Uncovering Sex-Specific Biological Mechanisms of Depression: Insights from Large-Scale Data Analysis

Depression causes feelings of low mood and a loss of interest in things that used to be enjoyable. One in six people suffer from depression during their lifetime. However, women are twice as likely to have depression compared to men. There are likely to be a number of reasons for this difference, although we don't yet fully understand them. Biology is likely to play an important role in this difference between the sexes and my research will explore this in more detail. My previous work has shown that different genes are involved in female depression compared to depression in men. This previous research used data from nearly 300,000 people. The new work will examine millions of people and will greatly improve on what we can detect. The results from this first project will also be used to identify the sections of DNA that might be good targets for antidepressant drugs. If we can discover which drugs are likely to work based on someone's DNA, we can also then figure out which drugs might not work. We will then test this using the UK Biobank. The UK Biobank has DNA information and is linked up to past prescription records. So, we can check whether the people we think won't respond to a drug based on their DNA actually end up switching treatments. It is hoped this work will help doctors decide on the best medication for each patient with depression. Some DNA is inherited via the sex chromosomes (known as the X and Y chromosomes). However, the sex chromosomes are often overlooked in depression research even though they might contain useful information. Genes are turned on and off at different points during our lives and so this may also happen when someone becomes depressed. Using the largest data available we will see if we can find evidence of genes on the sex chromosomes being turned on or off due to depression. Females get two X chromosomes, one inherited from their mother and one from their father. In every cell in the female body, one of these X chromosomes is inactivated. This is normally a random process. So, half of cells have the X chromosome from their mother inactivated, and the other half of cells have the X chromosome inherited from their father inactivated. However, in some women there are more cells that have either the X chromosome from their mother or father inactivated, which is known as skewness. This skewness has been observed in other mental health conditions and we will look at whether it occurs in depression. There are molecules that circulate in our blood that might put us at greater or lower risk of depression. We will look at new molecular data from the UK Biobank to identify those molecules that differ for people with depression. We will do this separately for women and men using state-of-the-art methods. This will provide us with molecular profiles for depression. We will then test whether any molecules differ between men and women in their link with depression. The final project will look at whether changes in particular molecules lead to depression, or these changes are because of having depression. Each of these projects will provide us with further clues about the biology of depression. The hope is that this information will identify the best treatment for those with the disorder.