Chemokine Receptor Variation in Schizophrenia
AK Malhotra, R Peterson, R Finnegan, RW Buchanan, D
Goldman, M Dean
Retroviruses have been implicated in the pathophysiology of
schizophrenia. Retroviruses are neurotropic, remain latent in host tissue
for extended periods of time, and can integrate into the host genome and be
transmitted to offspring. Susceptibility to retroviral infection is
dramatically influenced by genetic variation in the chemokine receptor
system. A chemokine receptor 5 allele (CCR5ڤ32) prematurely truncates the
receptor and CCR5 ڤ32 homozygotes are virtually
invulnerable to infection with the retrovirus, HIV-1. These data linking
genetic actors with differential susceptibility to retroviral infection provide
a novel means of testing the hypothesis that retroviral factors are associated
with the etiology of schizophrenia.
We have conducted a pilot study of the role of CCR5 in
schizophrenia utilizing the family-based Transmission Disequilibrium Test (TDT).
CCR5 genotyping was conducted in over 100 patients with schizophrenia or
schizoaffective disorder and both of their biological parents. Preliminary
data analysis indicates significantly reduced CCR5 ڤ32 transmission to schizophrenia
patients from heterozygous parents. In comparison to the expected 50%
transmission rate, CCR5 ڤ32 was only transmitted at a frequency
of 30%. Moreover, no CCR5 ڤ32 homozygotes were identified in
our cohort of over 200 schizophrenia patients. These data provide
preliminary molecular support for retroviral involvement in schizophrenia.
In addition to CCR5 ڤ32, a number of additional
functional chemokine receptors (CCR5P1, CR2, SDF-1) polymorphisms have been
recently found to influence retroviral infection. These polymorphisms are
currently being tested with the TNT design to provide further support for
retroviral involvement in the etiology of schizophrenia.