HOW DOES COMPLEX GENETICS AFFECT NEUROLOGICAL DISEASES?
Many neurological diseases are complex genetic diseases. Examples include autism, schizophrenia, depression, bipolar disorder, and late onset Alzheimer’s disease. That multiple genes are involved in these disorders likely reflects the complex biological processes that underlie human behavior and cognition. There may be many ways to perturb these processes genetically and environmentally, and, at the same time, there may be many compensatory mechanisms in place that help mask the effect of perturbations.
Thus, no one individual factor causes the disease by itself, and multiple factors together contribute to the disease.
Genetic mapping studies, and more recently exome sequencing and genetic tests to search for copy number variation, have been used to help identify genes involved in various neurological diseases. Many thousands of individuals with autism or schizophrenia, along with their family members, have had their DNA analyzed. A number of genes have been identified that appear to contain an increased number of mutations in certain neurological diseases. Thus far, over 370 candidate genes have been implicated in autism and over 200 in schizophrenia. It has also been discovered that gene copy number variations may contribute to disease and that gene dosage may be an important contributor to autism. Many of the genes that have been implicated in autism and schizophrenia are involved in synaptic functions; synapses are the junctions through which nerve cells communicate with one another and thus are important for proper functioning of the brain. Interestingly, many of the genetic loci implicated in autism and schizophrenia overlap, suggesting that these two diseases have some common features. Much effort is underway to identify additional biological pathways associated with each of these diseases.
Recently, research from the author’s laboratory utilized a novel approach to identify a molecular network underlying autism spectrum disorders. Essentially, existing information about which proteins like to work together through their physical interactions was used to create an “interactome map.” Genes previously implicated in autism were located onto this interactome and many of them mapped onto a particular molecular network or module. The expression pattern of the genes in this autism module was predicted by consulting a brain atlas that details which genes are expressed where in the brain. In addition to cortical neurons, the autism module genes are largely expressed in the corpus callosum and oligodendrocyte cells, a region of the brain and type of cell not usually considered to be linked to autism. Thus, this novel integrated omics approach suggested a molecular network (rather than just a gene or genes) underlying a complex disease and provided insight into how it functions. It also offered a new approach that can be used to help decipher other complex genetic disorders.
Although extensive effort has been devoted to understanding the genetic basis of neurological diseases, as with other complex diseases, to date there is not a strong predictive genetic test to help identify individuals at high risk. If we had this information, we might be able to screen subjects at high risk and detect disease earlier—and possibly improve outcomes with early intervention. In fact, despite the large number of genes that have been implicated in complex neurological diseases, less than 10% of the genetic or other factors underlying any of these diseases have been identified. It is likely that additional genes remain to be discovered. Furthermore, combinatorial effects of multiple genes (i.e., gene–gene interactions) and gene–environment interactions contribute to many complex diseases, and integrating these factors into the determination of disease risk is in its infancy.