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COMT haplotypes suggest P2 promoter region relevance for schizophrenia

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-O-methyl 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 3′ 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.

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Acknowledgements

We would like to thank Valeria Ruggeri, Roy Capper, and Lena Golovyan for their technical help. This work was supported by PHS grants, MH62495, AA09379 and GM57672, to KKK and NS01795 to MAP. We want to acknowledge and thank the following additional individuals for their help over the years in assembling the samples from the diverse populations: FL Black, William Byerley, LL Cavalli-Sforza, J Friedlaender, Kenneth Kendler, William Knowler, Frank Oronsaye, Leena Peltonen, Leslie O Schulz and Kenneth Weiss. Some cell lines were made available by the Coriell Institute for Medical Research and by the National Laboratory for the Genetics of Israeli Populations. Special thanks are due to the many hundreds of individuals who volunteered to give blood samples for studies such as this. Without such participation of individuals from diverse parts of the world, we would be unable to obtain a true picture of the genetic variation in our species.

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Correspondence to K K Kidd.

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ALFRED is a database of allele frequency information accessible over the worldwide web at the URL; http://alfred.med.yale.edu/

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Palmatier, M., Pakstis, A., Speed, W. et al. COMT haplotypes suggest P2 promoter region relevance for schizophrenia. Mol Psychiatry 9, 859–870 (2004). https://doi.org/10.1038/sj.mp.4001496

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  • DOI: https://doi.org/10.1038/sj.mp.4001496

Keywords

  • COMT
  • haplotypes
  • schizophrenia
  • linkage disequilibrium
  • functional variation
  • P2 promoter
  • population variation

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