Psychiatric Disorders

Genetic studies of psychiatric disorders have become an important specialty area within medical genetics. Much of the progress in the area is the result of advances in molecular genetics techniques, The Human Genome Project, developments in the neurosciences, and recent genetic findings in complex brain disorders such as Alzheimer's and Huntington's disease.

Psychiatric Disorders with Genetic Involvement

It is well accepted that many of the psychiatric disorders listed in the Diagnostic and Statistical Manual, fourth edition, have hereditary predispositions. (The DSM-IV is the official diagnostic manual for mental disorders in the United States.) In the last two decades, clinical genetic (family, twin, and adoption) studies have provided some valuable information about both the genetic and environmental aspects that lead to the development of these psychiatric disorders. More recently, a growing number of molecular genetics studies have provided more data about the genetics of the disorders. However, there has been little success in the identification of specific genes involved in the etiology of these complex disorders.

The DSM-IV includes more than 350 diagnoses and at least one third of the disorders have had one or more clinical genetic study completed. Additionally, some of the disorders have been subjected to molecular genetic studies. Several of the most frequently examined DSM-IV psychiatric disorders from a "genetic study" perspective are listed below:

Alcoholism
Alzheimers
Attention Deficit Hyperactivity Disorder (ADHD)
Autism
Bipolar Disorder
Mental Retardation
Obsessive-Compulsive Disorder (OCD)
Panic Disorder
Schizophrenia

Social Phobia

Substance Use Disorder

Tourette's Syndrome

Major psychiatric disorders, such as schizophrenia and bipolar disorder, have been shown in numerous studies to have significant genetic factors involved in their etiology. The effects of environment and gene-environment interactions on the expression of the disorders are thought to be important, but need more study. Several childhood onset disorders, such as mental retardation, autism, and ADHD, also have strong genetic components in their etiology. All of these disorders are considered complex and are thought to have multiple genes acting together with nongenetic factors, with each gene typically contributing only small effects.

Inheritance Patterns and Linkage Studies

Complex disorders such as schizophrenia and bipolar disorder usually do not follow classic Mendelian inheritance patterns, but they can frequently mimic a pattern of autosomal dominance with reduced penetrance. Explanatory models for these complex disorders include multifactorial inheritance (multiple genes with nongenetic components) and epistasis (few genes acting jointly). But, since the mode of inheritance is unknown, a range of analytic methods must be used to study the genetic aspects of these disorders. Linkage and allelic association studies are frequently methods used to investigate possible causal genes for complex psychiatric disorders. However, in large populations, there are likely to be several causal or susceptibility genes and nongenetic causes, as well.

Historically, the first positive linkage study to have a major impact on psychiatry was the linkage of bipolar disorder to chromosome eleven in a large Amish family. However, a later assessment of the family failed to confirm the original linkage results. A similar situation occurred with the failure to replicate the findings of an early report of linkage of schizophrenia to a region on chromosome 5 in Icelandic and British families.

As a result of these early problems, it became clear that more rigorous methodology, such as more careful clinical phenotyping, the use of more genetic markers, and new analytic techniques would be necessary if molecular approaches were to be used in finding genes involved in psychiatric disorders.

Clinical genetic (family, twin, and adoptive) studies have been attempted in a large number of psychiatric disorders. However, these studies generally provide no information about what genes are involved in the disorder. Molecular studies are necessary to begin to elucidate this data. Schizophrenia and bipolar disorder are examples of psychiatric disorders that have been studied for nearly two decades.

Schizophrenia and Bipolar Disorder

Schizophrenia is a disorder characterized by psychotic symptoms such as hallucinations, delusions, and disordered thinking, as well as deficits in emotional and social behavior. Numerous family, twin, and adoption studies have provided substantial evidence for genetic factors in the etiology of this disorder. Nongenetic factors also appear to play an important role. The risk for relatives of an individual with schizophrenia is 6.5 percent, nearly eight times the population rate of the disorder. The concordance rate for monozygotic (identical) twins is 45 percent, and for dizygotic (fraternal) twins the rate is 12 percent. The higher rate for monozygotic twins, who share all their genes, is strong evidence that genes play a role in schizophrenia.

Molecular genetic (linkage and association) studies suggest that there are multiple genes with small effects that predispose one to the disorder. In an early study, chromosome 5q was implicated, but was not replicated. Areas on chromosome 6p and 8p have been replicated in at least one follow-up study. More recently, chromosome 1 has been implicated. While no causative genes have been identified, there have been molecular studies that implicate chromosomes 1q, 3p, 5, 6p, 6q, 8p, 10p, 13q, 18p and 22q in schizophrenia. Like other multifactoral diseases, the etiology of schizophrenia involves multiple genes and gene-environment interactions.

Bipolar disorder is characterized by episodes of depression and mania, elevated or irritable mood, and symptoms such as rapid thoughts, grandiose ideas, and reckless behavior. Population, twin, and adoption studies provide evidence for the role of genetics in the etiology of bipolar disorder. First-degree relatives have about a 7 to 10 percent risk of having the disorder once one family member is diagnosed. The concordance rate for monozygotic twins is 60 to 65 percent, and for dizygotic twins the rate is 10 to 15 percent, the same as for non-twin siblings.

One of the first bipolar disorder molecular genetic studies implicated chromosone 11, but this finding was not replicated in several other studies. A similar failure to replicate occurred with the initial reports of linkage on the chromosome X. Regions on chromosome four are reported to show strong evidence of linkage to some bipolar families. Major efforts in the last few years have been focused on chromosome seven and eighteen. Some of the studies have suggested a parent-of-origin effect, with maternal transmission more common than paternal. Both linkage and association studies have implicated chromosomes 4p, 6p, 12q, 13q, 16p, 18p, 18q, 21q, and 22q in bipolar disorder. Major depressive disorder has also been studied, but the underlying genetic factors have not been identified.

Tourette's Syndrome

Some psychiatric disorders, like Tourette's syndrome, have significant overlap (co-morbidity) with other psychiatric disorders (OCD and ADHD in the case of Tourette's). This may make the elucidation of genetic causes more difficult.

Tourette's syndrome is characterized by multiple motor tics and one or more vocal tics. It has onset before eighteen years and is one and one-half to three times more common in males. Twin, adoption, and segregation analysis studies support a genetic etiology for Tourette's syndrome. An autosomal dominant inheritance was initially suggested, but other inheritance patterns have been recently reported. There appears to be a relation with ADHD (up to 50 percent of individuals with Tourette's also have ADHD) and OCD (up to 40 percent of individuals with Tourette's have OCD). First-degree relatives are at high risk for developing tics and obsessive compulsive disorders.

Studying psychiatric disorders for genetic factors in their etiology is difficult because of the phenotype definition, co-morbidity, and multiple causal factors. The summary finding from the genetic studies to date suggest that there are multiple genes of small to moderate effect underlying the predisposition to these complex psychiatric disorders.

Harry H. Wright

and Ruth Abramson

Bibliography

Malhotra, A. K. "The Genetics of Schizophrenia." Current Opinions in Psychiatry 14, no. 1 (2001): 3-7.

Potash, J. B., and J. R. DePaulo. "Searching High and Low: A Review of the Genetics of Bipolar Disorder." Bipolar Disorders 2, no. 1 (2000): 8-26.

Roy, M. A., C. Merette, and M. Maziado. "Introduction to Psychiatric Genetics:Progress in the Search for Psychiatric Disorder Dusceptibility Genes." Canadian Journal of Psychiatry 46, no. 1 (2001): 52-60.