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Detection, causes and consequences of sex chromosome mosaicism


Type

Thesis

Change log

Abstract

Sex chromosome mosaicism, including male mosaic loss of chromosome Y (LOY) and female mosaic loss of chromosome X (LOX), is the most common form of clonal haematopoiesis (CH) that can be defined as the age-related clonal expansion of blood cells with somatic mutations. With the decreased cost of sequencing, the development of new bioinformatics methods and the emergence of large cohorts with both genotype and phenotype data, there has been much progress in the detection, causes and consequences of sex chromosome mosaicism especially LOY. On the contrary, the studies of LOX are still very limited.

The most recent genome-wide association study (GWAS) to investigate the genetic determinants of LOY in 205,011 males identified 156 independent signals and highlighted a key role for genes involved in cell-cycle regulation and DNA damage response. Population studies typically determine LOY using genotype intensities derived from genotype array data, the accuracy of which varies by the number of Y chromosome probes on the array and are technically noisy. Inaccurate estimation of LOY reduces the power to identify genetic and phenotypic associations with LOY. To overcome these constraints, I developed a robust estimator of LOY , which was derived from several orthogonal approaches using both whole exome sequence and genotype array data. The same method was also implemented for LOX.

In chapter 2, in genetic data derived from 205,604 UK Biobank males and 243,765 females, the new method improved the accuracy of LOY/LOX estimation as measured by the strength of association between LOY/LOX and age, smoking status, and polygenic risk of LOY/LOX derived from previous GWAS. In chapter 3, I then used this revised and validated LOY instrument to conduct a new GWAS of LOY status in the UK Biobank. Beyond the previously identified 156 signals, I identified 22 novel LOY-associated loci. I leveraged the shared genetic architecture between LOY and other related traits to improve the power to identify variants associated with the risk of myeloproliferative neoplasm (MPN). Based on available MPN GWAS summary statistics, I identified 13 novel loci reaching genome-wide significance, including locus near PARP1, which encodes an established target of cancer therapy.

The method used to detect somatic LOY/LOX can also be used to identify congenital sex chromosome abnormalities. In chapter 4, the detection method and characterisation of male sex chromosome abnormalities were reported, as a similar study on female sex chromosome abnormalities in UK Biobank had already been published.

The whole exome sequence also provided the chance to explore the effect of rare non-synonymous variants, which are rarely captured by GWAS arrays. In chapter 5, the first exome-wide association study (ExWAS) for LOY was conducted on over 80,000 men from UK Biobank. As well as CHEK2, which had been identified on a previous GWAS on LOY, a novel gene, GIGYF1, was identified, in which loss-of-function variants increased the risk of LOY and Type 2 diabetes (T2D) by 6-fold. This finding illuminated the potential link between LOY and metabolism. In chapter 6, the first ExWAS of LOX and an extended ExWAS of LOY were performed on over 450,000 samples from UK Biobank. For LOY, the power increase was observed for the two identified genes, CHEK2 and GIGYF1. In addition, loss of function variants in three clonal haematopoiesis of indeterminate potential (CHIP) genes, DNMT3A, TET2 and ASXL1, were negatively associated with LOY. For LOX, rare damaging variants in FBXO10 were identified to increase the risk of LOX.

In summary, this thesis shows that the accuracy of estimating LOY/LOX was improved by combining multiple approaches using both GWAS array and whole exome sequence data. Using both GWAS and ExWAS approaches, the thesis further improved the understanding of the genetic causes of sex chromosome mosaicism. This innovative approach improved the power to detect novel mechanisms that regulate clonal mosaicism in blood and can be used to enhance the identification of novel genes associated with the risk of related cancers.

Description

Date

2022-08-01

Advisors

Perry, John
Ong, Ken

Keywords

Sex chromosome mosaicism, clonal haematopoiesis, GWAS, mosaic loss of chromosome Y, WES

Qualification

Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge