Introduction
The idea that genes can influence mental health has been entertained from the early part of the twentieth century. Several studies have shown positive association of genetic components with various mental disorders such as schizophrenia and bipolar disorder. Although a plethora of evidence suggests that many mental and psychiatric diseases have tremendously influential genetic components, solid evidence pointing to specific genes or gene variations as the direct cause of particular diseases is still lacking. Mental disorders are fairly complicated, because in most cases, diagnosis is based on self-reported symptoms (which could be subjective and overlap with other disorders) or clinical observations (which are hampered by the lack of sophisticated diagnostic and screening tools). Most mental disorders are complex in nature, with varying degrees of manifestations, onset times, and symptoms. Determining a genetic basis for such complex mental disorders becomes even more challenging because a disorder can be polygenic (more than one gene is responsible for the symptoms) or multifactorial in nature (both genetic and environmental factors are responsible), the genes may not adhere to Mendelian patterns of inheritance (the segregation of genes into the following generations is complex), and the loci of the risk alleles is heterogeneous in nature. Some researchers suspect that genes merely mediate some disorders rather than determine them. As more information emerges about the role of genes and their variations in mental illnesses, researchers are hopeful that methods for detecting mental illnesses will improve, that better, more tailored treatments will become available, and that prevention may even be possible, if environmental exposures and other risk factors can be mitigated for those with genetic susceptibility.
Structure of Genes
Knowledge of the structure and functioning of genes provides a better understanding of how complex diseases can have a genetic basis. Genes are made up of deoxyribonucleic acid (DNA), which consists of bases called "nucleotides." Numerous nucleotides (called "polynucleotides"), interspersed with sugar molecules, are bound together through chemical bonds to form helical strands. Each DNA has two polynucleotide strands forming a double helical structure. Four bases have been identified—adenine (A), guanine (G), thiamine (T), and cytosine (C)—each of which has specific binding partners (A binds with T, and G binds with C).
Chromosomes consist of uninterrupted stretches of DNA molecules. During cell division, these DNA molecules get shuffled, and the resultant cells acquire a new combination of genes that are unique to an individual. This process is called "recombination of DNA." Recombination occurs through independent segregation and assortment of genes so that the unique combination of genes in the offspring has a fair mixture of the parents’ DNA. In some cases, however, genes that are located in close proximity to each other stay together and do not segregate during cell division. These genes are said to be linked together, and the process of inheritance of a group of genes together is called "linkage." Linkage aids enormously in studying the genetic basis of many phenomena, including the occurrence of diseases. Traits or characters that are expressed together are of particular interest to linkage studies. If the gene responsible for one of these traits has been characterized, it can be used as a biological marker to study the putative genes that are responsible for the other linked trait.
Epigenetic markers are special chemical "tags" that become attached to DNA and affect which genes are activated under certain environmental conditions. These markers are also heritable. The study of epigenetics is a growing area of mental health research.
Mutations
Alterations to the DNA sequences (called "mutations") can result in drastic changes, sometimes even changing a cell from a normal to a diseased state. Mutations can be at the level of one base pair (for example, A can mutate to G, which when copied will bind with C, instead of T), and this one base pair change (called a "point mutation") changes the code to a different amino acid, which can result in a malfunctioning or nonfunctional protein. Proper functioning of specific proteins is key for a normal or healthy state, and a point mutation can very well change that state of a cell. Mutations can also be insertions or deletions, in which a few additional nucleotides are added or deleted. All these can lead to drastic changes in the physiology of the cell.
In addition, mutations can also occur at the level of whole chromosomes. Chromosomal aberrations—deletions, duplications, inversions, insertions, or translocations—alter a whole array of genes, resulting in significant abnormalities. A common example of this is Down syndrome, in which the affected individual possesses either an extra copy of chromosome 21 or an additional piece attached to that chromosome because of a translocation event. The translocation of chromosomes that could be related to schizophrenia was first observed between chromosomes 1 and 11 in a large Scottish family study. Genes that elicited considerable interest in this region are DISC1 (Disrupted in Schizophrenia
1) and DISC2. In the genome of patients with schizophrenia, either one or both of these genes is disrupted.
Penetrance and Expressivity
The extent to which a certain gene mutation results in symptoms varies between and within specific diseases. Some mutations lead to a distinctly altered physical manifestation (phenotype) or symptoms, and all individuals carrying a certain genetic composition (genotype) manifest those symptoms. Such mutations are called "penetrant," and the state is called "complete penetrance." Penetrance directly indicates the onset of an illness, which is the point at which the affected individual begins to show enough symptoms that a diagnosis can be made. If a certain illness affects the succeeding generation earlier than it did the previous one (a phenomenon called "early onset" or "anticipation"), the gene is said to be more penetrant. Early onset can somewhat simplify the identification of genes involved in mental disorders, but many individuals with the disease genes do not develop the disease until a later stage or do not develop the disease at all. Such incomplete penetrations pose serious problems, especially when conducting large family studies.
The degree of manifestation of the symptoms may range from mild to serious. This is referred to as the "expressivity" of the gene. Factors such as penetrance and expressivity complicate the understanding of the genetic bases of most diseases.
