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

Frank Dudbridge,Louise V Wain,Nuala A Sheehan,R Gisli Jenkins,Richard J Allen,Aroon D Hingorani,Riyaz S Patel,A Floriaan Schmidt,James C Lee

doi:10.1038/s41467-019-09381-w

Abstract

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.

Highlights

Following numerous genome-wide association studies of disease susceptibility, there is increasing interest in genetic associations with prognosis, survival or other subsequent events
Together our results suggest that the paradoxical association of mucin 5B (MUC5B) with increased survival could be due to index event bias, and that the risk allele of MUC5B is associated with decreased survival
Awareness of index event and related biases[2,10,11] has grown as attention turns to follow-up of genome-wide association studies (GWAS). Our interest in this problem arose within the GENetIcs of sUbSequent Coronary Heart Disease (GENIUS-CHD) consortium[30], which aims to identify risk factors for recurrent coronary events in patients with coronary heart disease

Summary

Introduction

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. With many collections of disease cases genotyped by studies of susceptibility, more Association studies of such subsequent events are vulnerable to index event bias, whereby biased associations can result from selection of subjects according to their disease status[9]. We will refer to subsequent events as prognosis, with the understanding that this could refer to any phenotype subsequent to, and not a cause of, the index event

Objectives

Methods

Results

Conclusion