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

Catechol-O-methyltransferase (COMT) has been investigated as a candidate gene in many neurologic disorders involving catecholaminergic systems. The NlaIII 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.

We typed 1314 individuals from 30 different populations using PCR of the relevant region followed by digestion with NlaIII and electrophoresis.

The frequencies of the low activity allele (COMT*L, NlaIII 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.

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.