Types of Genetic Analyses
Many types of genetic analyses are performed to identify the genes involved and to decipher their roles in mental illnesses. Chief among them are linkage analysis, family studies, association studies, twin studies, and the candidate gene approach.
Linkage Analysis
Linkage analysis is a powerful statistical tool that bases its findings on linkage maps and deduces the combination of alleles that are inherited together from multiple loci (haplotypes). It uses the location of commonly known markers (such as color blindness) and attempts to map potential genes of interest in the chromosome. Linkage mapping helps reduce the number of genes that need to be studied in a certain chromosome. A variety of associated biomarker tests help in narrowing down the genes associated with illnesses. Data are mostly collected from large families with multiple members, consisting of cases and probands (the first member of the family who reported the disease). Data from large samples are pooled in meta-analyses, and statistical tests are applied to deduce the probability of certain genes being linked and cosegregated and to exhibit certain disease phenotypes (called the "logarithm-of-odds ratio," or "lod score"). Most diseases that have a high degree of penetration use linkage studies for determining the relevant genes. Linkage studies, however, are limited by the number of genetic recombinations occurring within the specific set of chromosomes and sometimes (as in major mental illnesses such as schizophrenia and bipolar diseases) by the heterogeneous nature of specific loci in chromosomes.
Several studies identified strong linkage associations to chromosome 13 (13q) with schizophrenia. Other studies pointed to chromosomes 8 (8p), 22 (22q) and 1. Chromosomes 13 (13q) and 22q showed significant linkage to both schizophrenia and bipolar disease in a meta-analysis. However, much of the data on schizophrenia could not be replicated or yielded disappointing results. More consistent results have been obtained for autism, showing strong and reproducible linkages to chromosomes 2q, 7q, 15q, and 16p. Chromosomes 6 and 8 have strong genome-wide significance for bipolar disorder.
Family Studies
Family studies have proved to be valuable in studies investigating the genetic basis of various mental illnesses. They are usually performed on the affected individual and the two parents (called a "trio") and siblings (first-degree relatives). Both bipolar disease and schizophrenia have about a 5 to 10 percent occurrence rate for siblings and parents. Large populations of individuals need to be studied to gain further insight. The linkage of schizophrenia to chromosomes 13 and 1 was derived from a few family studies involving a large Canadian population. This study concluded that schizophrenia is manifested in three to four generations in this family. Another family study involving a large and isolated Finnish population, consisting of eighteen thousand individuals, revealed a linkage of schizophrenia to chromosome 1. However, many family studies cannot be replicated or are not followed up as rigorously as they should be. Some family studies on autism have identified a linkage to the gene WNT2, and this result has been consistent and repeatable.
Association Studies
A closely related approach is to study associations among genes in different chromosomes. Association studies use linkage disequilibrium maps, in which tightly linked alleles from one or more chromosomes are mapped and identified. A test that is commonly used in linkage disequilibrium studies is the transmission disequilibrium test (TDT), which provides a ratio of transmitted versus nontransmitted alleles from both parents. Linkage and association studies are used in tandem to deduce the genes potentially involved in mental illnesses. After the decoding of the human genome, approaches have come to involve genome-wide tracking of associated genes. Genome-wide association studies (GWASs) have added value to association studies by increasing the number of genes studied 1,000- to 10,000-fold and making high-throughput genotyping possible. GWASs are able to circumvent the impediments posed by the sheer number of samples involved in several meta-analyses and have yielded valuable information about many mental illnesses. One GWAS, which pooled the results from a large number of studies, showed a significant genome-wide linkage of chromosomes 6 and 8 to bipolar disorder.
A technique called "positional cloning" is used to amplify the genes of interest and to identify those that are mutated in the patients compared with the control subjects. Several genes of interest have been cloned from the chromosomal regions that have been identified from linkage, family, and association studies. In recent years, specific variations (polymorphisms) occurring on single nucleotides, called "single nucleotide polymorphisms," or SNPs, have been paid serious consideration. Some particularly interesting genes have emerged for bipolar disorder and schizophrenia. The gene
DISC1, whose linkage to schizophrenia is based on evidence converging from multiple approaches and studies, is the first gene that has been reported as a causative gene for a mental disorder. Strong linkage association of DISC1 is reported with schizophrenia and to different forms of biopolar disorders. Genome-wide analysis of SNPs for schizophrenia recently identified strong association with the CSF2RA (colony stimulating factor 2 receptor, type A) gene. G72 is another gene that exhibits robust association with bipolar disorder and depression. In addition, a few genes, such as dysbindin (DTNBP1), DISC1, COMT, and BDNF, have been implicated in rendering individuals susceptible to both schizophrenia and bipolar disease. Some hypothesize that both bipolar disorder and schizophrenia are modulated by clusters of genes that overlap with each other.
