The role of somatic chromosomal abundance in risk and prognosis of Age-related Macular Degeneration

Brief Lay Background

Age-related Macular Degeneration (AMD) is the loss of central vision resulting from damage to the macula which is a concentrated area of light-sensitive cells at the back of the eye.

As it progresses, AMD causes severe vision impairment and can lead to loss of sight. There are two types of AMD. Dry AMD progresses more slowly, whereas wet AMD can progress rapidly to severe disease and sight loss. If detected early, treatment for wet AMD can help prevent the disease from getting worse. There is currently no treatment for dry AMD.

The main risk factors for AMD are increasing age, being female, smoking, and a family history of the disease. Lifestyle factors such as being overweight, not exercising and having high blood pressure are also thought to increase the risk of AMD.

What problem/knowledge gap does it help address

Although there is some understanding of how inherited genes influence AMD risk, the role of small genetic changes that accumulate from lifestyles and the environment over our lifetimes remains unclear.

As we age, we tend to lose or gain genetic material from cells in the body. Our genetic material is packaged up as 22 pairs of chromosomes (called autosomal chromosomes) and two sex chromosomes called X and Y. Loss of entire chromosomes is a hallmark of aging and is influenced by factors such as smoking and higher body mass index. For example, in men, entire loss of the Y chromosome in blood cells is thought to signal weakening of the immune system.

Previous research from Dr Grassmann’s team has recently shown that loss of the Y chromosome in blood cells increases the risk of AMD, regardless of other lifestyle or genetic risks. This loss occurs long before the onset of AMD, which means loss or gain of chromosomes could be an early marker of AMD.

However, it is unknown whether the loss of other chromosomes such as the autosomal or X sex chromosomes are linked to risk of AMD. Understanding if such links exist could help to predict risk of AMD and reveal potential molecules to target with treatments.

Aim of the research project

The project has three main aims:

• Determine whether chromosome abundance is a risk factor for early-, mid- and late-stage AMD to identify people at increased risk.
• Understand the role of chromosome gain or loss in AMD severity and disease progression so this can be used as a marker to determine prognosis for people with existing AMD.
• Identify genes and molecules in the eye that are influenced by the loss or gain of chromosomes linked with AMD, which could potentially be targeted with treatments.

This award will also contribute to building capacity in AMD research as it will lead to a PhD for an early career researcher.

Key procedures/objectives

1. Combine estimates of chromosome abundance from people with and without AMD.
2. Explore chromosome abundance as a risk factor for AMD, differences between late stages of dry and wet AMD, related to early-stage AMD through the presence of drusen – the only known feature of the condition at this stage.
3. Study the impact of chromosome abundance on known clinical features that predict the course of disease.

Potential impact on people with sight loss

The PhD student’s work will provide crucial insights into the genes and biological pathways involved in development of AMD at all stages from early onset to the later, sight-threatening forms of the disease. Ultimately, it could help doctors more accurately predict the course of disease for individual patients and pave the way for urgently needed options for preventing and treating this leading cause of sight loss.