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Brooke N Wolford, Cristen J Willer, Ida Surakka
The combination of Electronic Health Records (EHRs) with genetic data has ushered in the next wave of complex disease genetics. Population-based biobanks and other large cohorts provide sufficient sample sizes to identify novel genetic associations across the hundreds to thousands of phenotypes gleaned from EHRs. In this review we summarize the current state of these EHR-linked biobanks, explore ongoing methods development in the field, and highlight recent discoveries of genetic associations. We enumerate the many existing biobanks with EHRs linked to genetic data, many of which are available to researchers via application and contain sample sizes > 50,000...
March 14, 2018: Human Molecular Genetics
Anurag Verma, Marylyn D Ritchie
Purpose of Review: Over many decades, researchers have been designing studies to investigate the relationship between genotypes and phenotypes to gain an understanding about the effect of genetics on disease. Recently, a high-throughput approach called phenome-wide associations studies (PheWAS) have been extensively used to identify associations between genetic variants and many diseases and traits simultaneously. In this review, we describe the value of PheWAS along with methodological issues and challenges in interpretation for current applications of PheWAS...
December 2017: Current Epidemiology Reports
Shefali Setia Verma, Navya Josyula, Anurag Verma, Xinyuan Zhang, Yogasudha Veturi, Frederick E Dewey, Dustin N Hartzel, Daniel R Lavage, Joe Leader, Marylyn D Ritchie, Sarah A Pendergrass
The DrugBank database consists of ~800 genes that are well characterized drug targets. This list of genes is a useful resource for association testing. For example, loss of function (LOF) genetic variation has the potential to mimic the effect of drugs, and high impact variation in these genes can impact downstream traits. Identifying novel associations between genetic variation in these genes and a range of diseases can also uncover new uses for the drugs that target these genes. Phenome Wide Association Studies (PheWAS) have been successful in identifying genetic associations across hundreds of thousands of diseases...
March 15, 2018: Scientific Reports
April Barnado, Robert J Carroll, Carolyn Casey, Lee Wheless, Joshua C Denny, Leslie J Crofford
OBJECTIVE: Phenome-wide association studies (PheWAS) scan across billing codes in the electronic health record (EHR) and re-purpose clinical EHR data for research. We examined if PheWAS could function as an EHR discovery tool for SLE and uncover novel clinical associations in male versus female SLE patients. METHODS: We used a de-identified version of the Vanderbilt University Medical Center EHR with over 2.8 million subjects. We performed PheWAS comparing 1) SLE cases vs...
February 26, 2018: Arthritis Care & Research
Xue Li, Xiangrui Meng, Athina Spiliopoulou, Maria Timofeeva, Wei-Qi Wei, Aliya Gifford, Xia Shen, Yazhou He, Tim Varley, Paul McKeigue, Ioanna Tzoulaki, Alan F Wright, Peter Joshi, Joshua C Denny, Harry Campbell, Evropi Theodoratou
OBJECTIVES: We aimed to investigate the role of serum uric acid (SUA) level in a broad spectrum of disease outcomes using data for 120 091 individuals from UK Biobank. METHODS: We performed a phenome-wide association study (PheWAS) to identify disease outcomes associated with SUA genetic risk loci. We then implemented conventional Mendelian randomisation (MR) analysis to investigate the causal relevance between SUA level and disease outcomes identified from PheWAS...
February 6, 2018: Annals of the Rheumatic Diseases
Junfei Zhao, Feixiong Cheng, Peilin Jia, Nancy Cox, Joshua C Denny, Zhongming Zhao
BACKGROUND: Genome-phenome studies have identified thousands of variants that are statistically associated with disease or traits; however, their functional roles are largely unclear. A comprehensive investigation of regulatory mechanisms and the gene regulatory networks between phenome-wide association study (PheWAS) and genome-wide association study (GWAS) is needed to identify novel regulatory variants contributing to risk for human diseases. METHODS: In this study, we developed an integrative functional genomics framework that maps 215,107 significant single nucleotide polymorphism (SNP) traits generated from the PheWAS Catalog and 28,870 genome-wide significant SNP traits collected from the GWAS Catalog into a global human genome regulatory map via incorporating various functional annotation data, including transcription factor (TF)-based motifs, promoters, enhancers, and expression quantitative trait loci (eQTLs) generated from four major functional genomics databases: FANTOM5, ENCODE, NIH Roadmap, and Genotype-Tissue Expression (GTEx)...
