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Background: Genetic studies of biomedical phenotypes in underrepresented populations identify disproportionate numbers of novel associations. However, current genomics infrastructure--including most genotyping arrays and sequenced reference panels--best serves populations of European descent. A critical step for facilitating genetic studies in underrepresented populations is to ensure that genetic technologies accurately capture variation in all populations. Here, we quantify the accuracy of low-coverage sequencing in diverse African populations. Results: We sequenced the whole genomes of 91 individuals to high-coverage (>20X) from the Neuropsychiatric Genetics of African Population-Psychosis (NeuroGAP-Psychosis) study, in which participants were recruited from Ethiopia, Kenya, South Africa, and Uganda. We empirically tested two data generation strategies, GWAS arrays versus low-coverage sequencing, by calculating the concordance of imputed variants from these technologies with those from deep whole genome sequencing data. We show that low-coverage sequencing at a depth of ≥4X captures variants of all frequencies more accurately than all commonly used GWAS arrays investigated and at a comparable cost. Lower depths of sequencing (0.5-1X) performed comparable to commonly used low-density GWAS arrays. Low-coverage sequencing is also sensitive to novel variation, with 4X sequencing detecting 45% of singletons and 95% of common variants identified in high-coverage African whole genomes. Conclusion: These results indicate that low-coverage sequencing approaches surmount the problems induced by the ascertainment of common genotyping arrays, including those that capture variation most common in Europeans and Africans. Low-coverage sequencing effectively identifies novel variation (particularly in underrepresented populations), and presents opportunities to enhance variant discovery at a similar cost to traditional approaches. ### Competing Interest Statement A.R.M. serves as a consultant for 23andMe and is a member of the Precise.ly Scientific Advisory Board. B.M.N. is a member of the Deep Genomics Scientific Advisory Board. He also serves as a consultant for the Camp4 Therapeutics Corporation, Takeda Pharmaceutical and Biogen. M.J.D. is a founder of Maze Therapeutics. J.K.P. is an employee of Gencove, Inc. The remaining authors declare no competing interests. D.J.S. has received research grants and/or consultancy honoraria from Lundbeck and Sun.

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