RT Journal Article
SR Electronic
T1 Quantifying the extent to which index event biases influence large genetic association studies
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 074781
DO 10.1101/074781
A1 Hanieh Yaghootkar
A1 Michael P. Bancks
A1 Sam E. Jones
A1 Aaron McDaid
A1 Robin Beaumont
A1 Louise Donnelly
A1 Andrew R. Wood
A1 Archie Campbell
A1 Jessica Tyrrell
A1 Lynne J. Hocking
A1 Marcus A. Tuke
A1 Katherine S. Ruth
A1 Ewan R. Pearson
A1 Anna Murray
A1 Rachel M. Freathy
A1 Patricia B. Munroe
A1 Caroline Hayward
A1 Colin Palmer
A1 Michael N. Weedon
A1 James S. Pankow
A1 Timothy M. Frayling
A1 Zoltán Kutalik
YR 2016
UL http://biorxiv.org/content/early/2016/09/12/074781.abstract
AB As genetic association studies increase in size to 100,000s of individuals, subtle biases may influence conclusions. One possible bias is “index event bias” (IEB), also called “collider bias”, caused by the stratification by, or enrichment for, disease status when testing associations between gene variants and a disease-associated trait. We first provided a statistical framework for quantifying IEB then identified real examples of IEB in a range of study and analytical designs. We observed evidence of biased associations for some disease alleles and genetic risk scores, even in population-based studies. For example, a genetic risk score consisting of type 2 diabetes variants was associated with lower BMI in 113,203 type 2 diabetes controls from the population based UK Biobank study (−0.010 SDs BMI per allele, P=5E-4), entirely driven by IEB. Three of 11 individual type 2 diabetes risk alleles, and 10 of 25 hypertension alleles were associated with lower BMI at p<0.05 in UK Biobank when analyzing disease free individuals only, of which six hypertension alleles remained associated at p<0.05 after correction for IEB. Our analysis suggested that the associations between CCND2 and TCF7L2 diabetes risk alleles and BMI could (at least partially) be explained by IEB. Variants remaining associated after correction may be pleiotropic and include those in CYP17A1 (allele associated with hypertension risk and lower BMI). In conclusion, IEB may result in false positive or negative associations in very large studies stratified or strongly enriched for/against disease cases.