A highly significant association between a COMT haplotype and schizophrenia.
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.
Shifman
Sagiv
S
Institute of Life Sciences, The Hebrew University of Jerusalem, Israel.
Bronstein
Michal
M
Sternfeld
Meira
M
Pisanté-Shalom
Anne
A
Lev-Lehman
Efrat
E
Weizman
Avraham
A
Reznik
Ilya
I
Spivak
Baruch
B
Grisaru
Nimrod
N
Karp
Leon
L
Schiffer
Richard
R
Kotler
Moshe
M
Strous
Rael D
RD
Swartz-Vanetik
Marnina
M
Knobler
Haim Y
HY
Shinar
Eilat
E
Beckmann
Jacques S
JS
Yakir
Benjamin
B
Risch
Neil
N
Zak
Naomi B
NB
Darvasi
Ariel
A
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
D002394:Catechol O-Methyltransferase