Etiology Genetic

Humans have 46 chromosomes: 22 pairs of autosomes and 1 pair of sex chromosomes (two X chromosomes in females, and one X and one Y chromosome in males). The approximately 80,000 genes in the human genome are arranged in a precise order along the chromosomes. Each gene is located at a precise position (locus) on a specific chromosome and has two alleles, one donated from the mother and the other from the father. These two alleles may be identical, or more commonly, they may have several variations in their sequences called polymorphisms.

The following is a summary of the research that has attempted to understand the genetic component of schizophrenia by studying its heritability, as well as chromosomes, their genes, and allelic variations in patients with schizophrenia and their families.

Heritability. While the rate of schizophrenia in the general population is approximately 1 percent, the incidence of schizophrenia in families is at least 10-fold greater, strong evidence that the disease runs in families. However, if schizophrenia was purely caused by a genetic abnormality, identical twins, who share 100 percent of their genes, should theoretically have a 100 percent concordance rate for the disease. In fact, the concordance rate for monozygotic twins is only about 45 percent, and dizygotic twins who share 50 percent of their genes, only have a concordance rate of 15 percent. The more genes a biological relative shares with a patient, the higher the incidence of schizophrenia (see Fig. 9.1). For instance, first-degree relatives such as parents, siblings, and children who share 50 percent of their genes, had a greater incidence of schizophrenia than second- or third-degree relatives, which only share 25 percent and 12.5 percent of their genes, respectively (Gottesman, 1991).

However, closer family members not only have more genes in common but generally also share social environments. To better understand the contribution of nature and nurture, several studies examined the incidence of schizophrenia among adoptees (Kringlen, 1991). The finding of higher rates of schizophrenia among the biological relatives of schizophrenia adoptees than normal adoptees is clear support for a genetic component. However, unlike primarily genetic diseases, such as Hunting-ton's or cystic fibrosis in which the mutation of a single allele of the gene is sufficient

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Figure 9.1. Relatives of schizophrenics' lifetime risk of developing the disease as a function of degree of genetic relatedness, compiled from all family and twin studies conducted in European samples between 1920 and 1987 [Adapted from Gottesman (1991), Figure 1 (p. 96). © 1991 by Irving I. Gottesman. Reprinted by permission of Henry Holt and Company, LLC.]

to express the disorder, or recessive diseases such as phenylketonuria in which a mutation of both alleles of the gene are required to produce the disorder, the transmission of schizophrenia is more complex. The most likely explanation for the unusual genetic transmission of schizophrenia is that there are several genes that may contribute to the risk of schizophrenia, or more precisely, several alleles of genes involved; and what is inherited may not be the certainty of the disease accompanying a particular genotype, but rather the susceptibility or predisposition to develop the disease.

Linkage Studies. In linkage analysis, entire genomes are screened for the presence of allelic variations in regions of the chromosome to identify susceptibility loci or "hot spots" that may be co-transmitted with the disease in families containing two or more affected individuals. Linkage studies thus far have failed to identify any locus of large effect size, that is, where mutation of a gene(s) is common to most patients. This is consistent with the idea that schizophrenia is in fact a heterogeneous disease and that different susceptibility loci or combinations of susceptibility loci are necessary to predispose an individual to the disease, and that these loci vary among families. Linkage studies have revealed at least 15 susceptibility loci that have weak to moderate linkage to schizophrenia on several chromosomes1 (DeLisi and Crow, 1999; Berrettini, 2001).

1 Susceptibility loci that have been linked with schizophrenia: 1q21-22, 2q, 3p26-24, 4q, 5p13, 5q, 6q, 6p24-22, 8p22-21, 9p23, 9q, 13q32, 15q13-14, 18p11.2, 20p12, 22q11-12, Xp.

Linkage studies therefore have been valuable in identifying chromosomal hot spots where diseased genes can be found, without any prior knowledge of disease etiology. However, each of these chromosomal regions contains numerous genes, and in some cases, these regions contain susceptibility genes that overlap with other disorders. An excellent example of this is the deletion of chromosome 22q11 (Murphy and Owen, 2001). Deletions on this chromosome represent one of the highest known risk factors for the development of schizophrenia. They are also known to be associated with velo-cardial-facial-syndrome (VCFS), a syndrome characterized by heart, limb, and craniofacial anomalies. Interestingly, these individuals also have high rates of psychotic disorders with 10 to 40 percent of affected individuals developing symptoms of schizophrenia. It is not clear, however, which of the approximately 30 genes found in this region are implicated in either or both diseases. In addition, linkage studies have revealed a number of susceptibility loci that are common to both schizophrenia and bipolar disorder, a neuropsychiatric disease clinically and pathologically very similar to schizophrenia.

