Table of Contents > Genomics > Neurogenetics Print



Also listed as: Genetics and the nervous system
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  • Association studies, ataxia, behavioral functions, cognition, complex trait analysis, dementia, family history, gene-based therapeutics, gene expression atlas, gene mapping, genes, genetic linkage studies, genetics and the nervous system, Huntington's disease, migration, molecular genetics, multiple endocrine neoplasia (MEN) type 2, multiple sclerosis, mutagenesis, nervous system development, neurofibromatosis, neurological disorders, neuronal patterning, Parkinson's disease, phenotyping, schizophrenia, spinocerebellar ataxia, tuberous sclerosis complex, Von Hipple-Lindau syndrome.

  • Neurogenetics is the study of genetic influences on the nervous system. This field includes the study of nervous system development in an embryo and neurological conditions that have a genetic basis. Neurogenetics seeks to gain a better understanding of the genetic basis of normal and abnormal functioning of the nervous system and uses research from many different fields, such as biophysics, cell biology, human genetics, neuroanatomy, neurochemistry, neurology, neuropathology, neurosurgery, and psychiatry.
  • Neurogenetics aims to identify genes that act on the nervous system by collecting family data and applying molecular genetics methods. In this way, neurogeneticists may identify the molecular mechanisms of disease genes.
  • By using animal models and lab studies, researchers attempt to identify specific genes and their respective neurological outcomes, particularly if the outcome is a disease. The goal is to understand the genetic basis of normal and abnormal functioning of the nervous system. This understanding would allow researchers to create therapies and drugs that can compensate for lost or abnormal gene function in neurological disorders.
  • Neurogenetics also seeks to identify the genes responsible for brain and spinal cord development. Neural development consists of a number of steps, starting with the birth of neurons, which are the cells that make up the brain and spinal cord, and the process of how those cells develop to perform specific functions. These cells then migrate from their birthplace to their ultimate positions. Neural development includes the growth of axons, which form connections with other neurons, and the dynamic changes that occur in order to accommodate learning and memory.

