Adjustment for index event bias in genome-wide association studies of subsequent events
Following numerous genome-wide association studies of disease susceptibility, there is increasing interest in genetic associations with disease prognosis, survival or other subsequent events. Such associations are vulnerable to index event bias, by which selection of subjects according to their disease status creates biased associations if common causes of incidence and prognosis are not accounted for. We propose a novel 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 resolved a paradoxical association of the strong susceptibility gene MUC5B with increased survival, identifying instead a significant association with decreased survival. In re-analysis of a study of Crohns disease prognosis, four regions remained associated at genome-wide significance albeit with increased P-values.