Many major psychiatric disorders have been shown to have a strong hereditary predisposition. In the case of schizophrenia, for example, a first-degree relative of an affected patient has about a 10 percent chance of having the
, far in excess of the 1 percent risk in the general population. Monozygotic twins display nearly 50 percent concordance for
. Bipolar I disorder and major depressive disorder exhibit similar familial clustering, in that first-degree relatives are 8 to 18 times more likely to have a mood
than is the general population, and monozygotic twins show a 33 to 90 percent concordance rate. Tourette's syndrome shows an even more convincing genetic association. Several family pedigrees have been
in which transmission of the syndrome is consistent with an autosomal-dominant mode, with penetrance of 99 percent in males and 70 percent in females. Only 10 percent of
with Tourette's syndrome do not have an affected family member. These facts stimulate the expectation that a specific genetic basis will emerge for certain psychiatric diseases.
are clinically defined features, such as sickle
anemia or blue eyes. Some traits are determined by a single gene, whereas others emerge from the interactions of the products of (in some cases) hundreds of genes. Behavior likely is the expression of the products of thousands of genes, although specific single-gene
may influence certain behaviors in consistent ways. Studies of animal behavior,
that of the fruit fly and the laboratory mouse, have documented many behaviors inherited as single-gene traits. These heritable behaviors have often been traced to a specific gene, whereas others are only known to be heritable. The former category, however, is
expanding at the expense of the latter. A glossary of genetic terms is given in
For traits determined by single genes, three common inheritance patterns are recognized:
transmission. In autosomal dominant transmission of disease only one of the two copies of the gene in the cell nucleus needs to be inherited to produce the clinical trait. A parent with one copy of a dominant mutation has a 50 percent chance of passing the trait to his or her child. In autosomal recessive transmission, the trait can be passed on only when both copies are inherited. Thus, a parent with an autosomal recessive trait can transmit it to a child only when the other parent also
on the mutant gene. In X-linked recessive transmission, the gene is found on an unpaired X chromosome and, thus, is the only copy of the gene in the nucleus. An X-linked recessive trait, therefore, occurs in males, who have only one X chromosome; females are
, but they do not display the clinical traits because they have a second, normal X chromosome (
In psychiatry, the largest
in the process of assigning behavioral traits to specific genes is the
clinical definition of psychiatric traits. The text revision of the fourth edition of
Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV-TR), which provides exact categorization for most psychiatric disorders, nonetheless probably includes a genetically heterogeneous population of patients under each diagnostic category. The situation is further muddled by the lack of objective, quantifiable tests for psychiatric disorders. Moreover, because familial clustering of certain behavioral traits can result from either
(nature) or upbringing (nurture), constructing accurate pedigrees
according to genetic criteria may be
. Finally, the multigenic determination of behavioral traits serves to increase the complexity of analysis exponentially.
Table 3.6-1 Glossary of Genetic Terms
One of the variant forms of a gene at a particular locus, or location, on a chromosome. Different alleles produce variation in inherited characteristics, such as hair
or blood type.
: In DNA or RNA, a sequence of three nucleotides that codes for a certain amino acid or signals the termination of translation (stop or termination codon).
: Any heritable influence (in the progeny of
or of individuals) on gene activity, unaccompanied by a change in DNA sequence.
: The complete DNA sequence, containing all genetic information and supporting
, in the chromosomes of an individual or species.
: The genetic constitution of an organism or cell; also refers to the specific set of alleles inherited at a locus.
: A statistical method that examines pedigree data to determine whether a trait cosegregates with a genetic marker.
: The combined contribution of one or more often unspecified genes and environmental factors, often unknown, in the causation of a particular trait or disease.
: Observable characteristics of an organism produced by the organism's genotype interacting with the environment.
: Genetic disorder resulting from the combined action of alleles of more than one gene. Although such disorders are inherited, they depend on the simultaneous presence of several alleles; thus, the hereditary patterns usually are more complex than those of single-gene disorders.
: Natural variations in a gene, DNA sequence, or chromosome that have no adverse effects on the individual and occur with
high frequency in the general population.
: The process of
a specific gene to a clinical trait.
: The individual in a pedigree who causes the pedigree to come to the attention of medical or research personnel.
: A research area that uses a range of bioinformatics approaches to analyze the expression and function of proteins within specific systems, cells, or organisms.
: An inherited characteristic.
At this writing, pedigrees have been
for each of the main psychiatric disorders, and chromosomal linkage has been sought with the tools of molecular genetics. Even in the apparently straightforward case of Tourette's syndrome, screening of almost all chromosomes has failed to identify a specific genetic locus always inherited with the clinical behavior. This finding suggests that Tourette's syndrome is a multigenic trait, that is, a disorder that may be caused by the combined influences of several genes. Screening for mutations in genes that regulate the dopamine
in patients with Tourette's syndrome, as well as neurotransmitters in other disorders, is ongoing.