  • The field of neurogenetics uses many methods to identify genes that cause neurological diseases. Generally, animal and laboratory experiments are performed to study gene function with the goal of developing gene-based therapies for neurological disorders and identifying gene therapy and drugs to target specific gene products. In addition, neurogenetics seeks to analyze the genetic basis of normal neurological development and function.
  • Complex trait analysis: Complex traits are controlled by more than one quantitative trait loci, which are sections of DNA that are closely linked to the genes that underlie the trait in question. This can make it difficult to identify the gene that may be responsible for a particular trait. For some diseases, a large number of quantitative trait loci exist, resulting in complex phenotypes associated with "candidate" genes. Patterns of gene expression in the central nervous system are highly variable and heritable. This genetic variation among normal individuals leads to considerable structural, functional, and behavioral differences. Techniques have been developed to dissect genetic networks, starting from base pairs to behavior, using a reference population of recombinant inbred strains. From this analysis, a relationship between gene expression and pharmacological and behavioral traits can be determined.
  • Neuronal patterning: Neuronal patterning involves research that centers around a signaling pathway responsible for nervous system development. Using the mechanisms of the nervous system, researchers identify the point in the pathway responsible for a specific cascade of morphological changes they are studying and then backtrack. They use gene arrays to identify the signaling targets of specific DNA. In a growing embryo, cells develop differently, for example, in the head or tail end of the embryo. They also form segments, which develop into different body parts. The hedgehog signaling pathway gives cells the information they need to make the embryo develop properly. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The signaling pathway also has roles in the adult, and when it malfunctions, it can result in diseases such as basal cell carcinoma.
  • Migration: The study of migration involves a branch of genetics that studies the way in which the frequencies of different alleles (alternative forms of a gene) in populations of organisms change, as a result of natural selection and other processes. During early brain development, neurons are born and move to reach their target, eventually making up the different parts of the brain. This process is controlled by various environmental and genetic factors. The focus of this research is to identify how the genes control this process. Research in this area typically uses mice that lack the gene of interest so that researchers can examine the behavior of the animal without the effects of that gene.
  • Cognitive and behavioral functions: This type of research aims to determine how certain genes work to control cognition and behavior. One way to do this is to examine the brain activity of animals that lack a particular gene using various brain imaging techniques. Researchers may also examine the brain activity of populations characterized as having a certain genetic disorder. Genetic risk factors are also being determined through cognitive assays, which are tests that require certain parts of the brain to be functioning correctly, such as the medial temporal lobe for recall memory functions.
  • Gene expression atlas: This is a database of known and theoretical gene sequencing and related functions. This database serves to determine gene expression levels in tissues of different species, such as mouse and human. The mouse gene expression atlas was developed with a technique that inserts labeled genes into a live mouse. If these genes are turned on, they will glow. This allows researchers to learn about a gene's function based on where and when it is expressed in the brain.
  • Mutagenesis: Mutagenesis involves the study of how changes in the genetic information of an organism, known as a mutation, affect the behavior of the organism. Mutagenesis can occur naturally or artificially through the use of chemicals or radiation.
  • Phenotyping methodologies: This type of methodology involves studying observable characteristics of traits or abnormalities and variation in how they are expressed. The genetic basis of these traits is then inferred. Phenotypes express environmental influences as well as genetic ones, so these methods look at the functional genetic puzzle from the point of view of environmental influences. In a tiered phenotyping approach, there is an initial evaluation of traits, followed by a second level of investigation, which is more targeted and focused. The goals of this approach are to combine in vivo evaluations, imaging strategies, and clinical and anatomic pathology to characterize complex phenotypes, including multisystemic phenotypes or syndromes, and to develop and validate genetically engineered mouse (GEM) models, which will allow researchers to study the effects of certain mutations on a phenotype.
  • Gene mapping: Gene mapping refers to the mapping of genes to specific locations on chromosomes, a critical step in the understanding of genetic diseases. There are two types of gene mapping. Genetic mapping uses linkage analysis to determine the relative position between two genes on a chromosome. Physical mapping uses all available techniques or information to determine the absolute position of a gene on a chromosome. The ultimate goal of gene mapping is to clone genes, especially disease genes. Once a gene is cloned, its DNA sequence can be determined and its protein product can be studied. For example, cystic fibrosis (CF) is the most common lethal inherited disease in the United States. As many as one in 2,500 Americans of Northern European descent carry a gene for CF. In 1985, the gene was mapped to chromosome 7q31-q32 by linkage analysis, and four years later, it was cloned. It is now known that the disease is caused by the defect of a chloride channel, which is the protein product of this disease gene.
  • Sterology: This is a method used to determine positional information in gene mapping. Sterology allows researchers to determine the location of genes on chromosomes so they can be targeted for manipulation.
  • Genetic linkage studies: These studies are used to identify regions of the genome containing genes that predispose an individual to disease. Genes that are physically closer together on the genome are more likely to be passed on from parent to child together, whereas those that are farther apart have a better chance of being passed on independently. Genetic association studies are performed to determine whether a genetic variant is associated with a disease or trait. If an association is present, a particular genotype of a polymorphism will be seen more often than expected by chance in an individual carrying the trait. Thus, a person carrying one or two copies of a high-risk variant is at increased risk of developing the associated disease or having the associated trait. One way an association study is conducted is by case-control studies, which study people who already have a disease, trait, or other condition, to determine whether there are characteristics of these patients that differ from those who do not have the disease or trait. In genetic case-control studies, the frequency of alleles or genotypes is compared between the cases and controls. A second way in which association can be determined is by measuring an association and linkage in families with observed transmissions of genetic markers from parents to offspring.

