Low-coverage sequencing cost-effectively detects known and novel variation in underrepresented populations

Am J Hum Genet. 2021 Apr 1;108(4):656-668. doi: 10.1016/j.ajhg.2021.03.012. Epub 2021 Mar 25.


Genetic studies in underrepresented populations identify disproportionate numbers of novel associations. However, most genetic studies use genotyping arrays and sequenced reference panels that best capture variation most common in European ancestry populations. To compare data generation strategies best suited for underrepresented populations, we sequenced the whole genomes of 91 individuals to high coverage as part of the Neuropsychiatric Genetics of African Population-Psychosis (NeuroGAP-Psychosis) study with participants from Ethiopia, Kenya, South Africa, and Uganda. We used a downsampling approach to evaluate the quality of two cost-effective 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 ≥4× captures variants of all frequencies more accurately than all commonly used GWAS arrays investigated and at a comparable cost. Lower depths of sequencing (0.5-1×) performed comparably to commonly used low-density GWAS arrays. Low-coverage sequencing is also sensitive to novel variation; 4× sequencing detects 45% of singletons and 95% of common variants identified in high-coverage African whole genomes. Low-coverage sequencing approaches surmount the problems induced by the ascertainment of common genotyping arrays, effectively identify novel variation particularly in underrepresented populations, and present opportunities to enhance variant discovery at a cost similar to traditional approaches.

Keywords: Africa; GWAS; GWAS arrays; cost comparison; low-coverage sequencing; study design; whole-genome sequencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Africa
  • DNA Mutational Analysis / economics*
  • DNA Mutational Analysis / methods
  • DNA Mutational Analysis / standards*
  • Genetic Variation / genetics*
  • Genetics, Population / economics*
  • Genetics, Population / methods
  • Genome, Human / genetics
  • Genome-Wide Association Study
  • Health Equity
  • Humans
  • Microbiota
  • Whole Genome Sequencing / economics
  • Whole Genome Sequencing / standards