Wide agreement now exists that the rate of schizophrenia among
first-degree family members of persons with schizophrenia is higher than in
control families. The chance of occurrence is approximately 10 times greater
among these individuals than in individuals with no first-degree relatives with
schizophrenia. There is approximately six times and two times greater chance of
developing schizophrenia in second- and third-degree relatives of individuals
with schizophrenia respectively. In addition, the higher prevalence of
schizophrenia spectrum disorders among family members of individuals with
schizophrenia, such as schizoaffective disorder and schizoid and schizotypal
personality disorders, provides support for a common genetic basis for this
family of schizophrenia-like illnesses.
Adoption studies constitute a powerful experimental strategy for
examining the role of genetic versus environmental factors. In these studies,
the rates of schizophrenia are compared in relatives of adoptees with and
without schizophrenia. Danish adoption studies conducted in the 1960s and 1970s
provided compelling evidence that adoptees with schizophrenia had higher rates
of schizophrenia in their first-degree relatives than control adoptees. A
reanalysis of these data in the late 1980s confirmed the original finding that
biological relatives of schizophrenia adoptees had significantly higher rates
of schizophrenia (4.1%) than biological relatives of nonschizophrenia (control)
adoptees (0.5%). Several methodo-logical issues are important in interpreting
the data from adoption studies, including the diagnostic status of biological
fathers and levels of psychopathology in adoptive families. Additional factors
to consider are the intrauterine environment, birth complications and length of
time from birth to adoptive placement.
Another approach to examining genetic contributions to schizo-phrenia
involves concordance studies of dizygotic (nonidentical) and monozygotic
(identical) twin pairs. Available data indicate that the concordance of
schizophrenia among dizygotic twins is approximately 8 to 12%. This is much
greater than the 1% rate found in the general population and comparable to the
rate of concordance of schizophrenia among first-degree siblings. The
concordance of schizophrenia among monozygotic twins is ap-proximately 50%.
Even though the high rate of concordance among monozygotic twin pairs is
compelling evidence for ge-netic contributions, the fact that it is not higher
than 50% suggests a role for additional, perhaps nongenetic, factors in the
etiology of schizophrenia. The number of sets of adopted-away, monozy-gotic
twin pairs affected with schizophrenia is relatively small. However, data
available on the limited number of pairs meeting these criteria support the
strong concordance of schizophrenia in monozygotic twins.
The Human Genome Project with its 3 billion base pairs and approximately
35 000 genes has ushered us into the “Genomic Era”. However, systematic genome
scans done recently have not resulted in strong evidence for linkage to any
chromosomal region. At the time of this writing, no genetic linkage or
asso-ciation related to schizophrenia has been discovered. There have been
reports of suggestive linkages but there has been a failure to replicate these
findings. It has become painfully clear that the replication studies are, in
many ways, more important to estab-lishing linkage than the initial report.
Genes that have been found not to be associated with schizophrenia include the
dopamine D2 and D4 genes.
The initial enthusiasm for these strategies has waned as no gene has yet
been isolated for schizophrenia or bipolar dis-order. Impediments that have
limited the success of linkage and association studies are etiologic and
phenotypic heterogeneity of schizophrenia, lack of power and high false
positive rates. Thus, newer approaches such as multi-investigator collaborative
stud-ies to increase the power have already been implemented.
Meanwhile, modern functional genomic approaches such as DNA microarrays,
based on the principles of nucleic acid hy-bridization, can check a tissue
sample for presence of thousands of genes simultaneously. For example, Mirnics
and colleagues (2000) employed cDNA microarrays and compared transcrip-tomes in
schizophrenia and matched control subjects and found that only a few gene
groups consistently differed between sub-jects and controls. In all subjects
with schizophrenia, the most changed gene group was related to presynaptic group secretory function (PSYN) gene group and in
particular the “mechanics” of
neurotransmitter release.
Weinberger and colleagues (2001) suggest that the gene that encodes the
postsynaptic enzyme catechol-o-methyl
trans-ferase (COMT) is preferentially involved in the metabolism of dopamine in
frontal lobe. Dopamine is hypothesized to underlie aspects of cognition in
frontal lobe such as information process-ing. Based on animal studies,
family-based association studies and fMRI studies in schizophrenia patients and
general popula-tion, Weinberger and colleagues propose an interesting
hypoth-esis that the COMT genotype with valenine allele (val/val type) may
increase the risk of developing schizophrenia due to its ef-fect on
dopamine-mediated prefrontal information processing.
Researchers are urgently searching for schizophrenia phenotypes for
subgroups or dimensions that may define etio-logically or genetically distinct
subtypes. Similarly, the field is yearning for endophenotypes with simpler architecture than schizophrenia
possibly to guide to newer leads in research. Latent genetically influenced
traits, which may be related only indirectly to the classic disease symptoms
defined in major clas-sification systems, are known as “endophenotypes”. They
reflect an underlying susceptibility to the disease phenotype (or some form of
it). In schizophrenia we are interested in endophenotypes that are measurable
by neurophysiological or neuropsychological means. Crucial characteristics of
any endophenotype include the fact that it can be measured before the explicit
onset of the illness, and that it represents the genetic liability of
nonaffected relatives of probands with the disorder.
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