title: A highly significant association between a COMT haplotype and schizophrenia.
abstract: 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=9.5x10-8). The approach presented can be widely implemented for the genetic dissection of other common diseases.
authors.affiliation: Institute of Life Sciences, The Hebrew University of Jerusalem, Israel.
authors.forename: Sagiv
authors.initials: S
authors.lastname: Shifman
authors.forename: Michal
authors.initials: M
authors.lastname: Bronstein
authors.forename: Meira
authors.initials: M
authors.lastname: Sternfeld
authors.forename: Anne
authors.initials: A
authors.lastname: Pisanté-Shalom
authors.forename: Efrat
authors.initials: E
authors.lastname: Lev-Lehman
authors.forename: Avraham
authors.initials: A
authors.lastname: Weizman
authors.forename: Ilya
authors.initials: I
authors.lastname: Reznik
authors.forename: Baruch
authors.initials: B
authors.lastname: Spivak
authors.forename: Nimrod
authors.initials: N
authors.lastname: Grisaru
authors.forename: Leon
authors.initials: L
authors.lastname: Karp
authors.forename: Richard
authors.initials: R
authors.lastname: Schiffer
authors.forename: Moshe
authors.initials: M
authors.lastname: Kotler
authors.forename: Rael D
authors.initials: RD
authors.lastname: Strous
authors.forename: Marnina
authors.initials: M
authors.lastname: Swartz-Vanetik
authors.forename: Haim Y
authors.initials: HY
authors.lastname: Knobler
authors.forename: Eilat
authors.initials: E
authors.lastname: Shinar
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: Benjamin
authors.initials: B
authors.lastname: Yakir
authors.forename: Neil
authors.initials: N
authors.lastname: Risch
authors.forename: Naomi B
authors.initials: NB
authors.lastname: Zak
authors.forename: Ariel
authors.initials: A
authors.lastname: Darvasi
mesh_terms: D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007585:Jews / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012107:Research Design; D018401:Sample Size; D012559:Schizophrenia / Q000235:genetics*; D012727:Sex Characteristics
chemical_list: D002394:Catechol O-Methyltransferase