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Mosaic loss of chromosome Y in leukocytes matters

Nature Genetics volume 51, pages 4–7 (2019)Cite this article

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To the Editor — Recent studies have found associations between loss of chromosome Y (LOY) in leukocytes and an increased risk for all-cause mortality1 as well as various diseases affecting organs outside the hematopoietic system, i.e., non-hematological cancer diagnosis/mortality1, colorectal and prostate cancer2, Alzheimer’s disease3 and cardiovascular events in a severely atherosclerotic population4 as well as autoimmune conditions5,6. These studies analyzed LOY in DNA extracted from blood, indicating that LOY in nucleated peripheral blood cells might have a phenotypic effect on (or be a marker for) disease processes in other tissues. A plausible hypothesis to mechanistically link and explain these associations could be that immune system functions in circulating leukocytes with LOY are compromised1,3,7,8,9. If this hypothesis holds true, a consequence would be that only studies of leukocytes would generate positive associations between LOY and the studied outcomes.

A paper by Zhou et al.10 reported inconsistent results regarding mosaic LOY and studied outcomes. For example, men with LOY were found to have an increased risk for incident bladder and prostate cancer, but no increased risk for lung cancer (Table 2 in ref. 10). Furthermore, Zhou et al.10 did not fully replicate the findings of increased risk for all-cause mortality as well as overall cancer survival presented by Forsberg et al.1, and here we highlight three potential reasons that can help explain this. First, the study from Zhou et al.10 was performed using DNA from different tissues, i.e., blood or buccal samples from about 70% and 30% of participants, respectively, collected from three separate cohorts. This design for a study of phenotypic effects from postzygotic genetic variation might be fundamentally unsound, especially when considering that the LOY frequency in buccal mucosa and the phenotypic effect of LOY in buccal cells are not yet established. Although analyses by Zhou et al.10 adjusted for DNA source, this approach cannot be viewed as valid if LOY causes the pathological effects via compromised immune functions. Hence, mixing the samples collected from blood and buccal mucosa would tend to dilute an association caused by LOY in leukocytes, resulting in loss of statistical power and false-negative results. Furthermore, the mixed analysis of blood and buccal DNA might also affect conclusions regarding associations between LOY and smoking7,10. It is currently unknown whether smoking induces LOY across multiple tissues with the same efficiency.

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Fig. 1: Comparison of the level of LOY mosaicism in blood leukocytes and buccal samples from each individual for the entire dataset of 121 studied subjects, sampled at the age of 93 years.

Data availability

The data that support the findings of this study are shown in Supplementary Table 1 and are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank E. Tiensuu Janson, S. Enroth and C. Polychronakos for review of the manuscript. K. Ström is acknowledged for collection of samples from the ULSAM cohort. The study was sponsored by funding from the European Research Council (ERC) Starting Grant, the Swedish Research Council, the Olle Enqvist Byggmästare Foundation, the Kjell and Märta Beijers Foundation to L.A.F. and by the Swedish Cancer Society, the Swedish Research Council, Konung Gustav V:s och Drottning Viktorias Frimurarestiftelse and the Science for Life Laboratory, Uppsala, to J.P.D. Genotyping and sequencing were performed by the SNP&SEQ Technology Platform in Uppsala, which is part of the Science for Life Laboratory at Uppsala University and is supported as a national infrastructure by the Swedish Research Council.

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Authors and Affiliations

  1. Departments of Immunology, Genetics and Pathology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden

    Lars A. Forsberg, Jonatan Halvardson, Edyta Rychlicka-Buniowska, Marcus Danielsson, Behrooz Torabi Moghadam, Jonas Mattisson, Chiara Rasi, Hanna Davies & Jan P. Dumanski

  2. Beijer Laboratory of Genome Research, Uppsala University, Uppsala, Sweden

    Lars A. Forsberg

  3. Department of Medical Sciences, Uppsala University, Uppsala, Sweden

    Lars Lind

  4. Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden

    Vilmantas Giedraitis, Lars Lannfelt, Lena Kilander & Martin Ingelsson

  5. Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland

    Jan P. Dumanski

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  1. Lars A. Forsberg
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Corresponding authors

Correspondence to Lars A. Forsberg or Jan P. Dumanski.

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Competing interests

J.P.D. and L.A.F. are cofounders and shareholders in Cray Innovation AB.

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Supplementary Figures 1–5, Supplementary Table 1 and Supplementary Note

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Forsberg, L.A., Halvardson, J., Rychlicka-Buniowska, E. et al. Mosaic loss of chromosome Y in leukocytes matters. Nat Genet 51, 4–7 (2019). https://doi.org/10.1038/s41588-018-0267-9

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