A Comparison of Case-Control and Family-Based Association Methods: The Example of Sickle-Cell and Malaria

Summary There has been much debate about the relative merits of population- and family-based strategies for testing genetic association, yet there is little empirical data that directly compare the two approaches. Here we compare case-control and transmission/disequilibrium test (TDT) study designs using a well-established genetic association, the protective effect of the sickle-cell trait against severe malaria. We find that the two methods give similar estimates of the level of protection (case-control odds ratio = 0.10, 95% confidence interval 0.03‐0.23; family-based estimate of the odds ratio = 0.11, 95% confidence interval 0.04‐0.25) and similar statistical significance of the result (case-control: χ 2 = 41.26, p = 10 − 10 , TDT: χ 2 = 39.06, p = 10 − 10 ) when 315 TDT cases are compared to 583 controls. We propose a family plus population control study design, which allows both case-control and TDT analysis of the cases. This combination is robust against the respective weaknesses of the case-control and TDT study designs, namely population structure and segregation distortion. The combined study design is especially cost-effective when cases are difficult to ascertain and, when the case-control and TDT results agree, offers greater confidence in the result.