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Data availability
All the data used in this study are available with the permission of the UK Biobank.
References
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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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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.
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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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DOI: https://doi.org/10.1038/s41591-019-0710-1
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