Main The number of genetic variants identified by genome-wide association and sequencing studies is now so large that a complete picture of the genetic architecture of many complex traits is starting to emerge 1 , 3 . Illustrating all known variants for a complex trait or disease on a spectrum of allele frequency versus effect size produces a characteristic ‘trumpet’ shape 4 , 5 , in which rarer alleles have increasingly larger effects owing to stabilizing selection 6 . These effects are sometimes so large relative to those of common alleles that they cause extreme trait values on most genetic backgrounds. For example, mutations in ACAN usually result in short stature, those in LEP cause leptin deficiency, and those in HNF1A produce large deviations in glucose homeostasis 7 , 8 , 9 . Moreover, Fiziev et al.…