Nature and nurture: Insights from genetic, environmental and epigenomic studies of late-life depression

Abstract

Late-life depression (LLD) is a significant public health problem. It is one of the most common neuropsychiatric disorders in later life, and is associated with increased disability, morbidity and mortality. This thesis aims to obtain new insights into its pathophysiology by exploring the genetic, environmental and epigenetic influences on LLD in samples from the Older Australian Twins Study and the Sydney Memory and Ageing Study.

First, the relative contributions of genetic and environmental influences on LLD and its co-variation with anxiety and hypertension were investigated in twin pairs. It replicated previous findings that LLD is significantly heritable, and additionally demonstrated that LLD shares genetic influences with anxiety but not with hypertension. Next, a systematic review of genetic association studies of LLD revealed there was limited research with a general lack of replication. The meta-analysis identified three variants (APOE ?2/?3/?4, BDNF Val66Met and SLC6A4 5-HTTLPR) as significantly associated with LLD. Using the Australian cohorts, replication of LLD or major depressive disorder (MDD) candidate single-nucleotide polymorphisms (SNPs) was attempted, with no significant results. Furthermore, the effects of early-life trauma on LLD were examined, with childhood emotional abuse and exposure to Holocaust trauma significantly predicting LLD. Neither type of early-life trauma showed significant gene-environment interactions with LLD or MDD candidate SNPs. Finally, an epigenome-wide association study of LLD was conducted using blood DNA methylation from monozygotic twin pairs. It identified 69 differentially methylated probes, some of which are located near or in genes that have previously been implicated in neuropsychiatric or neurodegenerative disorders. The genes associated with the top-ranked probes appeared to be enriched for a range of developmental processes, including central nervous system development and neurogenesis.

This thesis provides several novel contributions to the literature by identifying some important genetic, environmental and epigenetic influences on LLD. Taken together, the findings highlight the potential role of neurodevelopment in the pathophysiology of LLD, which can have significant implications for the prevention and treatment of LLD. Research on the genetics and epigenetics of LLD is clearly still at a nascent stage, and more research is warranted to further our understanding.