we performed a retrospective EHR study based on a cohort of 3,652 individuals with self-reported sleep behaviors documented from visits to the sleep clinic. These individuals were obese (mean body mass index 33.6 kg/m2 ) and had a high prevalence of sleep apnea (60.5%), however we found sleep behaviors largely concordant with prior prospective cohort studies...
September 5, 2018: Chronobiology International
Lillias H Maguire, Samuel K Handelman, Xiaomeng Du, Yanhua Chen, Tune H Pers, Elizabeth K Speliotes
Diverticular disease is common and has a high morbidity. Treatments are limited owing to the poor understanding of its pathophysiology. Here, to elucidate its etiology, we performed a genome-wide association study of diverticular disease (27,444 cases; 382,284 controls) from the UK Biobank and tested for replication in the Michigan Genomics Initiative (2,572 cases; 28,649 controls). We identified 42 loci associated with diverticular disease; 39 of these loci are novel. Using data-driven expression-prioritized integration for complex traits (DEPICT), we show that genes in these associated regions are significantly enriched for expression in mesenchymal stem cells and multiple connective tissue cell types and are co-expressed with genes that have a role in vascular and mesenchymal biology...
October 2018: Nature Genetics
Jie Zheng, Tom G Richardson, Louise A C Millard, Gibran Hemani, Benjamin L Elsworth, Christopher A Raistrick, Bjarni Vilhjalmsson, Benjamin M Neale, Philip C Haycock, George Davey Smith, Tom R Gaunt
Background: Identifying phenotypic correlations between complex traits and diseases can provide useful etiological insights. Restricted access to much individual-level phenotype data makes it difficult to estimate large-scale phenotypic correlation across the human phenome. Two state-of-the-art methods, metaCCA and LD score regression, provide an alternative approach to estimate phenotypic correlation using only genome-wide association study (GWAS) summary results. Results: Here, we present an integrated R toolkit, PhenoSpD, to use LD score regression to estimate phenotypic correlations using GWAS summary statistics and to utilize the estimated phenotypic correlations to inform correction of multiple testing for complex human traits using the spectral decomposition of matrices (SpD)...
August 1, 2018: GigaScience
QiPing Feng, Wei-Qi Wei, Cecilia P Chung, Rebecca T Levinson, Alexandra C Sundermann, Jonathan D Mosley, Lisa Bastarache, Jane F Ferguson, Nancy J Cox, Dan M Roden, Joshua C Denny, MacRae F Linton, Digna R Velez Edwards, C Michael Stein
BACKGROUND: Observations from statin clinical trials and from Mendelian randomization studies suggest that low low-density lipoprotein cholesterol (LDL-C) concentrations may be associated with increased risk of type 2 diabetes mellitus (T2DM). Despite the findings from statin clinical trials and genetic studies, there is little direct evidence implicating low LDL-C concentrations in increased risk of T2DM. METHODS AND FINDINGS: We used de-identified electronic health records (EHRs) at Vanderbilt University Medical Center to compare the risk of T2DM in a cross-sectional study among individuals with very low (≤60 mg/dl, N = 8,943) and normal (90-130 mg/dl, N = 71,343) LDL-C levels calculated using the Friedewald formula...
August 2018: PLoS Medicine
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
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
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
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
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
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
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
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
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
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...
May 30, 2018: ELife
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