January 29, 2018: Genome Medicine
A Mesut Erzurumluoglu, Denis Baird, Tom G Richardson, Nicholas J Timpson, Santiago Rodriguez
Y-chromosomal (Y-DNA) haplogroups are more widely used in population genetics than in genetic epidemiology, although associations between Y-DNA haplogroups and several traits, including cardiometabolic traits, have been reported. In apparently homogeneous populations defined by principal component analyses, there is still Y-DNA haplogroup variation which will result from population history. Therefore, hidden stratification and/or differential phenotypic effects by Y-DNA haplogroups could exist. To test this, we hypothesised that stratifying individuals according to their Y-DNA haplogroups before testing for associations between autosomal single nucleotide polymorphisms (SNPs) and phenotypes will yield difference in association...
January 22, 2018: Genes
Bhavisha Patel, Chung-Il Wi, M Earth Hasassri, Rohit Divekar, Imad Absah, Eyad Almallouhi, Euijung Ryu, Katherine King, Young J Juhn
BACKGROUND: Although human leukocyte antigen (HLA)-DR and HLA-DQ genes and gluten play crucial roles in developing celiac disease (CD), most patients with these risk factors still do not develop CD, which indicates additional unrecognized risk factors. OBJECTIVE: To determine the association between asthma and the risk of CD in children. METHODS: We conducted a population-based retrospective case-control study in children who resided in Olmsted County, Minnesota...
January 1, 2018: Allergy and Asthma Proceedings:
Rebecca N Jerome, Jill M Pulley, Dan M Roden, Jana K Shirey-Rice, Lisa A Bastarache, Gordon R Bernard, Leeland B Ekstrom, William J Lancaster, Joshua C Denny
INTRODUCTION: When a new drug enters the market, its full array of side effects remains to be defined. Current surveillance approaches targeting these effects remain largely reactive. There is a need for development of methods to predict specific safety events that should be sought for a given new drug during development and postmarketing activities. OBJECTIVE: We present here a safety signal identification approach applied to a new set of drug entities, inhibitors of the serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9)...
March 2018: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
Yannick Girardeau, Anne-Sophie Jannot, Gilles Chatellier, Olivier Saint-Jean
BACKGROUND: Even small variations of serum sodium concentration may be associated with mortality. Our objective was to confirm the impact of borderline dysnatremia for patients admitted to hospital on in-hospital mortality using real life care data from our electronic health record (EHR) and a phenome-wide association analysis (PheWAS). METHODS: Retrospective observational study based on patient data admitted to Hôpital Européen George Pompidou, between 01/01/2008 and 31/06/2014; including 45,834 patients with serum sodium determinations on admission...
November 22, 2017: BMC Medical Informatics and Decision Making
Lu Wang, Scott M Damrauer, Hong Zhang, Alan X Zhang, Rui Xiao, Jason H Moore, Jinbo Chen
The linkage between electronic health records (EHRs) and genotype data makes it plausible to study the genetic susceptibility of a wide range of disease phenotypes. Despite that EHR-derived phenotype data are subjected to misclassification, it has been shown useful for discovering susceptible genes, particularly in the setting of phenome-wide association studies (PheWAS). It is essential to characterize discovered associations using gold standard phenotype data by chart review. In this work, we propose a genotype stratified case-control sampling strategy to select subjects for phenotype validation...
October 11, 2017: Genetic Epidemiology
Jixia Liu, Ran Zhao, Zhan Ye, Alexander J Frey, Emily R Schriver, Nathaniel W Snyder, Scott J Hebbring
Human cytosolic sulfotransferase 1A1 (SULT1A1) is considered to be one of the most important SULT isoforms for metabolism, detoxification, and carcinogenesis. This theory is driven by observations that SULT1A1 is widely expressed in multiple tissues and acts on a wide range of phenolic substrates. SULT1A1 is subject to functional common copy number variation (CNV) including deletions or duplications. However, it is less clear how SULT1A1 CNV impacts health and disease. To better understand the biological role of SULT1A1 in human health, we genotyped CNV in 14,275 Marshfield Clinic patients linked to an extensive electronic health record...
November 2017: Journal of Steroid Biochemistry and Molecular Biology
Shikha Chaganti, Kunal P Nabar, Katrina M Nelson, Louise A Mawn, Bennett A Landman
We examine imaging and electronic medical records (EMR) of 588 subjects over five major disease groups that affect optic nerve function. An objective evaluation of the role of imaging and EMR data in diagnosis of these conditions would improve understanding of these diseases and help in early intervention. We developed an automated image-processing pipeline that identifies the orbital structures within the human eyes from computed tomography (CT) scans, calculates structural size, and performs volume measurements...
