PREDICTION AND ANALYSIS OF A REGULATORY SNP MAP OF MAJOR DEPRESSIVE DISORDER

Major depressive disorder (MDD) constitutes the most frequently occurring mental health problem in the world and will affect up to 25% of us during our lifetimes. Worryingly, MDD is on the increase. This study will set out to find the genetic causes of MDD by examining changes in the DNA sequence of people who are more susceptible to depression. In addition, this study will determine why certain MDD sufferers do not respond to current treatments. Previous studies of this type have examined possible changes in the regions the genome that make protein. Recently, however, it has been demonstrated that the majority of differences between individuals, including disease susceptibility, may be caused by changes, not in the genes themselves, but in the poorly understood DNA sequences that act as switches for these genes. These switches ensure that genes essential to healthy brain function are only used in the correct parts of the brain at the proper times and in the right dose. Unlike genes, little is known of these switches as, up to now they have been very hard to find. However, teams led by Dr. MacKenzie have had considerable success in identifying switches responsible for driving the expression of genes known to be involved in depression, addiction and inflammatory pain. This project will combine Dr. Mackenzies ability to detect important switch sequences, that make up less than 5% of the genome, with our new ability to detect harmful mutations within these switches. Professor McGuffin and Dr. Breen will then analyse the DNA of over 1000 individuals suffering MDD to determine whether the occurrence of particular switch differences can be associated with susceptibility to MDD. Dr MacKenzie and Prof. Quinn will then carry out molecular biological studies of these switch differences to determine the biochemical pathways affected. In addition, Prof Quinn will evaluate how the activity of variants of these switches are affected by a number of known antidepressant drugs to determine the genetic causes of variation in MDD drug treatments. By combining a number of newly developed computer based, patent sample based and molecular biology techniques this study has the real potential of hugely expanding our understanding of the mechanisms regulating the use of key genes in the brain and how changes on these mechanisms may contribute to susceptibility to MDD. Furthermore, this study will allow us to examine why many MDD sufferers do not respond to current anti-depressive medications.