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

Background: Catechol-O-methyltransferase (COMT) has been investigated as a candidate gene in many neurologic disorders involving catecholaminergic sys tems. The NlaIII restriction site polymorphism (RSP) at COMT is a G left ri ght arrow A (site absent left right arrow site present) single nucleotide p olymorphism (SNP) at nucleotide 322/472 (in the short or long mRNA) that re sults in a Val left right arrow Met polymorphism at amino acid 108/158 (in soluble or membrane-bound) COMT protein and different enzyme activity level s, high for Val, low for Met. COMT enzyme activity is known to vary among e thnic groups, presumably as a result of different population frequencies of these COMT alleles. We have undertaken a direct survey of allele frequenci es 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 NlaIII and electrophoresi s. Results: The frequencies of the low activity allele (COMT*L, NlaIII site-pr esent) vary significantly from 0.01 to 0.62. Europeans have nearly equal fr equencies 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 primat es indicates that COMT*H is the ancestral allele in humans. Conclusions: This is the first global survey of the COMT*L and COMT*H allel e frequencies, confirming and extending earlier studies to show significant worldwide variation. This is also the first study establishing the COMT*L allele as the derived allele unique to humans. Henceforth, in any populatio n-based association studies of this polymorphism, the control allele freque ncies should be in agreement with these published values for corresponding ethnic groups. Biol Psychiatry 1999;46: 557-567 (C) 1999 Society of Biologi cal Psychiatry.