Post doc Andrew Brown
We have long known that diseases such as schizophrenia and bipolar disorder have genetic risk factors, from observing when the disease is present in multiple family members or even pairs of identical twins.
Can we use gene expression to construct a mechanistic model of how DNA increases the risk of mental illness?
More recently we have been able to discover 100s of places in our DNA (or loci) which predispose us to these diseases. However, we currently have little idea of how these loci act. Gene expression is one way in which we are trying to answer this question. Gene expression is the first step in how the genetic code is read: DNA is transcribed into mRNA, later this mRNA is converted into proteins. DNA itself can affect this process, we know that there exist certain loci (called eQTL) which make a gene create more of this mRNA. If we see that such an eQTL also predisposes someone to mental illness, then we can infer that the increase in mRNA is in some sense mediating this process.
What form does the genetic influence on desease take?
Another gap in our current knowledge is about the genetic architecture of diseases such as schizophrenia: most of the genetic influence on disease is unknown and there is much debate on what form it takes.
Competing theories include:
1) there are a great number of genetic influences, most very small (polygenic model),
2) genetic influences are usually rare in the population (rare variants),
3) genetic influences do not work alone, but in combination with each other (epistasis), and
4) genetic influences only exhibit in certain environments (gene-environment interactions).
Despite much work in this area, this is still very much an open question. Because gene expression is a phenomenon so close to DNA, we observe much larger effects. This means that aspects of genetic architecture which require hundreds of thousands of people to observe when studying diseases such as schizophrenia (more than the total number with the disease in Norway), we can observe with hundreds. I have looked for evidence of these four phenomena affecting gene expression: the assumption being that if they work as this level they likely "bubble up" to act on disease traits as well.