Both of our previously unreported genotype-trait associations involve coding variants of HBB, which encodes the beta polypeptide chains in adult hemoglobin. The HBB stop gain (p.Gln40Ter) variant 11:5226774:G:A (rs11549407) is the most common cause of beta zero thalassemia in West Mediterranean countries, particularly among the founder population of Sardinia [32, 33], where the variant has a population allele frequency of ~5%. The Sardinian population is represented in the HRC reference panel (~3500 individuals), which likely contributes to the reasonable imputation quality observed using HRC in most but not all cohorts, in contrast to the absence of this variant in the 1000G reference panel due to very low minor allele count, though imputation quality was clearly improved with the TOPMed freeze 5b reference panel. The p.Gln40Ter mutation is much less prevalent outside of the Western Mediterranean, but has been detected among individuals with beta thalassemia among admixed populations from Central and South America [34, 35], which are geographically and genetically similar to some of the Hispanic/Latino samples included in our imputation-based discovery sample. While the individuals carrying the HBB p.Gln40Ter allele