Genetic causes are being sought for other psychiatric disorders. Based on an analysis of 22 pedigrees, a locus that confers an increased risk of bipolar disorder has been identified on chromosome 18. The correlation is not robust, which indicates a need for further investigation. For the personality trait of anxiety, a genetic variant of the serotonin transporter gene has been
described that alters the number of transporter molecules in the presynaptic
neurons. This alternative version of the transporter has been calculated to account for less than 5 percent of the genetic variance for anxiety in the general population.
Transmission of traits through sexual reproduction. Sexual reproduction
the propagation of
advantageous mutations through a population. This pedigree shows seven generations in which a dominant trait (
dark circles and squares
) is transmitted from generation to generation. From a single trait-
individual in generation I, the trait is transmitted to
half of the offspring of 17 unaffected individuals (
circles and squares
): one in generation I, two in generation II, three in generation III, five in generation IV, four in generation V, and two VI. (Modified from
Jones S, Martin R, Pilbeam D.
The Cambridge Encyclopedia of Human Evolution.
Cambridge, UK: Cambridge University Press, 1992:258
, with permission.)
Persons with schizophrenia may have difficulty filtering auditory input to screen out extraneous sounds. A
performed positional cloning project has identified a locus on chromosome 15 that encodes the a1 nicotinic acetylcholine receptor and appears to account for the abnormality in auditory processing in several pedigrees of patients with schizophrenia. Another study, examining the previously described negative association between schizophrenia and rheumatoid arthritis, found that the human lymphocyte antigen (HLA) DRB1*04 allele was significantly associated with a reduced risk of rheumatoid arthritis in 94 unrelated patients with schizophrenia. A study of 265 Irish families with a high incidence of schizophrenia found two loci, one on chromosome 8 and the other on chromosome 6, each of which accounted for the vulnerability to schizophrenia in 10 to 30 percent of the families. These findings should be
as preliminary, and each will require further work.
Alzheimer's disease can be definitively diagnosed only by pathological examination of brain
, either at autopsy or from brain biopsy. Whereas
of neuronal volume without loss of neurons is a feature of normal aging, loss of neurons is typical of Alzheimer's disease. The two characteristic neuropathological features are senile plaques and neurofibrillary tangles. A recent clinicopathological study found that elderly nuns with senile plaques and neurofibrillary tangles do not always have dementia, but the risk is greatly increased (from 57 to 93 percent) if they also have had strokes. A separate study of nuns showed that writing style at age 20
the onset of dementia (presumably Alzheimer's) over the age of 70 years. Nuns with a simple writing style in their youth were more likely to develop dementia than nuns with a complex command of written language. These two studies
that dementia of the Alzheimer's type likely results from a combination of genetically determined and
Of cases of Alzheimer's disease, 10 percent are hereditary, and the remaining 90 percent are sporadic, but even sporadic cases seem to associate with certain genetic predispositions. Of the hereditary cases, 70 to 80 percent are attributable to mutations in the presenilin 1 gene, located on chromosome 14, which causes onset of symptoms at age 40 to 50 years. Another 20 to 30 percent are attributable to mutations in a
gene, presenilin 2, located on chromosome 1, which causes onset of symptoms at age 50 years. A final 2 to 3 percent of the familial cases are attributable to mutations in the ²-amyloid
protein (APP) gene, located on chromosome 21, which causes onset of symptoms at age 50 years. APP and a cytoskeletal protein called
are prominent components of senile plaques and neurofibrillary tangles in both familial and sporadic cases of Alzheimer's disease. Tau protein polymerizes into the paired helical filaments that are the main
of neurofibrillary tangles if it is not protected from phosphorylation. This protection is afforded by apolipoprotein E (Apo E), encoded by a gene on chromosome 19 that has three alleles. The e2 allele protects tau, whereas the e3 and (especially) the e4 alleles do not associate as strongly with tau and leave it susceptible to phosphorylation and eventual polymerization. Presence of the e3/e4 or the e4/e4 alleles has been claimed to account for 10 to 50 percent of the risk of sporadic Alzheimer's disease with onset of symptoms about age 60 years. Such individuals seem to have a particular loss of acetylcholine-containing neurons and, thus, may be less likely to respond to acetylcholinesterase
, such as donepezil (Aricept). The known genetic risk factors for Alzheimer's
disease so far account for less than 50 percent of cases (
Chromosomal location of the genes implicated in Alzheimer's disease. Apo E, apolipoprotein E; APP, amyloid precursor protein. (Courtesy of Carol A. Matthews, M.D. and Nelson B. Freimer, M.D.)
The human genome consists of between 30,000 and 50,000 genes, of which more than 20,000 have been identified. More than 5,000 genetic disorders, each transmitted through a single mutant gene, have been characterized. The application of more powerful quantitative
of analysis, new molecular technologies, and more detailed maps of the human genome have permitted localization to chromosomal
of more than 400 of these disease genes, with precise identification of more than 80.