Twin Studies
Twin studies
are conducted by comparing twins who share a certain mental illness or share the risks of developing one by having affected members in the family. Twins could be either monozygotic (from the same zygote, share identical genotypes) or dizygotic (from two zygotes, share 50 percent of genes). Both schizophrenia and bipolar disorder have shown a concordance rate of about 10 percent for dizygotic and 50 percent for monozygotic twins. In autism, the concordance rate for monozygotic twins is 60 percent. The influence of environment on these disorders is studied through adoption studies, using twins who were separated at a very early stage. Data from adoption studies have strengthened the genetic basis of various mental disorders by demonstrating that even if twins are separated at very early stages, the individual twin still carries the same amount of risk.
Candidate Gene Approach
In this method, specific candidate genes (genes that are suspected of causing a particular mental illness) are studied. Genes involved in the dopaminergic system (involving the common neurotransmitter dopamine, its receptors, and transporters in the brain) are the most widely studied in relation to a variety of mental illnesses. An impaired dopaminergic system is responsible for many mental illnesses. Among the candidate genes, those encoding the serotonin transporter (5-HTT), monoamine oxidase A (MOA), dopamine transporter (DAT), and the precursor enzyme tryptophan hydroxylase have received some evidence supporting their linkage to bipolar disorder. Genes involved in the glutamatergic system (involving another excitatory neurotransmitter, glutamate) are also of great interest. The gene encoding for the mGlu2/3 receptor showed so much promise that agonists of these receptors have been developed as drugs for schizophrenia. Neuregulin
1 is another gene that exhibits strong linkage associations with schizophrenia. It is also surmised that the interaction of both dopaminergic and glutamatergic systems may influence the pathophysiology of schizophrenia.
Genes that are crucial in the circadian rhythm pathway, such as BMAL1, Timeless, and Period 3 (PER3) are found to have some association with bipolar disorder. PER3, Timeless, and another circadian gene, CLOCK, have been found to have linkage associations for schizophrenia. Circadian rhythm gene changes have also been found in postmortem studies on patients with Alzheimer disease.
Most mental disorders are influenced by not just one gene, but rather by a cluster of genes exerting their influence independently, making individuals vulnerable to a certain disorder. Identification of the genes influencing mental health is just the first step. For these studies to culminate in a treatment therapy, several studies, involving multifarious approaches, need to be performed. First, the fact that alteration of these genes results in altered protein function needs to be confirmed. Often, there are compensatory mechanisms for the loss or modifications of important proteins by induction or suppression of gene expression. Several studies using animal models have been undertaken to confirm this. Next, the fact that such alterations actually result in biologically significant and diagnosable symptoms should be confirmed. This would give a correlation between the genotypes and the phenotypes. For complex mental disorders, with all the limitations of diagnostics, requirements, and variabilities, these validations still require a lot more work and time. However, it is also true that there is a clear genetic component in most mental disorders, however complicated they are, and that the risk rate for families with affected individuals is in fact higher than for those without affected individuals. With genome-wide screening becoming increasingly available and affordable, with the knowledge of the entire human genome, and with more investigators focusing on the genetic aspects of mental health, the prospects for finding the genetic basis for mental health and eventually developing it into a therapy that can be administered are much higher.
Bibliography
A.D.A.M. Medical Encyclopedia. "Genetics." Medline Plus. US Dept. of Health and Human Services, National Institutes of Health, 16 May 2012. Web. 21 May 2014.
Andreasen, Nancy. Brave New Brain: Conquering Mental Illness in the Era of the Genome. New York: Oxford UP, 2001. Print.
Collier, D. A., and T. Li. “The Genetics of Schizophrenia: Glutamate Not Dopamine?” European Journal of Pharmacology 480.1–3 (2003): 177–84. Print.
Cowan, W. M., et al. “The Human Genome Project and Its Impact on Psychiatry.” Annual Review of Neuroscience 25 (2002): 1–50.
Detera-Wadleigh, S. D., and F. J. McMahon. “Genetic Association Studies in Mood Disorders: Issues and Promise.” International Review of Psychiatry 16.4 (2004): 301–10. Print.
Lakhan, S. E., and A. Kramer. “Schizophrenia Genomics and Proteomics: Are We Any Closer to Biomarker Discovery?” Behavioral and Brain Functions 5.2 (2009): 1–9. Print.
Lin, P. I., and B. D. Mitchell. “Approaches for Unraveling the Joint Genetic Determinants of Schizophrenia and Bipolar Disorder.” Schizophrenia Bulletin 34.4 (2008): 791–97. Print.
"Looking at My Genes: What Can They Tell Me?" National Institute of Mental Health. US Dept. of Health and Human Services, National Institutes of Health, n.d. Web. 21 May 2014.
Losh, M., P. F. Sullivan, D. Trembath, and J. Piven. “Current Developments in the Genetics of Autism: From Phenome to Genome.” Journal of Neuropathology and Experimental Neurology 67.9 (2008): 829–37. Print.
Reilly, Philip R. Is It in Your Genes? The Influence of Genes on Common Disorders and Diseases That Affect You and Your Family. Cold Spring Harbor: Cold Spring Harbor Laboratory P, 2004. Print.
Stahl, Rebecca J. "Genetics and Mental Health." Health Library. EBSCO, 4 Feb. 2014. Web. 21 May 2014.
Weir, Kirsten. "The Roots of Mental Illness." Monitor on Psychology 43.6 (2012): 30. Print.
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