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

Biol Psychiatry. 1999 Aug 15;46(4):557-67. doi: 10.1016/s0006-3223(99)00098-0.

Abstract

Background: 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.

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

Results: 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.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles*
  • Animals
  • Catechol O-Methyltransferase / genetics*
  • Central Nervous System Diseases / genetics
  • Continental Population Groups / genetics*
  • Female
  • Gene Frequency / genetics*
  • Genetic Linkage
  • Genetic Markers
  • Humans
  • Male
  • Mental Disorders / genetics
  • Polymerase Chain Reaction
  • Polymorphism, Restriction Fragment Length
  • Primates / genetics
  • Reference Values

Substances

  • Genetic Markers
  • Catechol O-Methyltransferase