Major public health implications exist to identifying genes that influence an individual's risk of developing the more common familiar mental disorders such as schizophrenia, bipolar I disorder, alcoholism (alcohol abuse or dependence), and obsessive “compulsive disorder. Such findings may ultimately have relevance for many affected individuals and their relatives, given the potential for developing a genetic test to identify individuals at risk, and equally important, provide the
industry with new drug
targets. Clinicians and researchers must understand the basic principles of genetics and genetic epidemiology so that they can appreciate the relevance of new data derived from the genetic analysis of mental disorders.
Basic Molecular Biology
The central dogma of molecular biology is DNA makes RNA makes protein. Deoxyribonucleic acid (DNA) is a genetic code consisting of a series of bases, adenine (A), cytosine (C), guanine (G), and thymine (T), which are covalently linked to form extremely long molecules (
). Genes consist of strings of DNA that serve as templates for messenger ribonucleic acid (mRNA) molecules, which in
specify a sequence of amino acids, the building blocks of proteins. mRNA is assembled according to the DNA code by the stepwise addition of bases according to a complementation algorithm. Ribonucleic adenine (rA) is complementary to deoxyribonucleic thymine (T), rG to C, rC to G, and ribonucleic uracil (rU) to adenine (A). Thus, the DNA string ATGTCTTAG would encode the mRNA string UACAGAAUC. mRNA has stretches of protein-coding sequences, called
, which are
by noncoding sequences, called
. Soon after the mRNA is transcribed from the DNA, the exons are spliced together to form a continuous stretch of coding sequence. The mRNA moves into the cytoplasm and binds to
, which read it as a series of base triplets, called
. Each codon specifies an amino acid, and the amino acids are strung together to form a specific protein. There are 20 amino acids, each with a common
atomic structure, but unique side chains. Depending on the primary amino acid sequence, the protein
into a three-dimensional
with other proteins, carbohydrates, nucleic acids, or lipids to carry out the functions of the cell.
of various proteins in the cell may be
by the rate of mRNA transcription, at the level of mRNA translation into protein, or at the level of the degradation of the protein molecules. mRNA transcriptional control is the most common type of specific gene regulation. Initiation of mRNA transcription involves general factors, called
, common to all genes, but it is regulated by specific transcription factors that bind only to certain genes and are
regulated by intracellular and extracellular signals. Thus,
diffuse into the cell and bind to the thyroid receptors, and the hormone-receptor complex, which
acts as a transcription factor, enters the nucleus and activates certain genes by binding to specific DNA sequences immediately adjacent to these genes. Psychiatry is very interested in gene regulation by neurotransmitters and in the regulation of the synaptic neurochemical milieu by variations in the levels of gene transcription.
The chemical structure of a DNA molecule. (
) A short segment of DNA showing the sugar and phosphate backbone of each
, together with the four different DNA bases: adenine, guanine, cytosine, and thymine. The complementary
of A with T and G with C is what holds the strands together and permits the molecule to make copies of itself of almost infinite length. (
) Replication of DNA, showing how the molecule unwinds and, by pairing of the complementary bases with each other, makes two identical copies of the original DNA sequence. (Modified from
Jones S, Martin R, Pilbeam D.
The Cambridge Encyclopedia of Human Evolution
. Cambridge, UK: Cambridge University Press, 1992:11
, with permission.)
The human genetic material consists of 3 billion bases of DNA, which are divided into units of roughly 60 million bases, called
. The normal cell nucleus contains 23 pairs of chromosomes: 22 matched pairs of autosomes and the X and Y sex chromosomes (
Color Plate 3.6-4
on p. 84). Chromosomes are bound by a variety of structural and regulatory proteins. The most important structural proteins are
, which are small, positively charged proteins that serve to package DNA into structures that fit into the cell nucleus. The DNA
is wrapped around core histones to form a simple beads on a string structure that is then folded into a higher-order structure called
. Modification of chromatin structure by transcription proteins serves as one important mechanism of activating or repressing mRNA transcription initiation.
are estimated to have about 30,000 to 40,000 distinct genes, and of these, the function of only a few thousand is known at this time. Only about 1 percent of the total DNA encodes genes that may be translated into proteins; and the remaining 99 percent is noncoding, junk DNA. Complexity arises because most proteins seem to be modified in complex ways and can be the products of differential splicing. Consequently, the relatively low number of human genes has a very high potential to generate an
proteome of great complexity.
Some genes encode proteins that play housekeeping roles within the cell; that is, they are present in all cells and are essential to the survival of the cell. Other genes play specific regulatory roles and are cell-type specific. Among these latter genes are those of particular interest to psychiatrists. Intense research is under way to identify both those genes that, when
, may cause psychiatric illness and those that may determine normal emotional behaviors and responses. At this time, these goals tax, and in most cases exceed, the data-processing capabilities of even the most sophisticated
, but major technical advances are appearing at a rapid rate. With the complete sequencing of the human genome, most gene experts now anticipate significant advances in the identification of the genetic basis of complex human behaviors early in the 21st century.
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