4.8 Article

GCAT|Panel, a comprehensive structural variant haplotype map of the Iberian population from high-coverage whole-genome sequencing

Journal

NUCLEIC ACIDS RESEARCH
Volume 50, Issue 5, Pages 2464-2479

Publisher

OXFORD UNIV PRESS
DOI: 10.1093/nar/gkac076

Keywords

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Funding

  1. Accion de Dinamizacion del ISCIII-MINECO
  2. Ministry of Health of the Generalitat of Catalunya [ADE 10/00026]
  3. Aencia de Gestio dAjuts Universitaris i de Recerca (AGAUR) [2017-SGR 529]
  4. VEIS project [001-P001647]
  5. European Regional Development Fund (ERDF)
  6. Spanish Government [SEV-2011-00067, SEV2015-0493]
  7. Spanish Ministry of Science [TIN2015-65316-P]
  8. Generalitat de Catalunya [2014-SGR-1051]
  9. Agencia Estatal de Investigacion (AEI, Spain) [BFU2016-77244-R, PID2019-107836RB-I00]
  10. European Regional Development Fund (FEDER, EU)
  11. Spanish Ministry of Science and Innovation [FPI BES-2016-0077344]
  12. European Union [H2020-MSCACOFUND-2016-754433]
  13. UK10K Consortium from UK10KCOHORT IMPUTATION [EGAS00001000713]
  14. Netherlands Organization for Scientific Research [184021007]
  15. [PI18/01512]

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This study presents a dense haplotype map focused on structural variants (SVs) and provides a comprehensive catalog of variants, including SNVs, indels, and SVs, within the Iberian population. The haplotype panel enables the imputation of a large number of SNVs/indels and SVs, showing a significant increase in SVs compared to existing variation panels. The value of this panel is demonstrated through the identification of a rare Alu element associated with a rare neuromuscular disease.
The combined analysis of haplotype panels with phenotype clinical cohorts is a common approach to explore the genetic architecture of human diseases. However, genetic studies are mainly based on single nucleotide variants (SNVs) and small insertions and deletions (indels). Here, we contribute to fill this gap by generating a dense haplotype map focused on the identification, characterization, and phasing of structural variants (SVs). By integrating multiple variant identification methods and Logistic Regression Models (LRMs), we present a catalogue of 35 431 441 variants, including 89 178 SVs (>= 50 bp), 30 325 064 SNVs and 5 017 199 indels, across 785 Illumina high coverage (30x) whole-genomes from the Iberian GCAT Cohort, containing a median of 3.52M SNVs, 606 336 indels and 6393 SVs per individual. The haplotype panel is able to impute up to 14 360 728 SNVs/indels and 23 179 SVs, showing a 2.7-fold increase for SVs compared with available genetic variation panels. The value of this panel for SVs analysis is shown through an imputed rare Alu element located in a new locus associated with Mononeuritis of lower limb, a rare neuromuscular disease. This study represents the first deep characterization of genetic variation within the Iberian population and the first operational haplotype panel to systematically include the SVs into genome-wide genetic studies.

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