Original Article | Published:

2SNP heritability and effects of genetic variants for neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio

Journal of Human Genetics volume 62, pages 979988 (2017) | Download Citation

Abstract

Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are important biomarkers for disease development and progression. To gain insight into the genetic causes of variance in NLR and PLR in the general population, we conducted genome-wide association (GWA) analyses and estimated SNP heritability in a sample of 5901 related healthy Dutch individuals. GWA analyses identified a new genome-wide significant locus on the HBS1L-MYB intergenic region for PLR, which replicated in a sample of 2538 British twins. For platelet count, we replicated three known genome-wide significant loci in our cohort (at CCDC71L-PIK3CG, BAK1 and ARHGEF3). For neutrophil count, we replicated the PSMD3 locus. For the identified top SNPs, we found significant cis and trans expression quantitative trait loci effects for several loci involved in hematological and immunological pathways. Linkage Disequilibrium score (LD) regression analyses for PLR and NLR confirmed that both traits are heritable, with a polygenetic SNP heritability for PLR of 14.1%, and for NLR of 2.4%. Genetic correlations were present between ratios and the constituent counts, with the genetic correlation (r=0.45) of PLR with platelet count reaching statistical significance. In conclusion, we established that two important biomarkers have a significant heritable SNP component, and identified the first genome-wide locus for PLR.

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Acknowledgements

This work was supported by: Genotype/phenotype database for genetic studies (ZonMW Middelgroot (911-09-032); Database Twin register (NWO 575-25-006); Twin family database for behavior genetics and genomics studies (NWO 480-04-004); Genome-wide analyses of European twin and population cohorts (EU/QLRT-2001-01254); Center for Medical Systems Biology (CMSB), Biobanking and Bimolecular Resources Research Infrastructure (BBMRI-NL) 184.021.007; GENOMEUTWIN/EU (QLG2- CT-2002-01254); NIH (NIHHEALTHF4-2007-201413); European Research Council (230374-GMI). TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union (EU) and the National Institute for Health Research (NIHR)- funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. B Lin received a PhD grant (201206180099) from the China Scholarship Council. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. We thank all the twin families who participated in The Netherlands Twin Register Biobank project and TwinsUK project.

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Affiliations

  1. Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    • Bochao Danae Lin
    • , Dorret I Boomsma
    • , Eco J de Geus
    • , Gonneke Willemsen
    •  & Jouke-Jan Hottenga
  2. Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK

    • Elena Carnero-Montoro
    • , Jordana T Bell
    • , Massimo Mangino
    •  & Tim D Spector
  3. EMGO+ Institute for Health & Care Research, VU Medical Center, Amsterdam, The Netherlands

    • Eco J de Geus
    •  & Jouke-Jan Hottenga
  4. Department of Psychiatry, VU Medical Center, Amsterdam, The Netherlands

    • Rick Jansen
    •  & Brenda Penninx
  5. Good Biomarker Sciences, Leiden, The Netherlands

    • Cornelis Kluft
  6. NIHR Biomedical Research Centre at Guy’s and St Thomas’ Foundation Trust, London, UK

    • Massimo Mangino

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The authors declare no conflict of interest.

Corresponding author

Correspondence to Jouke-Jan Hottenga.

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https://doi.org/10.1038/jhg.2017.76

Supplementary Information accompanies the paper on Journal of Human Genetics website (http://www.nature.com/jhg)

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