A comparison of case-control and family-based association methods: the example of sickle-cell and malaria.

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: chi(2)= 41.26, p= 10(-10), TDT: chi(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.