DNA methylation and breast cancer risk factors: insights from twin and family studies
AffiliationMelbourne School of Population and Global Health
Document TypePhD thesis
Access StatusOpen Access
© 2018 Dr Shuai Li
DNA methylation, the most studied epigenetic mechanism regulating gene expression, has been thought to play a critical role in the aetiology of complex diseases and traits, including breast cancer. Twin and family studies have investigated the unmeasured causes of DNA methylation variation; there are, however, several research gaps, such as interpreting the average heritability across sites as the heritability of genome-wide DNA methylation level and assuming DNA methylation variation across sites to have the same causes. Two DNA methylation features, genome-wide average DNA methylation (GWAM) and epigenetic age acceleration, are putatively associated with breast cancer risk. The causes of variation remain unknown for GWAM and have not been well investigated for epigenetic age acceleration. Understanding the potential causality between DNA methylation and conventional breast cancer risk factors, which has been rarely investigated for body mass index (BMI), mammographic density and smoking, might bring a better understanding of breast cancer aetiology. To address current research gaps, my thesis used DNA methylation data from multiple twin and family studies to investigate the causes of variation in GWAM, in site-specific DNA methylation and in epigenetic age acceleration, and to investigate the potential causality between DNA methylation and BMI, mammographic density and smoking with a novel analytic method using data for related individuals - Inference about Causation through Examination of FAmiliaL CONfounding (ICE FALCON). My thesis found that: a) genome-wide methylation level, measured as GWAM, is determined by prenatal environmental factors acting in utero, the effects of which last into old age, and by environmental factors shared by cohabitating family members, including spouse pairs (Chapter 4); b) site-specific variation DNA methylation has specific causes, and substantial variation is explained by measurement error and environmental factors (Chapter 5); c) evidence consistent with twin birth changing the intrauterine environment such that sibling pairs both born after a twin birth are correlated in DNA methylation while sibling pairs both born before a twin birth are not (Chapter 6); d) variation in epigenetic age acceleration is caused by shared environmental factors as well as genetic factors (Chapter 7); and e) BMI, mammographic dense area and smoking are associated with DNA methylation at several genetic loci, and these associations are likely due to the causal effects of the three factors on DNA methylation, the same conclusion to those made by Mendelian randomisation analysis (Chapters 8 to 10). The findings of my thesis suggest that DNA methylation appears to be fundamentally about the way the environment influences the way genes work. Although there might be methylation sites at which the variation has a genetic basis, these are rare. The effects of the environment can start from the time of conception, or at least while in the womb, and continue into adulthood. Some of those environmental effects are shared by family members, even spouse pairs, and these effects can potentially influence breast cancer risk in adulthood. Conventional breast cancer risk factors can cause changes to DNA methylation, indicating that DNA methylation might explain in part why these factors modifying risk. Most of the novel results of this thesis could not have come about without the use of data from twin pairs, or of data from other pairs of relatives including spouse pairs. The thesis has also shown the value of ICE FALCON in making inference about observational epigenetic association based on considering familial confounding - ICE FALCON gives the same conclusion as those being found by Mendelian randomisation. More importantly, ICE FALCON does not require extensive genome knowledge and data that are required by Mendelian randomisation.
KeywordsDNA methylation; epigenetics; breast cancer; twin studies; family studies; epigenome-wide association study (EWAS); causal inference
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