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Cited by 2Genomic variations and chromosomal abnormalitiesGenetic Associations and EpidemiologyGenomics and Rare Diseases

Population‐wide copy number variation calling using variant call format files from 6,898 individuals

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Png, Grace, Suveges, Daniel, Park, Young‐Chan, Walter, Klaudia, Kundu, Kousik, Ntalla, Ioanna, Tsafantakis, Emmanouil, Karaleftheri, Maria +3 more·2020·Genetic Epidemiology
DOI 10.1002/gepi.22260PMC PMC8653900

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Abstract

Copy number variants (CNVs) play an important role in a number of human diseases, but the accurate calling of CNVs remains challenging. Most current approaches to CNV detection use raw read alignments, which are computationally intensive to process. We use a regression tree‐based approach to call germline CNVs from whole‐genome sequencing (WGS, >18x) variant call sets in 6,898 samples across four European cohorts, and describe a rich large variation landscape comprising 1,320 CNVs. Eighty‐one percent of detected events have been previously reported in the Database of Genomic Variants. Twenty‐three percent of high‐quality deletions affect entire genes, and we recapitulate known events such as the GSTM1 and RHD gene deletions. We test for association between the detected deletions and 275 protein levels in 1,457 individuals to assess the potential clinical impact of the detected CNVs. We describe complex CNV patterns underlying an association with levels of the CCL3 protein (MAF = 0.15, p = 3.6x10 −12 ) at the CCL3L3 locus, and a novel cis‐ association between a low‐frequency NOMO1 deletion and NOMO1 protein levels (MAF = 0.02, p = 2.2x10 −7 ). This study demonstrates that existing population‐wide WGS call sets can be mined for germline CNVs with minimal computational overhead, delivering insight into a less well‐studied, yet potentially impactful class of genetic variant.

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  • Investigation of the effects of other structural variants, such as copy number variants (CNVs), on protein levels has thus far been limited.

    “Investigation of the effects of other structural variants, such as copy number variants (CNVs), on protein levels has thus far been limited15.”

    From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [15]

    The Introduction (page unavailable) says population-wide CNV detection remains challenging, and the Results’ Association analysis examines CNV deletions against measured protein levels. These passages support the context for limited investigation, but they do not specifically establish that research on CNVs’ effects on protein levels has been limited. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • None of the associations reported by Png et al. were replicated in this study.

    “None of the associations reported by Png et al.15 were replicated in this study”

    From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [15]

  • To the best of the authors' knowledge, one study has previously studied CNVs in this context, focusing only on deletions.

    “To the best of our knowledge, one study has previously studied CNVs in this context, focusing only on deletions15.”

    From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [15]

  • The lack of replication of Png et al. associations may be due to partial overlap between assayed protein sets, cohort differences (European ancestry vs a Greek population isolate with population-specific CNVs), and differences in CNV detection approach.

    “possibly because there was only a partial overlap between the assayed protein sets, differences between cohorts (European ancestry vs a Greek population isolate with population-specific CNVs)76, and differences in the approach used for CNV detection.”

    From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [15]

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Cited by

Sorted by citations

Authors
Png, G., Suveges, D., Park, Y., Walter, K., Kundu, K., Ntalla, I., Tsafantakis, E., Karaleftheri, M., Dedoussis, G., Zeggini, E., & Gilly, A.
Affiliations
  • University of Cambridge (GB)
  • Wellcome Sanger Institute Wellcome Genome Campus Hinxton United Kingdom
  • Wellcome Sanger Institute (GB)
  • William Harvey Research Institute, Barts and The London School of Medicine and Dentistry Queen Mary University of London London United Kingdom
  • Anogia Medical Centre Anogia Greece
  • Echinos Medical Centre Echinos Greece
  • Harokopio University of Athens (GR)
Corresponding author
Gilly, Arthur
ORCID
Venue
Genetic Epidemiology
Publisher
Wiley
Published
2019-09-14
Volume
44
Issue
1
Pages
79-89
ISSN
  • 0741-0395 (ISSN-L)
  • 1098-2272
DOI
10.1002/gepi.22260
PMC
PMC8653900
OpenAlex
W2973056867
Cited by
2
References
2
Citations by year
2024: 1 · 2023: 1
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Genetic Epidemiology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Site cant be reached (submittedVersion, other-oa)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
Funders
  • Wellcome Trust (098051)
  • European Research Council (ERC‐2011‐StG 280559‐SEPI)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
copy number variation, whole genome sequencing, gene deletion, GSTM1 null genotype, protein abundance, CCL3, European cohorts
MeSH terms
Whole Genome Sequencing, Genetics, Population, Glutathione Transferase, Humans, Recombinant Fusion Proteins, Genome, Human, Gene Deletion, Genomics, Chemokine CCL3, Genome-Wide Association Study, Nodal Protein, DNA Copy Number Variations

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