we expect to be able to conduct an even more comprehensive analysis of the genetic architecture for variants with ever lower frequencies. Ultimately, the discovery of low frequency with small effects will require even larger sample sizes. For example, for rare variant with MAF of .1% and effects of .2, .15, and 0.1 standard deviations on the phenotype, to identify associations at α = 5 × 10−8 with 80% of power, sample sizes of 500,000 890,000 and 1,990,000 are required. While such numbers seemed astronomical just a few years ago, they will indeed be attainable in the next few years with the availability of large biobank datasets and ever improving imputation. Another limitation of the present study is the limited samples sizes from non-European ancestries, where only exploratory analyses were possible. Substantial improvements can be made to the resolution of fine mapping analysis by leveraging disparate LD information across samples with diverse ancestry(33). Future research will do well to include individuals of diverse ancestry.
