RA was the sole disease for which the sex-differentiated analysis generated a strong signal due to different genetic effects in males and females. The SNP rs11761231 (chromosome 7) generates a P value of 3.9×10-7 for the 2-degrees of freedom (d.f.) sex-differentiated test which combines trend tests in males and females (Table 3). (The trend test ignoring the sex of the individuals has a P value of 1.7×10-6.) This genotype has no effect on disease status in males, but a strong apparently additive effect in females (P value in a logistic regression model with additive log-odds is 0.68 in males and 6.8×10-8 in females, additive OR for females 1.32), and may represent one of the first sex-differentiated effects in human diseases. Cluster plots for this SNP seem good, but it is surrounded by recombination hotspots and has no other SNPs on the Affymetrix chip with r2>0.1 (Supplementary Fig. 11). Some caution is therefore required, but this represents a potentially interesting finding which warrants further investigation, particularly given the sex-related prevalence difference characteristic of this condition.
