Schizophrenia

The Genetics and Evolution of Mental Illness Jamie Friedrich 11/29/2006

TABLE OF CONTENTS 1. Introduction 2. The Genetics of Schizophrenia 2.1 Family Studies 2.2 Mode of Transmission 2.3 Molecular Genetic Studies 3. The Evolution of Schizophrenia 3.1 The Heterozygous Advantage 3.2 The Social Brain 3.3 Language 3.4 Other Theories 4. Conclusion

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1. Introduction Schizophrenia is a psychotic disorder characterized by delusions, hallucinations, disorganized speech and behavior, as well as “negative symptoms” such as affective flattening and alogia (poverty of speech). This results in social and occupational dysfunction, greatly hindering the affected individual’s ability to sustain employment or normal social relations (American Psychiatric Association, 2000). The following paper will address the current theories and research on the genetics and evolution of schizophrenia. The questions asked about the genetics of schizophrenia seem simple enough: whether schizophrenia is hereditary, to what degree, by what mechanism, and where the genes are located. Issues regarding the evolution of such a disorder are less straight forward. Mental disorders such as schizophrenia are seemingly maladaptive. Indeed, a disorder is defined as a harmful dysfunction (Cosmides and Tooby, 1999). Theories on the evolution of schizophrenia try to understand how a trait with such negative impacts on functioning could maintain such a steady prevalence world wide. 2. The Genetics of Schizophrenia 2.1 Family Studies It is obvious through family, twin and adoption studies that schizophrenia is hereditary (Ban, 2004). First degree relatives of a person with schizophrenia are ten to 15 times more likely to develop the disorder than the general population. Second degree relatives such as aunts, uncles, half-siblings and grand children are about three times more likely. Data combined from 11 twin studies show that schizophrenia is not purely genetic. If one

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monozygotic twin is affected by schizophrenia, there is a 55.5% chance that the other will be affected as well. The rate is 13% in dizygotic twins. Kety et. al. studies 41 adoptees with schizophrenia in Denmark (1994). They found that biological relatives of affected adoptees were ten times more likely to be affected than in control families. Schizophrenia was absent in all adoptive families. These studies imply that schizophrenia has a significant genetic component, but that other factors also contribute to the development of the disorder. 2.2 Mode of Transmission While this data shows that schizophrenia is a largely genetic disorder, the exact mode of transmission is not clear (Ban, 2004). It is apparent that a single locus model does not sufficiently explain the amount of aggregation in families. “A polygenic (multilocus) model has been consistently supported—and a single major gene model consistently excluded—in the quantitative analysis of actual and simulated schizophrenia family data” (Moldin, 1999). Moldin goes on to say that a four locus multiplicative model seems to fit the data. In this model, four loci all have equal effect on the phenotype and the locusspecific risk recurrence rate fits with the observed prevalence of schizophrenia world wide. There is no concrete evidence to support this, however. Ban suggests the number of contributing loci is less than ten. 2.3 Molecular Genetic Studies Researchers have not found any convincing evidence for the location of any genes contributing to schizophrenia. While there is some evidence for linkage to chromosomes 6p and 8p, it is not strong and additional studies have not been able to replicate the findings. Other possibilities have even less evidence. To date, little convincing or

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significant evidence has been found on the actual location of the genes contributing to schizophrenia (Moldin, 1999). 3. The Evolution of Schizophrenia 3.1 Heterozygous Advantage The heterozygous advantage theory looks at the possibility that relatives of people with schizophrenia have a reproductive advantage. People affected by schizophrenia have lower fertility than the general population (Haukka, et. al. 2003). Usually this would imply that it is selected against, and allele frequencies (and therefore the incidence of phenotypic schizophrenia) would decline. This is not so, as schizophrenia maintains a prevalence of around 1% world wide (Burns, 2004). Avila et al. studied the fertility of first degree relatives of people with schizophrenia and found that schizophrenic patients had more siblings (3.66) than in normal controls (2.05) (2001). They conclude that “the findings are consistent with a model of compensatory reproductive fitness.” In other words, the siblings of people with schizophrenia pass on the genes responsible for the disease, compensating for the decreased fertility of the patients themselves. The siblings “provide one mechanism by which prevalence rates can remain stable despite lower reproductive rates among individuals with schizophrenia.” Haukka et al. takes the opposite stance (2003). They looked at the fertility rates of children of people with schizophrenia. In their study, daughters of schizophrenic patients had a slightly higher fertility rate than the general population (1.89 children as opposed to 1.83, on average). Sons, however, had a lower fertility, the mean number of children being 1.57, than the general population, who had 1.65 children on average.

