1. ¹Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
2. ²Vadaskert Child and Adolescent Psychiatric Clinic, Budapest, Hungary
3. ³Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary
4. ⁴Department of Biochemistry and Molecular Biology, Hubert Kairuki Memorial University, Dar es Salaam, Tanzania

Correspondence: Dr JR Kidd, Department of Genetics, Yale University School of Medicine, 333 Cedar Street, PO Box 208005, New Haven, CT 06520-8005, USA. E-mail: Judith.Kidd@yale.edu

Received 7 January 2008; Revised 13 May 2008; Accepted 16 May 2008; Published online 24 June 2008.

Abstract

Genetic variation at the catechol-O-methyltransferase (COMT) gene has been significantly associated with risk for various neuropsychiatric conditions such as schizophrenia, panic disorder, bipolar disorders, anorexia nervosa and others. It has also been associated with nicotine dependence, sensitivity to pain and cognitive dysfunctions especially in schizophrenia. The non-synonymous single nucleotide polymorphism (SNP) in exon 4—Val108/158Met—is the most studied SNP at COMT and is the basis for most associations. It is not, however, the only variation in the gene; several haplotypes exist across the gene. Some studies indicate that the haplotypic combinations of alleles at the Val108/158Met SNP with those in the promoter region and in the 3'-untranslated region are responsible for the associations with disorders and not the non-synonymous SNP by itself. We have now studied DNA samples from 45 populations for 63 SNPs in a region of 172 kb across the region of 22q11.2 encompassing the COMT gene. We focused on 28 SNPs spanning the COMT-coding region and immediately flanking DNA, and found that the haplotypes are from diverse evolutionary lineages that could harbor as yet undetected variants with functional consequences. Future association studies should be based on SNPs that define the common haplotypes in the population(s) being studied.