4.6 Article

Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations

Journal

PLOS GENETICS
Volume 15, Issue 12, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1008500

Keywords

-

Funding

  1. American Heart Association [18CDA34110116, 18SFRN34250007]
  2. NIH [1RO1HL092577, R01HL128914, K24HL105780, 1R01HL139731]
  3. AHA [18SFRN34110082]
  4. Fondation Leducq [14CVD01]
  5. [T32 HL129982]
  6. [R01 HL129132]
  7. [R01 EY027004]
  8. [R01 DK116738]
  9. [U01 HG007417]
  10. [R56HG010297]
  11. [U01 HG007419]
  12. [U01 HL72518]
  13. [R01 HL087698]
  14. [R01 HL112064]
  15. [3R01HL-117626-02S1]
  16. [3R01HL-120393-02S1]
  17. [HHSN268201500003I]
  18. [N01-HC-95159]
  19. [N01-HC-95160]
  20. [N01-HC-95161]
  21. [N01-HC-95162]
  22. [N01-HC-95163]
  23. [N01-HC-95164]
  24. [N01-HC-95165]
  25. [N01-HC-95166]
  26. [N01-HC-95167]
  27. [U01 HL089856]
  28. [NO1-HC-25195]
  29. [HHSN268201500001I]
  30. [R01 HL092577-06S1]
  31. [R01 HL055673]
  32. [U01HL072507]
  33. [R01HL087263]
  34. [R01HL090682]
  35. [R01 HL113323]
  36. [R01 HL119443]
  37. [R01 HL085571]
  38. [P01 HL132825]
  39. [R01HL104608]
  40. [R01 R01HL091397]
  41. [K01 HL130609 01]
  42. [R01 HL113326]
  43. [R01 HL92301]
  44. [R01 HL67348]
  45. [R01 NS058700]
  46. [R01 NS075107]
  47. [R01 AR48797]
  48. [R01 DK071891]
  49. [M01 RR07122]
  50. [F32 HL085989]
  51. [P60 AG10484]
  52. [R01HL071051]
  53. [R01HL071205]
  54. [R01HL071250]
  55. [R01HL071251]
  56. [R01HL071258]
  57. [R01HL071259]
  58. [UL1RR033176]
  59. [UL1TR001881]
  60. [N01-HC-95168]
  61. [N01-HC-95169]
  62. [UL1-TR-000040]
  63. [UL1-TR-001079]
  64. [UL1-TR-001420]
  65. [UL1-TR001881]
  66. [DK063491]

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Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was > 86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in similar to 21,600 African-ancestry and similar to 21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10(-15)] in African populations, rs11549407 with lower HGB [p = 1.5x10(-12)] and HCT [p = 8.8x10(-10)] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.

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