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No statistical evidence for an effect of CCR5-∆32 on lifespan in the UK Biobank cohort

Nature Medicine volume 26, pages 178–180 (2020)Cite this article

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The Original Article was published on 03 June 2019

arising from X. Wei & R. Nielsen Nature Medicine https://doi.org/10.1038/s41591-019-0637-6 (2019)

A recent study reported that a 32-base-pair deletion in the CCR5 gene (CCR5-∆32) is deleterious in the homozygous state in humans. Evidence for this came from a survival analysis in the UK Biobank cohort, and from deviations from Hardy–Weinberg equilibrium at a polymorphism tagging the deletion (rs62625034). Here, we carry out a joint analysis of whole-genome genotyping data and whole-exome sequencing data from the UK Biobank, which reveals that technical artifacts are a more plausible cause for deviations from Hardy–Weinberg equilibrium at this polymorphism. Specifically, we find that individuals homozygous for the deletion in the sequencing data are under-represented in the genotyping data due to an elevated rate of missing data at rs62625034, possibly because the probe for this single-nucleotide polymorphism overlaps with the ∆32 deletion. Another variant, which has a higher concordance with the deletion in the sequencing data, shows no associations with mortality. A phenome-wide scan for effects of variants tagging this deletion shows an overall inflation of association P values, but identifies only one trait at P < 5 × 10-8, and no mediators for an effect on mortality. These analyses show that the original reports of a recessive deleterious effect of CCR5-∆32 are affected by a technical artifact, and that a closer investigation of the same data provides no positive evidence for an effect on lifespan.

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Fig. 1: Survival rates for individuals with zero, one and two copies of the rare allele for two variants tagging the CCR5-∆32 deletion.

Data availability

All the data used in this study are available with the permission of the UK Biobank.

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Acknowledgements

This research has been conducted using the UK Biobank Resource under application no. 31063. We acknowledge the participants in the UK Biobank. We are grateful to B. Neale and A. Price for critical comments, and to S. Harrison for a blog posting that showed how the association results and HWE P values at rs113010081 were qualitatively discordant with those at rs62625034, which prompted us to re-examine these issues. We thank K. Karczewski, K. Stefansson and M. Daly for sharing with us early versions of two other manuscripts re-examining the evidence of association to mortality at CCR5, and working with us to post all manuscripts together. This work was funded in part by NIH grants GM100233 and HG006399, the Paul Allen Family Foundation, the John Templeton Foundation (grant 61220) and the Howard Hughes Medical Institute.

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Author notes

  1. These authors contributed equally: Robert Maier, Ali Akbari.

Authors and Affiliations

  1. Department of Genetics, Harvard Medical School, Boston, MA, USA

    Robert Maier, Ali Akbari & David Reich

  2. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Robert Maier, Ali Akbari, Nick Patterson & David Reich

  3. Department of Integrative Biology and Statistics, University of California, Berkeley, Berkeley, CA, USA

    Xinzhu Wei & Rasmus Nielsen

  4. Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA

    Nick Patterson & David Reich

  5. GeoGenetics Centre, University of Copenhagen, Copenhagen, Denmark

    Rasmus Nielsen

  6. Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA

    David Reich

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  1. Robert Maier
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Contributions

R.M. and A.A. performed all of the analyses except for the one presented in Supplementary Table 4, which was carried out by X.W. N.P., R.N. and D.R. supervised the study. R.M., A.A. and D.R. wrote the manuscript, with critical review from all co-authors.

Corresponding authors

Correspondence to Robert Maier or Ali Akbari.

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The authors declare no competing interests.

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Peer review information Kate Gao was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Survival analysis.

Survival rates for individuals with 0, 1, or 2 copies of the rare allele or No Call (NC) for variants tagging the CCR5-∆32 deletion. First row: Cumulative survival rates. Numbers are one-sided p-values of a Cox proportional hazard model which compares survival rates of individuals with 0 or 1 alleles to those with 2 alleles. Second row: non-cumulative survival rates. Third row: Number of individuals who have died in any given year with 2 copies of rare allele (see also Supplementary Table 7).

Extended Data Fig. 2 Concordance analysis.

Confusion matrix for different markers with missing data. The last column of the first panel shows that individuals with missing genotype at rs62625034 are enriched for ∆32/∆32 according to rs333_sequenced. This can lead to a violation of HWE at rs62625034. All white British samples of UK Biobank WES data shared with UK Biobank Axiom array data are used in this figure.

Extended Data Fig. 3 HWE p-values of linked variants.

Simulated HWE Chi-squared p-values at two variants with minor allele frequency of 11% with r2 of 0.95, in a sample of 400,000 individuals. Both variants are initially in HWE. We then remove a subset of samples which are homozygous for the rare allele at SNP 1. This leads to a deviation from HWE at SNP 1, but it also leads to a similar deviation from HWE at SNP 2. Only simultaneous selection acting in the opposing direction on SNP 2, or technical artifacts which create a dependence of missingness in one SNP on genotype in the other SNP explain a situation where HWE p-values are very different at both SNPs. Error bars denote the 5th and 95th percentile out of 100 replicates in each bin.

Extended Data Fig. 4 Power analysis.

Power to detect effects on mortality of a genotype with the frequency of ∆32/∆32 in a sample of the same total size and mortality rate as the cohort studied here, as a function of relative risk. The power to detect a 20% increase in mortality rate at a 0.05 significance level is 75%.

Extended Data Fig. 5 Odds ratios against sample prevalence.

Odds ratios (e𝛽) for all case-control phenotypes in five variants as a function of sample prevalence. Colors represent uncorrected p-values. Open circles represent case-control phenotypes with 10 or fewer cases in ∆32/∆32 individuals. Only phenotypes with more than five cases in ∆32/∆32 individuals are shown.

Extended Data Fig. 6 QQ-plot of the associations.

QQ-plot of the associations across all phenotypes. Each variant is plotted in a different color. Only phenotypes with more than five cases in ∆32/∆32 individuals are shown.

Supplementary information

Supplementary Information

Supplementary Text and Supplementary Tables 1–9.

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Maier, R., Akbari, A., Wei, X. et al. No statistical evidence for an effect of CCR5-∆32 on lifespan in the UK Biobank cohort. Nat Med 26, 178–180 (2020). https://doi.org/10.1038/s41591-019-0710-1

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