An Emerging Gene
As a promising technique, imaging genetics represents the specific ability to understand the neurobiological mechanisms through which genes may have an impact on variability in these emergent phenomena
By: Dr.Amit Kharat
Genes have an unparalleled potential impact on all levels of biology. In the context of disease states, particularly behavioral disorders, genes are fundamental to our understanding of the mechanisms involved in the development of disease. Whereas genes alone cannot explain most human behaviors, and certainly much of the variance in aspects of brain information processing will not be genetically determined directly, variations in a genetic sequence that have an impact on gene function will contribute a substantial amount of variance to these more complex phenomena. Neuroimaging techniques to investigate the effects of genetic variations on brain function or structure in order to better understand their impact on behavior and disease phenotypes is referred to as imaging genetics. As a promising technique, imaging genetics represents the specific ability to understand the neurobiological mechanisms through which genes may have an impact on variability in these emergent phenomena. So far, imaging genetics has dealt mostly with understanding the pathophysiology of disease and normal biology. Serving a dual objective, imaging genetics uncovers the effects of disease-risk gene variations on brain function or anatomy and at a theoretical level; it shows the role of identified risk genes with functional effects on imaging measures, which could provide novel drug targets. Imaging genetics is an emerging tool that is capable of identifying the genetic risk of a disease based on both clinical factors and imaging techniques. Genes are fundamental to our understanding of the mechanisms involved in the development of disease and Parkinson disease, obsessive–compulsive disorder, AD, schizophrenia and behavioral disorders are some of the conditions under study using this technique. There are now many successful examples of genetic imaging consortia, including ADNI (Alzheimer's disease Neuroimaging Initiative), IMAGEN (mental health and risk-taking behavior in teenagers), EPIGEN (epilepsy), the Saguenay Youth Study (development), fBIRN (schizophrenia), and CHARGE (heart and aging).
Molecular imaging's key utilisation is in the interrogation of biologic processes in the cells of a living subject in order to report on and reveal their molecular abnormalities that form the basis of disease
Modalities used in imaging genetics
Molecular imaging's key utilisation is in the interrogation of biologic processes in the cells of a living subject in order to report on and reveal their molecular abnormalities that form the basis of disease. Molecular imaging includes several imaging modalities under its umbrella; such as bioluminescence, fluorescence, positron emission tomography (PET), single photon emission computed tomography (SPECT), computed tomography (CT), optical imaging, ultrasound, and magnetic resonance imaging (MRI). Functional neuroimaging, using functional magnetic resonance imaging, EEG, or positron emission tomography, provides an efficient and effective tool with which to explore the impact of brain-relevant genetic polymorphisms by quantifying the activity of specific brain regions in association with particular cognitive and emotional tasks that the research participant is asked to perform during the procedure. These techniques promise to identify neural pathways through which these variants contribute to the emergence of variability in behavior and disease. Three basic principles have been articulated for imaging genetics namely selection of candidate genes, control for nongenotype factors, and selection of appropriate tasks for the subject to perform during functional imaging. Well-defined functional polymorphisms (single-nucleotide polymorphisms or other structural variants) in coding or promoter regions previously linked with specific physiological effects at the cellular level and whose impact has been described in distinct brain regions are an ideal starting point. Selecting variants that have known neurobiological consequences (e.g., increases in serotonin [5-HT] signaling) is important because of an emphasis in imaging genetics on specifying mechanisms through which genes have an impact on brain and related behavior. Because of small genetic effects, choosing a well-characterised behavioral task for subjects to perform during functional neuroimaging that is both sensitive and specific to the brain process under investigation is of crucial importance to the success of identifying functional correlates of genetic variation. The ideal tasks for these investigations are thus ones that have been established to engage specific brain systems robustly in all subjects, as well as display variance both across control subjects and between patients and comparison subjects. Moreover, in child and adolescent populations, tasks that are both developmentally appropriate and acceptable for use with the specific psychiatric sample being studied should be chosen. For example, in previous imaging studies, amygdala reactivity to threat-related emotional facial expressions has been assayed using a well-characterised challenge paradigm that robustly engages the amygdala and interconnected corticolimbic structures. Importantly, this task has been shown to effectively engage the amygdala in control subjects and to demonstrate altered amygdala function in diverse psychiatric disorders.
What do studies say?
The imaging genetic researches with the 5-HTTLPR highlights the effectiveness of this strategy in illuminating specific mechanisms that may mediate individual variability in behavior and risk for disease. Imaging genetic studies investigate the effects of genetic risk variations emerging from genome-wide association studies (GWAS). Another rapidly emerging area is applying GWAS directly to the imaging data and performing statistical inference on individual voxels or regions of interest rather than on behavior or disease phenotypes; this approach offers the advantage of testing the whole genome on imaging endpoints, thus allowing the identification of novel variants that influence specific brain circuitry or structure, which might be further investigated as putative disease risk factors or novel drug targets. Conventional imaging methods, such as computed tomography (CT), ultrasound, and magnetic resonance imaging (MRI), provide sensitive detection of anatomic information at the macroscopic level. As opposed to those anatomic techniques, molecular imaging can provide visualisation and quantification of biochemical processes at cellular and molecular levels. Initial approaches to molecular imaging involved directly targeting cell surface receptors, metabolic enzymes, and transporters using probe molecules that directly interact with their targets, e.g., antibodies, peptides, aptamers, and small molecules. The most widely used examples of such direct imaging are positron emission tomography with [18F] fluorodeoxyglucose (FDG-PET) for detecting cancer. Molecular-genetic imaging is an indirect imaging method where genetic material is introduced to and later detected within target cells using cognate probe. The technique requires a promoter to drive the expression of a reporter gene in a target cell, a reporter gene, a mechanism, e.g., a viral or nonviral vector, to enable transfection of the target cells with the reporter transgene, and an imaging probe that interacts with the reporter transgene in such a way as to enable visualization. A particularly malignant version of glioblastoma was identified by researchers and connected its MRI scans and genetic profile with poor patient outcomes. Instead of saying all patients with [glioblastoma] tumors are the same; they can be differentiated into two subtypes based on outcome. Their work suggests that these patients should be identified and treated more aggressively, while patients with less malignant cancers can be spared the side effects of aggressive treatment. At the genetic level, two patients with glioblastoma (or any particular cancer type) may have very different tumors. For example, one patient might respond well to a therapy targeting tumor blood-vessel growth, while the other patient's tumor might have activated a genetic program that allows it to resist such a therapy.
The merging of GWAS with neuroimaging appears to be a natural pairing to explain the biological roots of complex disease where genetics seeks explain the heritability of behavior, imaging illuminates its neural processes. The idea that linking genes and brain function might better describe mental processes provides hope for a frustratingly difficult-to-treat array of mental disorders. If the collaborative environment can continue to press forward with reliable science, great strides might be made in the areas of diagnosis, treatment, and prevention.