Uncovering additional common variants that are associated with disease, with a smaller effect size than those already found using the standard GWAS approach, will likely require significantly increasing sample sizes. This prospect becomes difficult to justify, however, as the expected effect size of additional common variants diminishes. Illustrating this point, a recent meta-analysis of human body mass index (BMI) GWAS, including 250 000 subjects, identified 32 associated single nucleotide polymorphisms (SNPs), accounting for only 1.45% of variation in BMI (11). It was estimated that while a 3-fold increase in sample size (to ∼750 000 subjects) would have likely resulted in detection of 10 times as many associations, the proportion of explained variance would be expected to remain under 5%.