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They conclude that the lower fertility rates of schizophrenics are not compensated by the fertility of their relatives and that the persistence of schizophrenia cannot be explained by this model. It is apparent that even though the first degree relatives of people affected by schizophrenia sometimes have higher than reproductive fitness, this model is too simple and does not sufficiently explain the sustained prevalence of schizophrenia. Also, neither study proposes a reason for the reproductive advantage. 3.2 Social Brain Burns proposes that schizophrenia is a trade off for our social brain (2004). He says that the evolution of the social brain (the prefrontal cortex and its connection to other parts of the brain) left it “particularly vulnerable to insult.” Because of the world wide incidence of schizophrenia, he assumes that it must have evolved before humans migrated out of Africa, dismissing the possibility of simultaneous development in different parts of the world due to random mutation. Schizophrenia is seen as a kind of bad connection between the parts of the brain that make normal human social functioning possible. The genes for schizophrenia are closely linked to those of the social brain and are inherited together. Burns says the change to a social brain would have been gradual, and the genes responsible for schizophrenia would have developed over a long period of time. 3.4 Language Another theory regarding the origins and evolution of schizophrenia relate it to the origin of language. This theory, like that of the social brain, says the origins of schizophrenia predate the migration of humans out of Africa. Crow makes three points:

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Schizophrenia is part of variation that spans the world population; It occurs only in humans; It is associated with the capacity for language (2000). He explains that the disorder is present when an individual’s brain does not properly distinguish between its thoughts, spoken language, and the speech of others. This would have happened quickly, as a single mutation of normal linguistic abilities (Berlim et al. 2003). 3.5 Other Theories Torrey and Yolken propose that schizophrenia and rheumatoid arthritis share many similarities (2001). Both have similar prevalence in North America and Europe, and are related to similar class II HLA antigens, among other parallels. There is “a well documented inverse correlation” between the two. Torrey and Yolken suggest that the two disorders may share an infectious or immune etiology, and that if a person has one disorder, they are immune to the other. Brown makes a preliminary case for the genes of related to schizophrenia also causing a resistance to infection (2003). He found that “resistance genes are shown to be located in human chromosome regions linked significantly, in at least one genome scan, with schizophrenia [or related functions or conditions].” Before research of this kind can be expanded, studies must find more evidence for the location of the genes contributing to schizophrenia. 4. Conclusion In conclusion, much research on the genetics and evolution of genetics of schizophrenia has been done, but few conclusions can be made. Although researchers know through family, twin and adoption studies that the disorder is largely genetic, a specific mode of inheritance has yet to be found. Researchers believe that it is a result of

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many genes interacting. Molecular genetic studies give no firm evidence as to the location of the genes in the human genome. Preliminary associations have been made to some loci, but more research is needed. There are many theories regarding the evolution of schizophrenia. Some research suggests that family members of individuals affected by schizophrenia have a reproductive advantage. However, other studies indicate there is no heterozygous advantage and that the model is too simple to explain the constant world wide prevalence of the disorder. Two theories suggest that schizophrenia is an evolutionary trade off for important functions in the human brain. One says that the disorder is related to the origins of the social brain, while the other relates it to the origins of language. Each says that the prevalence of schizophrenia is maintained as a result of the significance of these functions. Other theories relate schizophrenia to advantages such as an immunity to rheumatoid arthritis or infectious disease. Schizophrenia remains a mystery of the human brain, and much more research is needed and being done.

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WORKS CITED American Psychiatric Association. Diagnostic Statistical Manual of Mental Disorders. Fourth ed. Washington, DC: American Psychiatric Association, 2000. Avila, Matthew, Gunvant Thaker and Helene Adami. “Genetic Epidemiology and Schizophrenia: a Study of Reproductive Fitness.” Schizophrenia Research 47.2-3 (2001): 233-241. Ban, T. A. “Neuropsychopharmacology and the Genetics of Schizophrenia- A History of the Diagnosis of Schizophrenia.” Progress in Neuro-Psychopharmacology and Biological Psychiatry 28.5 (2004): 753-762. Berlim, Marcelo T., Betina S. Mattevi, Paulo Belmonte-de-Abreu and Timothy J. Crow. “The Etiology of Schizophrenia and the Origin of Lanugage: Overview of a Theory.” Comprehensive Psychiatry 44.1 (2003): 7-14. Brown, JS. “Identification of Candidate Genes for Schizophrenia Based on Natural Resistance to Infection Disease.” Acta Neuropsychiatrica 15 (2003): 108-114. Burns, Jonathan Kenneth. “An Evolutionary Theory of Schizophrenia: Cortical Connectivity, Metarepresentation, and the Social brain.” Behavioral and Brain Sciences 27 (2004): 831-885. Cosmides, Leda and John Tooby. “Toward an Evolutionary Taxonomy of Treatable Conditions.” Journal of Abnormal Psychology 108.3 (1999): 453-464. Crow, T. J. “Schizophrenia as the Price that Homo Sapiens Pay for Language: a Resolution of the Central Paradox in the Origin of Species.” Brain Research Reviews 31 (2001): 118-129.

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Haukka, Jari, Jaana Suvisaari and Jouko Lönnqvit. “Fertility of Patients with Schizophrenia, Their Siblings and the General Population: A Cohort Study from 1950 to 1959 in Finland.” American Journal of Psychiarty 160.3 (2003): 460463. Kety, Seymour S., Paul Wender, Bjorn Jacobsen, Loring J. Ingraham, Lennart Jansson, Britta Faber and Dennis K. Kinney. “Mental Illness in the Biological and Adoptive Relatives of Schizophrenic Adoptees: Replication of the Copenhagen Study in the Rest of Denmark.” Archives of General Psychiatry 51 (1994): 442455. Moldin, Steven. “Summary of Research.” Biological Psychiatry 45 (1999): 559-602. Torrey, E. Fuller and Robert H. Yolken. “The Schizophrenia-Rheumatoid Athritis Connection: Infectious, Immune, or Both?” Brain, Behavior, and Immunity 15 (2001): 401-410.

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