TY - JOUR
KW - Asthma
KW - Cohort Studies
KW - Databases, Factual
KW - Drug Discovery
KW - Genetic Association Studies
KW - Genetic Pleiotropy
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Humans
KW - Interferon-Induced Helicase, IFIH1
KW - Lipase
KW - Membrane Proteins
KW - Molecular Targeted Therapy
KW - Phenotype
KW - Polymorphism, Single Nucleotide
KW - Reproducibility of Results
KW - Thromboembolism
KW - United Kingdom
AU - Dorothée Diogo
AU - Chao Tian
AU - Christopher S. Franklin
AU - Mervi Alanne-Kinnunen
AU - Michael March
AU - Chris C. A. Spencer
AU - Ciara Vangjeli
AU - Michael E. Weale
AU - Hannele Mattsson
AU - Elina Kilpeläinen
AU - Patrick M. A. Sleiman
AU - Dermot F. Reilly
AU - Joshua McElwee
AU - Joseph C. Maranville
AU - Arnaub K. Chatterjee
AU - Aman Bhandari
AU - Khanh-Dung H. Nguyen
AU - Karol Estrada
AU - Mary-Pat Reeve
AU - Janna Hutz
AU - Nan Bing
AU - Sally John
AU - Daniel G. MacArthur
AU - Veikko Salomaa
AU - Samuli Ripatti
AU - Hakon Hakonarson
AU - Mark J. Daly
AU - Aarno Palotie
AU - David A. Hinds
AU - Peter Donnelly
AU - Caroline S. Fox
AU - Aaron G. Day-Williams
AU - Robert M. Plenge
AU - Heiko Runz
AB - 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. Our analyses replicate 75% of known GWAS associations (P < 0.05) and identify nine study-wide significant novel associations (of 71 with FDR < 0.1). We describe associations that may predict ADEs, e.g., acne, high cholesterol, gout, and gallstones with rs738409 (p.I148M) in PNPLA3 and asthma with rs1990760 (p.T946A) in IFIH1. Our results demonstrate PheWAS as a powerful addition to the toolkit for drug discovery.
BT - Nature Communications
DA - 2018-10-16
DO - 10.1038/s41467-018-06540-3
IS - 1
LA - eng
N2 - 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. Our analyses replicate 75% of known GWAS associations (P < 0.05) and identify nine study-wide significant novel associations (of 71 with FDR < 0.1). We describe associations that may predict ADEs, e.g., acne, high cholesterol, gout, and gallstones with rs738409 (p.I148M) in PNPLA3 and asthma with rs1990760 (p.T946A) in IFIH1. Our results demonstrate PheWAS as a powerful addition to the toolkit for drug discovery.
PY - 2018
EP - 4285
T2 - Nature Communications
TI - Phenome-wide association studies across large population cohorts support drug target validation
VL - 9
SN - 2041-1723
ER -