The human genome has been cracked wide open in recent years and is spilling many of its secrets. More than 100 genome wide association studies have been conducted for scores of hu man diseases, identifying hun dreds of polymorphisms that are widely seen to influence disease risk. After many years in which the study of complex human traits was mired in false claims and methodologic inconsistencies, ge nomics has brought not only com prehensive representation of com mon variation but also welcome rigor in the interpretation of sta tistical evidence. Researchers now know how to properly account for most of the multiple hypothesis testing involved in mining the ge nome for associations, and most reported associations reflect real biologic causation. But do they matter?

Unfortunately, most common gene variants that are implicated by such studies are responsible for only a small fraction of the genetic variation that we know exists. This observation is par ticularly troubling because the studies are largely comprehensive in terms of common singlenucle otide polymorphisms (SNPs), the genomic markers that are geno typed and with which disease as sociations are tested. We’re find ing the biggest effects that exist for this class of genetic variant, and common variation is packing much less of a phenotypic punch than expected. Some experts em phasize that small effect sizes don’t necessarily mean that a gene variant is of no interest or use. Effect size is a function of what a variant does: it may change