Development of polyphenotypic scores to prioritize detection of G6PD rs1050828 heterozygotes in African and African American populations.

Abstract

The G6PD missense variant rs1050828 (NP_000393.4:p.Val98Met) is common in African and African American populations. It lowers HbA1c levels independent of glycemia, increasing the risk of underdiagnosis or delayed diagnosis of diabetes. We aimed to develop polyphenotypic scores (PPS) using routinely collected phenotypes to identify likely heteroygotes. Using data from 31,083 African or African American participants in the All of Us Research Program, we developed sex-specific PPS through multistage variable selection. We validated the PPS in independent African or African American individuals from All of Us Research Program (N = 8846), BioMe Biobank (N = 8839), and UK Biobank (N = 6811) and evaluated their utility among individuals without diagnosed diabetes. The PPS achieved an area under the receiver operating characteristic curve ranging from 0.7614 to 0.8686 in identifying male hemizygotes and from 0.7378 to 0.8654 identifying female homozygotes. Among individuals without diagnosed diabetes and with HbA1c < 6.5%, PPS-based screening reduced the number needed to screen for identifying male hemizygotes by 65% to 90% and female homozygotes by 80% to 90%, compared with random screening. The PPS may help identify likely rs1050828 heterozygotes in African and African American populations, supporting prioritization for confirmatory testing or alternative diagnostic approaches for diabetes.