Chemokine Receptor Variation in Schizophrenia

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.