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.

Major Depressive Disorders (MDD) make up the most prevalent class of psychiatric disorders and will affect ~25% of us. The social and economic costs of these disorders are enormous with an estimated loss to the UK economy alone of some #9 billion per year. An additional problem facing the treatment of sufferers is variability in the efficacy of the drugs used to treat MDD.
These disorders have a strong genetic basis. Although many of these studies are still ongoing it is becoming clear that studying the effects of polymorphisms on coding regions alone will not give us a complete picture of the underlying causes.
We will explore the hypothesis that susceptibility to MDD and variation in drug efficacy may also involve polymorphisms within the gene regulatory regions responsible for maintaining normal gene expression of components of systems including the serotoninergic, dopaminergic, tachykininergic, and NPY pathways.
The objectives of this project will be to use a predictive systems biology approach to identify regulatory regions within the human genome by comparative genomics. The tissue specific and inducible status of these enhancer candidates will be analysed initially in primary cell lines and subsequently in transgenic animals in both the MacKenzie and Quinn labs.
By concentrating on SNPs within highly conserved and thus functional regions of the genome this novel approach will greatly accelerate the association of SNPs within these regions with susceptibility to MDD that will be examined in large MDD patient samples in the Institute of Psychiatry by a team headed by McGuffin and Breen.
Molecular analysis of protein-DNA interactions affected by these polymorphic ECRs will also be examined using a combination of EMSA and ChIP assay in the MacKenzie and Quinn labs. Finally, translational pharmacogenomic studies of the affects of a number of different psychoactive compounds on positively associated regulatory polymorphisms will be further examined using primary culture and in transgenic animals in the Quinn lab.
This is a novel, ambitious and multi-disciplined approach involving a unique collaboration between 3 laboratories that are individually recognised as being international leaders in their respective fields. By applying a unique combination of systems biology, patient based association study and translational pharmacogenomics this exciting collaboration has the potential of changing our understanding of the causes of MDD and will act as a translational platform that will allow for the development of more effective and specific anti-depressive therapies.