Effect of case and control definitions on genome-wide association study (GWAS) findings

Genome-wide association studies (GWAS) have significantly advanced our understanding of the genetic underpinnings of diseases, but case and control cohort definitions for a given disease can vary between different published studies. For example, two GWAS for the same disease using the UK Biobank data set might use different data sources (i.e., self-reported questionnaires, hospital records, etc.) or different levels of granularity (i.e., specificity of inclusion criteria) to define cases and controls. The extent to which this variability in cohort definitions impacts the end-results of a GWAS study is unclear. In this study, we systematically evaluated the effect of the data sources used for case and control definitions on GWAS findings. Using the UK Biobank, we selected three diseases—glaucoma, migraine, and iron-deficiency anemia. For each disease, we designed 13 GWAS, each using different combinations of data sources to define cases and controls, and then calculated the pairwise genetic correlations between all GWAS for each disease. We found that the data sources used to define cases for a given disease can have a significant impact on GWAS end-results, but the extent of this depends heavily on the disease in question. This suggests the need for greater scrutiny on how case cohorts are defined for GWAS.