title: Phenome-wide association studies on a quantitative trait: application to TPMT enzyme activity and thiopurine therapy in pharmacogenomics.
abstract: Phenome-Wide Association Studies (PheWAS) investigate whether genetic polymorphisms associated with a phenotype are also associated with other diagnoses. In this study, we have developed new methods to perform a PheWAS based on ICD-10 codes and biological test results, and to use a quantitative trait as the selection criterion. We tested our approach on thiopurine S-methyltransferase (TPMT) activity in patients treated by thiopurine drugs. We developed 2 aggregation methods for the ICD-10 codes: an ICD-10 hierarchy and a mapping to existing ICD-9-CM based PheWAS codes. Eleven biological test results were also analyzed using discretization algorithms. We applied these methods in patients having a TPMT activity assessment from the clinical data warehouse of a French academic hospital between January 2000 and July 2013. Data after initiation of thiopurine treatment were analyzed and patient groups were compared according to their TPMT activity level. A total of 442 patient records were analyzed representing 10,252 ICD-10 codes and 72,711 biological test results. The results from the ICD-9-CM based PheWAS codes and ICD-10 hierarchy codes were concordant. Cross-validation with the biological test results allowed us to validate the ICD phenotypes. Iron-deficiency anemia and diabetes mellitus were associated with a very high TPMT activity (p = 0.0004 and p = 0.0015, respectively). We describe here an original method to perform PheWAS on a quantitative trait using both ICD-10 diagnosis codes and biological test results to identify associated phenotypes. In the field of pharmacogenomics, PheWAS allow for the identification of new subgroups of patients who require personalized clinical and therapeutic management.
authors.affiliation: Biomedical Informatics and Public Health Department, University Hospital HEGP, AP-HP, Paris, France ; INSERM UMR_S 872 Team 22: Information Sciences to support Personalized Medicine, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Neuraz
authors.affiliation: INSERM UMR-S 775, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Chouchana
authors.affiliation: Gastroenterology Department, University Hospital HEGP, AP-HP, Paris, France.
authors.forename: Georgia
authors.initials: G
authors.lastname: Malamut
authors.affiliation: Pharmacovigilance Center, University Hospital HEGP, AP-HP, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Le Beller
authors.affiliation: Biochemistry, Pharmacogenetics and Molecular Oncology Unit, University Hospital HEGP, AP-HP, Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Roche
authors.affiliation: INSERM UMR-S 775, Université Paris Descartes, Sorbonne Paris Cité, Paris, France ; Biochemistry, Pharmacogenetics and Molecular Oncology Unit, University Hospital HEGP, AP-HP, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Beaune
authors.affiliation: Biomedical Informatics and Public Health Department, University Hospital HEGP, AP-HP, Paris, France ; INSERM UMR_S 872 Team 22: Information Sciences to support Personalized Medicine, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Degoulet
authors.affiliation: Biomedical Informatics and Public Health Department, University Hospital HEGP, AP-HP, Paris, France ; INSERM UMR_S 872 Team 22: Information Sciences to support Personalized Medicine, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Anita
authors.initials: A
authors.lastname: Burgun
authors.affiliation: INSERM UMR-S 775, Université Paris Descartes, Sorbonne Paris Cité, Paris, France ; Biochemistry, Pharmacogenetics and Molecular Oncology Unit, University Hospital HEGP, AP-HP, Paris, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Loriot
authors.affiliation: Biomedical Informatics and Public Health Department, University Hospital HEGP, AP-HP, Paris, France ; INSERM UMR_S 872 Team 22: Information Sciences to support Personalized Medicine, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Avillach
mesh_terms: D055106:Genome-Wide Association Study; D006801:Humans; D038801:International Classification of Diseases; D008780:Methyltransferases / Q000378:metabolism*; D010597:Pharmacogenetics; D010641:Phenotype; D011687:Purines / Q000627:therapeutic use*; D040641:Quantitative Trait Loci
chemical_list: D011687:Purines; D008780:Methyltransferases; C022745:thiopurine methyltransferase