  • There are more than 200 inherited neurological conditions. In each of these, unique alterations in the molecules in the brain and nerves lead to the development of the condition. Although rare, these collected conditions affect about 1% of the population and remain relatively poorly understood.
  • The field of neurogenetics is adding to a growing body of knowledge on conditions such as dementia, Huntington's disease, multiple sclerosis, Parkinson's disease, and ataxias, a group of disorders that are characterized by lack of muscle coordination. Understanding how diseases develop may lead to new therapies.
  • Research is being conducted in order to figure out where in the map of DNA certain proteins bind to and how that translates into how the nervous system develops and functions. It also seeks to determine how the differences in binding location create different developmental patterns.
  • Tuberous sclerosis complex (TSC): TSC is a rare genetic disease that causes benign, or noncancerous, tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. It commonly affects the central nervous system. In addition to the benign tumors that frequently occur in TSC, other common symptoms include seizures, intellectual disability, behavioral problems, and skin abnormalities. TSC may be present at birth, but signs of the disorder may be subtle, and full symptoms may take some time to develop. Three types of brain tumors are associated with TSC: cortical tubers, which generally form on the surface of the brain; subependymal nodules, which form in the walls of the ventricles, the fluid-filled cavities of the brain; and giant-cell astrocytomas, a type of tumor that can block the flow of fluids within the brain. The true prevalence of TSC is unknown, but its incidence has recently been estimated to be one in 6,000 live births. This means about 50,000 individuals in the United States, and more than one million worldwide have TSC. It occurs in both sexes and in all races and ethnic groups.
  • Two genes have been identified that can cause tuberous sclerosis. Only one of the genes needs to be affected for tuberous sclerosis to be present. The TSC1 gene is located on chromosome 9 and is called the hamartin gene. The other gene, TSC2, is located on chromosome 16 and is called the tuberin gene. Researchers are now trying to determine what these genes do and how defects in these genes can cause tuberous sclerosis.
  • The National Institute of Neurological Disorders and Stroke (NINDS) conducts TSC research in its laboratories at the National Institutes of Health (NIH) and also supports TSC research through grants to major medical institutions across the country. Scientists in one study are learning more about the genes that can cause TSC and the function of the proteins those genes produce. Another study focuses on two major brain disorders (autism and epilepsy) that occur in children with TSC. Other scientists are trying to determine what causes skin tumors to develop in individuals with TSC and to find the molecular basis of these tumors. Scientists hope knowledge gained from their current research will improve the genetic test for TSC and lead to new avenues of treatment, methods of prevention, and, ultimately, a cure.
  • Early intervention is helping to overcome developmental delays. Advancements in research are bringing new and improved therapeutic options. Surgery to remove tumors or stop tumor growth has been effective in preserving the function of affected organs. Technology is pinpointing the exact portions of the brain stimulated during seizures, and is creating new therapies to help control seizures.
  • The TS Alliance has supported the development of comprehensive TSC1 and TSC2 variation databases, which contain all of the known variations in the TSC genes. This database will be regularly updated and revised as new variations are reported.
  • TSC1 and TSC2 knockout mice have also been developed and characterized to determine the function of these genes in this disorder.
  • Neurofibromatosis: Neurofibromatosis is a genetically transferred disease in which nerve tissue grows tumors that may cause no harm or may cause severe damage by putting pressure on other nerves or tissues. Although many affected individuals inherit the disorder, between 30% and 50% of new cases arise spontaneously through mutations in an individual's genes. Once this change has taken place, the mutated gene can be passed on to succeeding generations.
  • Scientists have classified the disorders as neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2). NF1 is the more common of the neurofibromatoses. Several years ago, research teams located the exact position of the NF1 gene on chromosome 17. The product of the NF1 gene is a large and complex protein called neurofibromin. One portion of this protein is similar to a family of proteins called GAP (guanosine triphosphatase-activating protein). Scientists have demonstrated that GAP proteins can suppress the growth of tumors in certain cancers. The similarity of the NF1 protein to GAP proteins suggests that the NF1 protein may also be able to suppress tumor growth. Scientists theorize that defects in the gene may lessen or inhibit the normal output of its protein, which may lead to tumor development.
  • The NF2 gene, located on chromosome 22, produces a protein that inhibits the growth of tumors. Basic studies in molecular genetics may lead one day to nonsurgical or pharmacologic treatments aimed at suppressing tumors associated with the neurofibromatoses. The Interinstitute Medical Genetics Research Program at the NIH Clinical Center conducts NF2 family history research. Using specimens from some of the families, scientists have isolated and sequenced the NF2 gene and have described two different patterns of clinical features in NF2 patients. Investigators are continuing to study these patterns to see whether they correspond to specific types of gene mutations.
  • Von Hippel-Lindau (VHL) syndrome: VHL is a rare inherited genetic disorder affecting multiple systems of the body. It is characterized by abnormal growth of newly formed blood vessels. While blood vessels normally grow in a branching pattern similar to that in trees, in people with VHL the blood capillaries sometimes form small knots, resulting in tumors (angiomatosis) and fluid-filled sacs (cysts) in various parts of the body. VHL affects about one in 32,000 individuals.
  • Hemangiomas of the retina, which in VHL are noncancerous tumors formed from blood vessels in the eye, and hemangioblastomas of the cerebellum, noncancerous tumors in the central nervous system (specifically, the cerebellum in VHL) formed from cells that create blood vessels, are the most characteristic growths of VHL. Other types of tumors or cysts may develop in the adrenal glands, the kidneys, the pancreas, or the male genital tract. Tumors are most commonly found in areas of the body rich in blood vessels.
  • VHL is inherited as an autosomal dominant trait. This means that if one parent has the mutated gene, each of their children has a 50% chance of being born with the disorder. The mutated gene that causes the disorder is called VHL and normally functions to suppress the formation of tumors in the body by stopping uncontrolled cell growth. This action is decreased or lost completely in patients with VHL disease. There is no known cure for VHL. Treatment usually requires surgery to remove tumors that are causing symptoms before they lead to more serious complications.
  • Several research groups have been working to understand how the VHL gene works; the goal of this research is to identify the specific protein encoded by the VHL gene, to understand what it does, and how it affects the life of a cell. Once these characteristics are defined, various medications and therapies can be developed to restore the defective gene and its proper function.
  • Research has used the body's normal immune response to characterize the VHL protein. This has been done by creating an antibody to the VHL protein in the bloodstream of a rabbit. It is the body's normal function to create an antibody, a substance that identifies and neutralizes a foreign substance. The antibody is then used to determine whether the VHL protein is present and how much of it is present. Another research team developed antibodies capable of recognizing the human VHL protein and were able to characterize its structure.
  • Other genes that are similar in structure to the VHL gene have been identified in other animals. These homologous genes can provide insight into the function of the corresponding human protein.
  • Multiple endocrine neoplasia (MEN) type 2: Multiple endocrine neoplasia (MEN) type 2 syndromes are genetic disorders characterized by tumors in the medulla, a specific brain region, and are thus called medullary thyroid carcinomas (MTC). Point mutations of the germline RET gene, located on chromosome 10, are associated with inheritance of the MEN 2A, MEN 2B, or FMTC genes associated with this particular MTC. The ability to accurately predict the risk of this disease by genetic RET analysis has resulted in the active follow up of children at risk for developing early metastatic tumors that can be prevented by removing the thyroid before it becomes cancerous. RET is known to be involved in cellular signaling processes during development and controls the survival, proliferation, differentiation, and migration of nervous system cells that have not yet become specialized.
  • Schizophrenia: Schizophrenia is a psychiatric disease characterized by abnormalities in perception or the expression of reality. People with this disease may experience hallucinations, delusions, or disorganized speech or thinking. Families with a member who has schizophrenia have a greater chance of developing the disorder than families who do not. It is believed that both environmental and genetic factors play a role in the development of this disorder. Using genetic focus studies, researchers use a family's genetic and environmental history to better understand what may place one family member at risk while other family members are not affected. Genetic information is collected through various techniques including genotyping, which is an analysis of one's DNA.

