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No statistical evidence for an effect of CCR5-Δ32 on lifespan in the UK Biobank cohort

View ORCID ProfileRobert Maier, View ORCID ProfileAli Akbari, Xinzhu Wei, Nick Patterson, Rasmus Nielsen, David Reich
doi: https://doi.org/10.1101/787986
Robert Maier
1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
2Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
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  • For correspondence: rmaier@broadinstitute.org Ali_Akbari@hms.harvard.edu
Ali Akbari
1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
2Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
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  • For correspondence: rmaier@broadinstitute.org Ali_Akbari@hms.harvard.edu
Xinzhu Wei
3Department of Integrative Biology and Statistics, University of California, Berkeley, Berkeley, CA, 94720, USA
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Nick Patterson
2Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
4Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA
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Rasmus Nielsen
3Department of Integrative Biology and Statistics, University of California, Berkeley, Berkeley, CA, 94720, USA
5GeoGenetics Centre, University of Copenhagen, 1350 Copenhagen, Denmark
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David Reich
1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
2Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
4Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA
6Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA
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Abstract

A recent study reported that a 32-base-pair deletion in the CCR5 gene (CCR5-Δ32) 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 underrepresented in the genotyping data due to an elevated rate of missing data at rs62625034, possibly because the probe for this SNP overlaps with the Δ32 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-Δ32 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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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 02, 2019.
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No statistical evidence for an effect of CCR5-Δ32 on lifespan in the UK Biobank cohort
Robert Maier, Ali Akbari, Xinzhu Wei, Nick Patterson, Rasmus Nielsen, David Reich
bioRxiv 787986; doi: https://doi.org/10.1101/787986
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No statistical evidence for an effect of CCR5-Δ32 on lifespan in the UK Biobank cohort
Robert Maier, Ali Akbari, Xinzhu Wei, Nick Patterson, Rasmus Nielsen, David Reich
bioRxiv 787986; doi: https://doi.org/10.1101/787986

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