title: Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eosinophilic Esophagitis.
abstract: OBJECTIVE
  We report the first pediatric specific Phenome-Wide Association Study (PheWAS) using electronic medical records (EMRs). Given the early success of PheWAS in adult populations, we investigated the feasibility of this approach in pediatric cohorts in which associations between a previously known genetic variant and a wide range of clinical or physiological traits were evaluated. Although computationally intensive, this approach has potential to reveal disease mechanistic relationships between a variant and a network of phenotypes.
  
  
  METHODS
  Data on 5049 samples of European ancestry were obtained from the EMRs of two large academic centers in five different genotyped cohorts. Recently, these samples have undergone whole genome imputation. After standard quality controls, removing missing data and outliers based on principal components analyses (PCA), 4268 samples were used for the PheWAS study. We scanned for associations between 2476 single-nucleotide polymorphisms (SNP) with available genotyping data from previously published GWAS studies and 539 EMR-derived phenotypes. The false discovery rate was calculated and, for any new PheWAS findings, a permutation approach (with up to 1,000,000 trials) was implemented.
  
  
  RESULTS
  This PheWAS found a variety of common variants (MAF > 10%) with prior GWAS associations in our pediatric cohorts including Juvenile Rheumatoid Arthritis (JRA), Asthma, Autism and Pervasive Developmental Disorder (PDD) and Type 1 Diabetes with a false discovery rate < 0.05 and power of study above 80%. In addition, several new PheWAS findings were identified including a cluster of association near the NDFIP1 gene for mental retardation (best SNP rs10057309, p = 4.33 × 10(-7), OR = 1.70, 95%CI = 1.38 - 2.09); association near PLCL1 gene for developmental delays and speech disorder [best SNP rs1595825, p = 1.13 × 10(-8), OR = 0.65(0.57 - 0.76)]; a cluster of associations in the IL5-IL13 region with Eosinophilic Esophagitis (EoE) [best at rs12653750, p = 3.03 × 10(-9), OR = 1.73 95%CI = (1.44 - 2.07)], previously implicated in asthma, allergy, and eosinophilia; and association of variants in GCKR and JAZF1 with allergic rhinitis in our pediatric cohorts [best SNP rs780093, p = 2.18 × 10(-5), OR = 1.39, 95%CI = (1.19 - 1.61)], previously demonstrated in metabolic disease and diabetes in adults.
  
  
  CONCLUSIONS
  The PheWAS approach with re-mapping ICD-9 structured codes for our European-origin pediatric cohorts, as with the previous adult studies, finds many previously reported associations as well as presents the discovery of associations with potentially important clinical implications.
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA ; College of Medicine, University of Cincinnati Cincinnati, OH, USA.
authors.forename: Bahram
authors.initials: B
authors.lastname: Namjou
authors.affiliation: College of Medicine, University of Cincinnati Cincinnati, OH, USA ; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Marsolo
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine Nashville, TN, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Caroll
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine Nashville, TN, USA ; Department of Medicine, Vanderbilt University School of Medicine Nashville, TN, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
authors.affiliation: Center for Systems Genomics, The Pennsylvania State University Philadelphia, PA, USA.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: Center for Systems Genomics, The Pennsylvania State University Philadelphia, PA, USA.
authors.forename: Shefali S
authors.initials: SS
authors.lastname: Verma
authors.affiliation: College of Medicine, University of Cincinnati Cincinnati, OH, USA ; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Lingren
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA ; College of Medicine, University of Cincinnati Cincinnati, OH, USA ; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
authors.forename: Aleksey
authors.initials: A
authors.lastname: Porollo
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
authors.forename: Beth L
authors.initials: BL
authors.lastname: Cobb
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital Boston, MA, USA.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Perry
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA ; College of Medicine, University of Cincinnati Cincinnati, OH, USA ; Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
authors.forename: Leah C
authors.initials: LC
authors.lastname: Kottyan
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA ; College of Medicine, University of Cincinnati Cincinnati, OH, USA.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Thompson
authors.affiliation: Division of Genetics and Genomics, Department of Pediatrics, The Manton Center for Orphan Disease Research, Harvard Medical School, Boston Children's Hospital Boston, MA, USA.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Holm
authors.affiliation: Children's Hospital Informatics Program, Center for Biomedical Informatics, Harvard Medical School Boston, MA, USA.
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Kohane
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA ; College of Medicine, University of Cincinnati Cincinnati, OH, USA ; U.S. Department of Veterans Affairs Medical Center Cincinnati, OH, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
keywords: ICD-9 code; PheWAS; genetic polymorphism