Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles.

Abstract Background: Catechol- O -methyltransferase (COMT) has been investigated as a candidate gene in many neurologic disorders involving catecholaminergic systems. The Nla III restriction site polymorphism (RSP) at COMT is a G↔A (site absent↔site present) single nucleotide polymorphism (SNP) at nucleotide 322/472 (in the short or long mRNA) that results in a Val↔Met polymorphism at amino acid 108/158 (in soluble or membrane-bound) COMT protein and different enzyme activity levels, high for Val, low for Met. COMT enzyme activity is known to vary among ethnic groups, presumably as a result of different population frequencies of these COMT alleles. We have undertaken a direct survey of allele frequencies of this polymorphism in a global sample of populations. Methods: We typed 1314 individuals from 30 different populations using PCR of the relevant region followed by digestion with Nla III and electrophoresis. Results: The frequencies of the low activity allele (COMT∗L, Nla III site-present) vary significantly from 0.01 to 0.62. Europeans have nearly equal frequencies of the two alleles while the COMT∗H allele is much more common in populations in all other parts of the world. Sequencing in nonhuman primates indicates that COMT∗H is the ancestral allele in humans. Conclusions: This is the first global survey of the COMT∗L and COMT∗H allele frequencies, confirming and extending earlier studies to show significant world-wide variation. This is also the first study establishing the COMT∗L allele as the derived allele unique to humans. Henceforth, in any population-based association studies of this polymorphism, the control allele frequencies should be in agreement with these published values for corresponding ethnic groups.