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: chi2= 41.26, p= 10(-10), TDT: chi2= 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.
Ackerman
H
H
Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK.
Usen
S
S
Jallow
M
M
Sisay-Joof
F
F
Pinder
M
M
Kwiatkowski
D P
DP
D000483:Alleles; D000818:Animals; D016022:Case-Control Studies; D016001:Confidence Intervals; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D005787:Gene Frequency; D005828:Genetics, Population; D005838:Genotype; D005914:Globins / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D015810:Linkage Disequilibrium; D008288:Malaria / Q000235:genetics*; D008297:Male; D015233:Models, Statistical; D016017:Odds Ratio; D010963:Plasmodium falciparum / Q000378:metabolism; D012107:Research Design; D012805:Sickle Cell Trait / Q000235:genetics*
D006454:Hemoglobins; D005914:Globins