This Month in The Journal.

Auer et al., page 794 Exome sequencing in small cohorts has been successfully employed for the discovery of rare, highly penetrant mutations in familial diseases. However, the use of exome sequencing for identifying low-frequency variants in large populations has been confounded by technical limitations and prohibitive costs. To apply low-frequency variants captured by exome sequencing to a large population in African Americans, Auer et al. exome sequenced a reference panel of 761 individuals and then imputed these variants into a cohort of 13,000 individuals. After imputation, a series of blood traits, including hemoglobin, hematocrit, white blood cell, and platelet counts, were tested for associations with the identified variants. Some of the interesting associations included those between variants in MPL (the thrombopoietin receptor) and high platelet count, between LCT and high white blood cell count, between CD36 and low platelet count, and between several variants in alpha-globin and low hemoglobin count. Leveraging rare variants identified in exome sequencing to a larger population uncovered associations that have been missed by traditional genome-wide association studies, thus highlighting some of the inherent limitations of genotyping arrays. This work not only explains some of the heterogeneity in blood cell traits observed in African Americans but also demonstrates the feasibility of using this approach in other studies aimed at better understanding the role of low-frequency variants in populations.