Gene expression refers to the process of converting genetic information in the DNA into protein. DNA is first transcribed into RNA in the nucleus. The sequences in the DNA that code for protein are called exons. It was a remarkable discovery that the sequence that codes for protein is interrupted in eukaryotic genes into multiple exons separated by non-coding sequences termed introns.

Exons are typically 100 base pairs long and the average gene may contain between 1 and 20 of them. Hence, only about 10% of a genes DNA sequence actually codes for protein. The gene’s DNA is first transcribed into RNA. This transcript is then edited so as to remove the intronic sequence and to primarily include the sequences that code for protein. After further processing, this becomes a messenger RNA that leaves the nucleus. In the endoplasmic reticulum, this mRNA is then translated into protein, which goes on to serve its designated function in the cell.

Genetic Disorders
Strongly genetic disorders are termed Mendelian after Gregor Mendel. In these traits, one or more SNPs or mutations typically have a very strong effect on gene function such as making the gene and its protein non-functional. In these disorders, such as cystic fibrosis or Huntington’s disease, one gene is responsible for all cases of the illness, though the illness may result from different mutations in the gene. Mendelian illnesses are transmitted in dominant or recessive modes depending on whether one or two copies of the disease gene are necessary to cause illness. These illnesses tend to be severe and relatively rare. However, more common medical disorders are not so simple. Many genes may be involved and interact to cause illness. In these complex genetic disorders, the effect of each gene may be relatively small. Individuals may inherit multiple genes with variations (termed alleles) that predispose to illness. The more such susceptibility alleles they inherit the greater their risk for illness. Together these genetic risk factors may make the individual more vulnerable to environmental factors that in turn cause illness. Therefore, in complex genetic disorder, such as psychiatric disorders, genes do not singularly dictate whether one is ill or not. Rather, they serve as risk factors that interact with environment and increase the risk that one may become ill. Many genes are involved that may affect different points in biochemical pathways involved in illness. No single gene will yield a test for the illness. Multiple genes can be tested that together may indicate someone’s risk or the probability that they have one diagnosis or another.

Mapping Genes
Advances over the last two decades have made it possible to map genes for genetic traits. Each gene is always in the same position on a chromosome. By using DNA markers, it is possible to identify segments of DNA that consistent are present along with illness and thereby mark the approximate location on a chromosome of a gene for a disease or trait. Because this approach is based on the position of genes rather than their known function, it has been termed gene mapping or positional cloning. A DNA maker is typically an anonymous segment of DNA with no known function that is variable between individuals in the population. The position of millions of such markers, most of which are SNPs, is known in the genome. This map of SNPs provides a powerful tool for finding genes for genetic disorders. This is typically done in two ways, linkage or association. In genetic linkage, markers are tested to see if their alleles consistently are transmitted within families along with illness. If this occurs in a sufficient number of cases, then one can surmise that a gene for the disorder is near a given marker. Since the position of the marker is known, then the approximate position of the disease gene can be inferred. Using this strategy, the entire genome can be covered using several hundred markers that span all the chromosomes. Association refers to the observation that a specific allele of a maker occurs more often in a set of unrelated patients, as compared to a set of unrelated control subjects. However, for association to be detected, the marker must either be the disease causing mutation or be extremely close to it, on the order of 10,000-20,000 bp. Until recently, the lack of markers has made it infeasible to cover the whole genome using association. However, the recent identification of millions of SNPs and microchip based methods to genotype hundreds of thousands of markers simultaneously now make such strategies possible. This approach, called whole genome association, is just beginning to be applied and promises new discoveries in complex disorders.

Genes and psychiatry and mood disorder
The data collected to date on psychiatric disorders are consistent with this model of complex genetic disorders. Studies of families have long indicated that bipolar disorder is familial, meaning that it is likely inherited. The relatives of someone with bipolar disorder on average have a 7% risk for bipolar disorder, 700% greater than the risk for the general population. Studies of identical twins have shown that this increase in risk is genetic. If one identical twin has bipolar disorder, in about 50-70% of cases, the other twin will also have bipolar disorder. This is compared to fraternal twins, who share only half their DNA and for whom the risk is about 15%. These studies suggest that about 50-70% of what causes bipolar disorder is genetic. It is important to note that this is not 100%. Again, the genes are risk factors that only explain a portion of the cause of bipolar disorder.

Application of genetic mapping methods in psychiatry have to date led to the identification of one or two dozen general chromosomal regions for bipolar disorder or schizophrenia and about 6-12 specific genes. The results so far indicate several things. First, consistent with expectations for a complex disorder, there are likely many genes involved. Secondly, some of the same regions and genes involved in bipolar disorder may also be involved in schizophrenia. This suggests a more complex relationship between these disorders than had been thought. This is also consistent with the idea raised earlier that biochemical pathologies involved in illness may cut across our current behaviorally defined diagnostic system.