COMT haplotypes suggest P2 promoter region relevance for schizophrenia
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Date
2004
Journal Title
Journal ISSN
Volume Title
Publisher
Molecular psychiatry
Abstract
A recent study found, in a large sample of Ashkenazi Jews, a highly significant association
between schizophrenia and a particular haplotype of three polymorphic sites in the catechol-Omethyl
transferase, COMT, gene: an IVS 1 SNP (dbSNP rs737865), the exon 4 functional SNP
(Val158Met, dbSNP rs165688), and a downstream SNP (dbSNP rs165599). Subsequently, this
haplotype was shown to be associated with lower levels of COMT cDNA derived from normal
cortical brain tissue, most likely due to cis-acting element(s). As a first step toward evaluating
whether this haplotype may be relevant to schizophrenia in populations other than Ashkenazi
Jews, we have studied this haplotype in 38 populations representing all major regions of the
world. Adding to our previous data on four polymorphic sites in the COMT gene, including the
Val158Met polymorphism, we have typed the IVS 1 rs737865 and 30 rs615599 sites and also
included a novel IVS 1 indel polymorphism, yielding seven-site haplotype frequencies for
normal individuals in the 38 globally distributed populations, including a sample of Ashkenazi
Jews. We report that the schizophrenia-associated haplotype is significantly heterogeneous in
populations worldwide. The three-site, schizophrenia-associated haplotype frequencies range
from 0% in South America to 37.1% in Southwest Asia, despite the fact that schizophrenia
occurs at roughly equal frequency around the world. Assuming that the published
associations found between the exon 4 Val158Met SNP and schizophrenia are due to linkage
disequilibrium, these new haplotype data support the hypothesis of a relevant cis variant linked
to the rs737865 site, possibly just upstream in the P2 promoter driving transcription of the
predominant form of COMT in the brain. The previously described HindIII restriction site
polymorphism, located within the P2 promoter, varies within all populations and may provide
essential information in future studies of schizophrenia.
Description
Keywords
COMT, Haplotypes, Schizophrenia
Citation
Palmatier, M.A., Pakstis, A.J., Speed, W., Paschou, P., Goldman, D., Odunsi, A., Okonofua, F., Kajuna, S., Karoma, N., Kungulilo, S. and Grigorenko, E., 2004. COMT haplotypes suggest P2 promoter region relevance for schizophrenia. Molecular psychiatry, 9(9), pp.859-870.