Gudbjartsson, D. | Search bioRxiv

bioRxiv2019

CCR5-del32 is not deleterious in the homozygous state in humans

Recently, Wei and Nielsen1 reported an analysis of UK Biobank data which suggested that the well-known HIV-protective variant CCR5-del32 is associated with a 21% increase in all-cause mortality. We demonstrate, using two well-powered population samples in Iceland and Finland with extensive health data and death information, neither an effect on mortality nor increase in risk of any disease. Further reexamination of the UK Biobank (UKBB) data suggests that the very modest association was with a SNP of poor genotyping quality - at a nearby proxy SNP, no statistically significant impact on mortality nor deviation from Hardy-Weinberg equilibrium exists in the UKBB sample. We thus find no evidence of any meaningful risk of increased mortality from homozygosity of CCR5-del32.

genetics↗

bioRxiv2019

Genetic predisposition to mosaic Y chromosome loss in blood is associated with genomic instability in other tissues and susceptibility to non-haematological cancers

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism, yet our knowledge of the causes and consequences of this is limited. Using a newly developed approach, we estimate that 20% of the UK Biobank male population (N=205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes involved in cell-cycle regulation, cancer susceptibility, somatic drivers of tumour growth and cancer therapy targets. Genetic susceptibility to LOY is associated with non-haematological health outcomes in both men and women, supporting the hypothesis that clonal haematopoiesis is a biomarker of genome instability in other tissues. Single-cell RNA sequencing identifies dysregulated autosomal gene expression in leukocytes with LOY, providing insights into how LOY may confer cellular growth advantage. Collectively, these data highlight the utility of studying clonal mosaicism to uncover fundamental mechanisms underlying cancer and other ageing-related diseases.

genetics↗