February 11, 2017: Proceedings of SPIE
Amrie C Grammer, Peter E Lipsky
Rheumatic Autoimmune Inflammatory Diseases such as Sjögren's and lupus lack modern treatments. Less than 5% of drugs approved by the FDA from 2014 to mid-2016 had a RAID indication. Many RAID standard-of-care drugs were repurposed based on serendipitous observations, similarity-of-disease categorization, and/or off-target effects. Recently, drug repurposing has become more intentional, relying on an evolving awareness of molecular underpinnings, as well as a better understanding of drug-target interactions by computational modeling...
August 2017: Rheumatic Diseases Clinics of North America
Wei-Qi Wei, Lisa A Bastarache, Robert J Carroll, Joy E Marlo, Travis J Osterman, Eric R Gamazon, Nancy J Cox, Dan M Roden, Joshua C Denny
OBJECTIVE: To compare three groupings of Electronic Health Record (EHR) billing codes for their ability to represent clinically meaningful phenotypes and to replicate known genetic associations. The three tested coding systems were the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, the Agency for Healthcare Research and Quality Clinical Classification Software for ICD-9-CM (CCS), and manually curated "phecodes" designed to facilitate phenome-wide association studies (PheWAS) in EHRs...
2017: PloS One
Rounak Dey, Ellen M Schmidt, Goncalo R Abecasis, Seunggeun Lee
The availability of electronic health record (EHR)-based phenotypes allows for genome-wide association analyses in thousands of traits and has great potential to enable identification of genetic variants associated with clinical phenotypes. We can interpret the phenome-wide association study (PheWAS) result for a single genetic variant by observing its association across a landscape of phenotypes. Because a PheWAS can test thousands of binary phenotypes, and most of them have unbalanced or often extremely unbalanced case-control ratios (1:10 or 1:600, respectively), existing methods cannot provide an accurate and scalable way to test for associations...
July 6, 2017: American Journal of Human Genetics
Jordan W Smoller
The widespread adoption of electronic health record (EHRs) in healthcare systems has created a vast and continuously growing resource of clinical data and provides new opportunities for population-based research. In particular, the linking of EHRs to biospecimens and genomic data in biobanks may help address what has become a rate-limiting study for genetic research: the need for large sample sizes. The principal roadblock to capitalizing on these resources is the need to establish the validity of phenotypes extracted from the EHR...
May 30, 2017: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Anne-Sophie Jannot, Anita Burgun, Eric Thervet, Nicolas Pallet
BACKGROUND AND OBJECTIVES: The exploration of electronic hospital records offers a unique opportunity to describe in-depth the prevalence of conditions associated with diagnoses at an unprecedented level of comprehensiveness. We used a diagnosis-wide approach, adapted from phenome-wide association studies (PheWAS), to perform an exhaustive analysis of all diagnoses associated with hospital-acquired AKI (HA-AKI) in a French urban tertiary academic hospital over a period of 10 years. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We retrospectively extracted all diagnoses from an i2b2 (Informatics for Integrating Biology and the Bedside) clinical data warehouse for patients who stayed in this hospital between 2006 and 2015 and had at least two plasma creatinine measurements performed during the first week of their stay...
June 7, 2017: Clinical Journal of the American Society of Nephrology: CJASN
Jamie R Robinson, Vanessa E Kennedy, Youssef Doss, Lisa Bastarache, Joshua Denny, Jeremy L Warner
OBJECTIVE: Systemic loxoscelism is a rare illness resulting from the bite of the recluse spider and, in its most severe form, can lead to widespread hemolysis, coagulopathy, and death. We aim to describe the clinical features and outcomes of the largest known cohort of individuals with moderate to severe loxoscelism. METHODS: We performed a retrospective, cross sectional study from January 1, 1995, to December 31, 2015, at a tertiary-care academic medical center, to determine individuals with clinical records consistent with moderate to severe loxoscelism...
2017: PloS One
Dan M Roden
In experimental physiological research, a common study design for examining the functional role of a gene or a genetic variant is to introduce that genetic variant into a model organism (such as yeast or mouse) and then to search for phenotypic consequences. The development of DNA biobanks linked to dense phenotypic information enables such an experiment to be applied to human subjects in the form of a phenome-wide association study (PheWAS). The PheWAS paradigm takes advantage of a curated medical phenome, often derived from electronic health records, to search for associations between 'input functions' and phenotypes in an unbiased fashion...
June 15, 2017: Journal of Physiology
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