Assessing the validity of the association between the SUMO4 M55V variant and risk of type 1 diabetes
NATURE GENETICS | VOLUME 37 | NUMBER 2 | FEBRUARY 2005 111 Supplementary Methods online). We also genotyped three SNPs, 001Msp (rs577001), 012Taq (rs237012) and 018Hha (rs237018) flanking 163A→G in the families from the UK, US, Finland, Romania, Norway and Northern Ireland and in the British casecontrol samples and obtained no evidence of association with T1D (Supplementary Tables 2 and 3 online). Guo et al.2 did report evidence of association from diverse ethnic groups, but the bulk of their supporting evidence came from European Americans, who would be well represented by the European American and British samples studied here (in fact, of 558 families, ∼300 directly overlap). Our results were not influenced by age-at-onset in the cases (P = 0.09, 0.47, 0.29 and 0.23 for 163A→G, 001Msp, 012Taq and 018Hha, respectively) or in the affected offspring (P = 0.87, 0.86, 0.90 and 0.37, respectively), as shown by regression analysis. Our study, with 18,132 individuals (3,007 transmissions and 7,230 cases and controls; Supplementary Table 4 online), is much larger than the two previously published studies combined. Taking into account all the results, we conclude that there is no convincing evidence for the association of the 163A→G SNP with T1D. The previous result of Guo et al.2 (P = 2.9 × 10–5) may be a false positive. In genetic association studies of common diseases, there is a very low prior probability of detecting a true positive result, given the large numbers of genes and polymorphisms in the genome, such that a P value on the order of 10–5 could still be false4–6. The problem of false positive results can be compounded by selection biases in the collection of samples, genotyping errors, population substructure and post-hoc subgroup analyses4–6. There are other explanations for the discrepant results obtained, such as complex gene-gene or geneenvironment interactions. In the first instance, however, it is necessary to attempt to exclude the possibility that the initial finding is a false positive. Both Bohren et al. and Guo et al. reported evidence of functional differences between the 55M and 55V allotypes of SUMO4 (refs. 1,2). Functional studies of candidate genes and variants are essential in the study of common diseases, but they do not solve the problem of false positives.