Association Studies. In a normal population, any gene at any locus can be present in a number of different forms called alleles. In association studies, the frequency of alleles is compared in samples of unrelated patients and controls to identify allelic variations that are associated with the disease more often than would be predicted by chance alone. Since studying such polymorphisms in entire genomes would be prohibitively large, susceptibility loci identified in linkage studies, or candidate genes stimulated by known pharmacological or neurochemical abnormalities are selected for study. This approach has identified potential allelic association between schizophrenia and polymorphisms in a subtype of serotonin receptors (5-HTR2A), and the D3 subtype of dopamine receptors (Owen, 2000). While these findings are interesting in that these receptor subtypes may be involved in the therapeutic effects of many antipsychotics, they have not yet been replicated.

Chromosomal Studies. Evidence about the contribution of particular genes to the etiology of schizophrenia also comes from direct studies of chromosomal abnormalities. These are changes in the structure of chromosomes (as opposed to specific genes) that can be seen, using appropriate techniques, at the light microscopic level. Usually these are chromosomal translocations in which there is a break in a chromosome, and the fragment that has broken off becomes attached to another chromosome. Because it is possible to identify the point at which the break takes place, it is possible to identify the gene or genes that straddle the break point. If such a translocation is associated with a disease, this means that it is possible to identify a gene that increases the risk of the disease. Chromosomal translocations have been found that increase the risk of schizophrenia. Although in one case (DISC1 and DISC2) the genes are known, to date the role of these proteins in normal brains is not understood, much less the role of the gene(s) in causing schizophrenia (Millar et al., 2000).

Trinucleotide Repeats. Genes are made up of long sequences of nucleotides. Trinucleotide repeats are triplets of nucleotides that are repeated in an unusually high number in the coding region of a gene. To date, more than 12 neurological disorders, including Huntington's disease and fragile X syndrome, have been shown to be caused by trinucleotide repeat expansions, most of which involve the CAG triplet (Margolis et al., 1997). CAG triplet repeats are thought to interfere with the normal function of the protein thereby mediating the disease process. These expansions have the propensity to increase in size over generations. One phenomenon of this type of dynamic mutation, called "anticipation," is an increased severity of the disease or a decreased age of onset in subsequent generations. Studies of CAG triplets in schizophrenia have found evidence of expanded repeats. Furthermore, anticipation has also been reported in families with schizophrenia (Vaswani and Kapur, 2001). In addition, a recent study found evidence of seven or eight CAG triplet repeats in two alleles of chromosome 22, the loci associated with schizophrenia and VCFS (Saleem et al., 2001). While more research on trinucleotide repeats is needed, it seems possible that an abnormally high number of such repeats may play a role in some cases of schizophrenia.

Epigenetic. There is substantial evidence that schizophrenia is heritable and likely involves mutations in the nucleotide sequence of several genes, leading to abnormal messenger ribonucleic acid (mRNA) (transcription) and hence abnormal protein (translation). However, nongenetic factors such as stress, learning, hormones, social environment, and development can also modify the expression of a protein by altering the transcription of perfectly normal genes. This epigenetic regulation may therefore contribute to the nonheritable component of schizophrenia. The search for genetic mutations may therefore be only part of the story since it is proteins that ultimately define the functioning of brain cells, and protein expression can be regulated by genetic as well as epigenetic mechanisms. Measuring proteins or the transcripts that encode them may therefore be fruitful in fully understanding the pathology of schizophrenia.

Microarray analysis simultaneously can compare relative levels of thousands of gene transcripts in postmortem tissue from patients with schizophrenia and matched controls. This technology is fairly new and has only been applied by a few teams to the study of postmortem brains from people with schizophrenia. These studies have revealed changes in the expression of gene transcripts with developmental relevance including transcription factors, receptors, genes important for myelination, as well as a host of proteins involved in synaptic functioning and neurotransmission (Mirnics et al., 2001). While there is good correspondence between the findings of microarray and linkage studies, this technology has also revealed many new candidates for the study of schizophrenia. More microarray studies are emerging that should rapidly advance our knowledge of the biological pathology underlying schizophrenia.

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