  • Findings from the field of neurogenetics will help identify those patients and populations at greater risk of developing certain neurological diseases. With that information, new means of preventing disease or managing existing disease may become available.
  • Several genetic disorders, including tuberous sclerosis complex (TSC) and neurofibromatosis, are associated with an increase in the occurrence of nervous system tumors. Having the tools to recognize these disorders will provide researchers and clinicians with tools for optimal clinical care and genetic counseling to affected patients and their families.

  • Neurogenetics is a relatively new field and although tremendous strides have been made, there is still much to learn about the genes that may be involved in the development of neurological disorders. This becomes particularly complex when scientists attempt to find the genetic cause of a disorder that involves thoughts and emotions, such as with schizophrenia.
  • A great deal of information has been gained through gene sequencing to help scientists determine what makes up certain genes. This is important because this information allows researchers to change a gene sequence in a meaningful way and to observe the effect of this change in an organism's behavior. There is still a considerable amount of missing gene-sequencing information, so not all genes have been fully characterized.
  • Although a great benefit to science and medicine, much of the research conducted to determine the genetic basis of neurological diseases has used animal models. These models are very helpful in determining the basic biology behind various neurological illnesses, but because mice do not naturally display human disorders there are some limitations as to how much information can actually be gained.
  • Understanding the role of the gene and its products in the context of a living organism in its own environment is the ultimate goal of functional genomics initiatives. Thus, functional genomics efforts in genetically engineered animals aim to produce and characterize phenotypes that clearly result from the intended genetic manipulations and help demonstrate gene function. However, phenotypes reflect genetic influences other than the intended genetic manipulations, and exposure to environmental factors, including infectious agents. The potential impact of variables outside the experimental setting must be considered when interpreting phenotype data.


Future research
  • Genetic analyses of common neurological conditions will be a long process. It will be particularly difficult to identify which genetic variants cause mild diseases and which cause severe diseases. Diseases of particular interest include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), and stroke.
  • Goals for future research include identifying the genes that cause neurological disorders. This involves collecting family data, applying techniques used to identify genes that may be responsible for the disorder, and developing gene-based therapies for neurological disorders.
  • Other important areas of research include investigating the genetic basis of normal neural development and function, which entails genetically based studies of neuronal patterning, migration, connectivity, and cognitive and behavioral function. Using animal models and in vitro techniques, researchers are able to study pathways of gene function.
  • Also important is the development of resources for neurogenetic research, which will contribute to tissue and information registries, atlases of gene expression and function, and methods of identifying gene mutations and expression.

Author information
  • This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (

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