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3.6

Neurogenetics

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 illness , far in excess of the 1 percent risk in the general population. Monozygotic twins display nearly 50 percent concordance for schizophrenia . 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 disorder 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 constructed 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 patients 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.

Traits are clinically defined features, such as sickle crises in sickle cell 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 mutations may influence certain behaviors in consistent ways. Studies of animal behavior, especially 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 rapidly expanding at the expense of the latter. A glossary of genetic terms is given in Table 3.6-1 .

For traits determined by single genes, three common inheritance patterns are recognized: autosomal dominant , autosomal recessive , and X-linked recessive 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 passes 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 carriers , but they do not display the clinical traits because they have a second, normal X chromosome ( Fig. 3.6-1 ).

In psychiatry, the largest hurdle in the process of assigning behavioral traits to specific genes is the rigorous 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 genetics (nature) or upbringing (nurture), constructing accurate pedigrees strictly according to genetic criteria may be impossible . Finally, the multigenic determination of behavioral traits serves to increase the complexity of analysis exponentially.

At this writing, pedigrees have been assembled 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 pathway 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

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FIGURE 3.6-1 Transmission of traits through sexual reproduction. Sexual reproduction permits the propagation of novel 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- bearing individual in generation I, the trait is transmitted to roughly half of the offspring of 17 unaffected individuals ( open 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 carefully 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 viewed as preliminary, and each will require further work.

Alzheimer's disease can be definitively diagnosed only by pathological examination of brain tissue , either at autopsy or from brain biopsy. Whereas shrinkage 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 years predicted 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 illustrate that dementia of the Alzheimer's type likely results from a combination of genetically determined and acquired factors.

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 related 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 precursor protein (APP) gene, located on chromosome 21, which causes onset of symptoms at age 50 years. APP and a cytoskeletal protein called tau 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 components 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 inhibitors , such as donepezil (Aricept). The known genetic risk factors for Alzheimer's

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FIGURE 3.6-2 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.)

Genome

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 methods of analysis, new molecular technologies, and more detailed maps of the human genome have permitted localization to chromosomal regions 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 pharmaceutical industry with new drug therapy 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 ( Fig. 3.6-3 ). Genes consist of strings of DNA that serve as templates for messenger ribonucleic acid (mRNA) molecules, which in turn 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 exons , which are interrupted by noncoding sequences, called introns . 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 ribosomes , which read it as a series of base triplets, called codons . 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 core atomic structure, but unique side chains. Depending on the primary amino acid sequence, the protein folds into a three-dimensional molecule that interacts specifically with other proteins, carbohydrates, nucleic acids, or lipids to carry out the functions of the cell.

The relative abundance of various proteins in the cell may be regulated 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 transcription factors , common to all genes, but it is regulated by specific transcription factors that bind only to certain genes and are themselves regulated by intracellular and extracellular signals. Thus, thyroid hormones diffuse into the cell and bind to the thyroid receptors, and the hormone-receptor complex, which

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FIGURE 3.6-3 The chemical structure of a DNA molecule. ( Left ) A short segment of DNA showing the sugar and phosphate backbone of each strand , together with the four different DNA bases: adenine, guanine, cytosine, and thymine. The complementary pairing 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. ( Right ) 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 chromosomes . The normal cell nucleus contains 23 pairs of chromosomes: 22 matched pairs of autosomes and the X and Y sex chromosomes ( see 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 histones , which are small, positively charged proteins that serve to package DNA into structures that fit into the cell nucleus. The DNA helix is wrapped around core histones to form a simple beads on a string structure that is then folded into a higher-order structure called chromatin . Modification of chromatin structure by transcription proteins serves as one important mechanism of activating or repressing mRNA transcription initiation.

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Humans 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 enormous 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 altered , 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 investigators , 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.

References

Botstein D, Risch N. Discovering genotypes underlying human phenotypes: Past successes for mendelian disease, future approaches for complex disease. Nat Genet . 2003;33[Suppl]:228

Bunney WE, Bunney BG, Vawter MP, Tomita H, Li J, Evans SJ, Choudary PV, Myers RM, Jones EG, Watson SJ, Akil H. Microarray technology: A review of new strategies to discover candidate vulnerability genes in psychiatric disorders. Am J Psychiatry . 2003;160:657.

Carlson CS, Eberle MA, Rieder MJ, Smith JD, Kruglyak L, Nickerson DA. Additional SNPs and linkage-disequilibrium analyses are necessary for whole-genome association studies in humans. Nat Genet . 2003;33:518.

Chakravarti A, Little P. Nature, nurture, and human disease. Nature . 2003;421:412.

Flouris AD, Faugth BE, Hay J, Cairney J. Exploring the origins of the developmental disorders. Dev Med Child Neurol . 2005;47(7):436.

Harnson PJ, Owen MJ. Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet. 2003;361:417.

Mathews CA, Freimer NB. Genetic linkage analysis of psychiatric disorders. In: Sadock BJ, Sadock VA, eds. Kaplan & Sadock's Comprehensive Textbook of Psychiatry . 8th ed. Vol. 1. Baltimore: Lippincott Williams & Wilkins; 2005:252.

Matise TC, Sachidanandam R, Clark AG, Kruglyak L, Wijsman E, Kakol J, Buyske S, Chui B, Cohen P, de Toma C, Ehm M, Glanowski S, He C, Heil J, Markianos K, McMullen I, Pericak-Vance MA, Silbergleit A, Stein L, Wagner M, Wilson AF, Winick JD, Winn-Deen ES, Yamashiro CT, Cann HM, Lai E, Holden AL. A 3.9-centimorgan-resolution human single- nucleotide polymorphism linkage map and screening set. Am J Hum Genet . 2003;73:271.

Mitchell AA, Cutler DJ, Chakravarti A. Undetected genotyping errors cause apparent overtransmission of common alleles in the transmission/disequilibrium test. Am J Hum Genet . 2003;72:598.

Moldin SO. Population genetics and genetic epidemiology. In: Sadock BJ, Sadock VA, eds. Kaplan & Sadock's Comprehensive Textbook of Psychiatry . 8th ed. Vol. 1. Baltimore: Lippincott Williams & Wilkins; 2005:236.

Moldin SO, Hyman SE. Genome, transcriptome, and proteome. In: Sadock BJ, Sadock VA, eds. Kaplan & Sadock's Comprehensive Textbook of Psychiatry . 8th ed. Vol. 1. Baltimore: Lippincott Williams & Wilkins; 2005:115.

O'Donovan MC, Williams NM, Owen MJ. Recent advances in the genetics of schizophrenia. Hum Mol Genet. 2003;12:125.

Patterson SD, Aebersold RH. Proteomics: The first decade and beyond. Nat Genet . 2003;33[Suppl]:311.

Pauls DL. An update on the genetics of Gilles de la Tourette syndrome. J Psychosom Res . 2003;55:7.

Plomin R, McGuffin P. Psychopathology in the postgenomic era. Annual Review of Psychology. 2003;54:205.

Reiss Al, Dant CC. The behavioral neurogenetics of fragile X syndrome: Analyzing gene-brain-behavior relationships in child developmental psychopathologies. Dev Psychopathol. 2003;15(4):927 “968.

Snyder M, Gerstein M. Genomics. Defining genes in the genomics era. Science . 2003;300:258.