A highly significant association between a COMT haplotype and schizophrenia

Sagiv Shifman, Michal Bronstein, Meira Sternfeld, Anne Pisanté-Shalom, Efrat Lev-Lehman, Avraham Weizman, Ilya Reznik, Baruch Spivak, Nimrod Grisaru, Leon Karp, Richard Schiffer, Moshe Kotler, Rael D. Strous, Marnina Swartz-Vanetik, Haim Y. Knobler, Eilat Shinar, Jacques S. Beckmann, Benjamin Yakir, Neil Risch, Naomi B. ZakAriel Darvasi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

624 Scopus citations


Several lines of evidence have placed the catechol-O-methyltransferase (COMT) gene in the limelight as a candidate gene for schizophrenia. One of these is its biochemical function in metabolism of catecholamine neurotransmitters; another is the microdeletion, on chromosome 22q11, that includes the COMT gene and causes velocardiofacial syndrome, a syndrome associated with a high rate of psychosis, particularly schizophrenia. The interest in the COMT gene as a candidate risk factor for schizophrenia has led to numerous linkage and association analyses. These, however, have failed to produce any conclusive result. Here we report an efficient approach to gene discovery. The approach consists of (i) a large sample size - to our knowledge, the present study is the largest case-control study performed to date in schizophrenia; (ii) the use of Ashkenazi Jews, a well defined homogeneous population; and (iii) a stepwise procedure in which several single nucleotide polymorphisms (SNPs) are scanned in DNA pools, followed by individual genotyping and haplotype analysis of the relevant SNPs. We found a highly significant association between schizophrenia and a COMT haplotype (P = 9.5 × 10-8). The approach presented can be widely implemented for the genetic dissection of other common diseases.

Original languageAmerican English
Pages (from-to)1296-1302
Number of pages7
JournalAmerican Journal of Human Genetics
Issue number6
StatePublished - 1 Dec 2002


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