Adjustment for index event bias in genome-wide association studies of subsequent events.

Change log
Dudbridge, Frank 
Sheehan, Nuala A 
Schmidt, A Floriaan 

Following numerous genome-wide association studies of disease susceptibility, there is increasing interest in genetic associations with prognosis, survival or other subsequent events. Such associations are vulnerable to index event bias, by which selection of subjects according to disease status creates biased associations if common causes of incidence and prognosis are not accounted for. We propose an adjustment for index event bias using the residuals from the regression of genetic effects on prognosis on genetic effects on incidence. Our approach eliminates this bias when direct genetic effects on incidence and prognosis are independent, and otherwise reduces bias in realistic situations. In a study of idiopathic pulmonary fibrosis, we reverse a paradoxical association of the strong susceptibility gene MUC5B with increased survival, suggesting instead a significant association with decreased survival. In re-analysis of a study of Crohn's disease prognosis, four regions remain associated at genome-wide significance but with increased standard errors.

Computer Simulation, Crohn Disease, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Idiopathic Pulmonary Fibrosis, Incidence, Models, Genetic, Mucin-5B, Odds Ratio, Polymorphism, Single Nucleotide, Regression Analysis
Journal Title
Nat Commun
Conference Name
Journal ISSN
Volume Title
Springer Science and Business Media LLC