The Genetics and Evolution of Mental Illness

Le Jamie
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 locus-

specific 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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