Week 16

It works! Our program made a list of candidate genes. After 150 iterations, the SZ positives made a novel list of genes that may be involved in Schizophrenia, ranging from potassium gating to Golgi associated proteins to proteins involved in cellular motility. This program can be refined, and so we will spend the upcoming weeks narrowing the list and making sure that this process can be as precise and accurate as it can be.

Another thing that I did myself was rank SZ genes, since I didn’t want to include all 2700 genes that are implicated. First, for every dataset (Psychiatric Genomics Consortium, Common Mind Consortium, SZGene, hiPSC rtRNA results, chromosome conformation predictions), I gathered the magnitude of the change in expression/ the frequency of mutation ¬†and the p value for each gene. Then I took the log base 2 of the change and the negative log base 2 of the p value and multiplied them together.

There are a couple of important things to note. Schizophrenia is primarily a regulation problem. As the Psychiatric Genomics Consortium study pointed out, there is very little genetic variation in SZ patients from control patients in coding regions; there are only a dozen significant mutations in coding regions. Of all the mutations, the one with the highest confidence, with a p value of 10^-15, has a frequency in SZ patients at 0.87 and a frequency in control patients at 0.85. SZ is undeniably a confluence of many, possibly hundreds or thousands, of tiny genetic variations.

Apparently, many of these mutations are common among several major psychiatric disorders. An article was recently published in Science that showed that Schizophrenia, Bipolar Disorder, Depression, and Autism all have highly correlated patterns of cortical gene expression (http://science.sciencemag.org/content/359/6376/693.full). The tool we are developing will hopefully be powerful enough to help us identify the underlying causes of these diseases.