Original Investigation

Human Genetics

, Volume 111, Issue 6, pp 521-537

First online:

Population variation in linkage disequilibrium across the COMT gene considering promoter region and coding region variation

  • Mellissa M. DeMilleAffiliated withDepartment of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005, USA
  • , Judith R. KiddAffiliated withDepartment of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005, USA
  • , Valeria RuggeriAffiliated withDepartment of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005, USA
  • , Meg A. PalmatierAffiliated withDepartment of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005, USA
  • , David GoldmanAffiliated withNeurogenetics Laboratory, NIAAA, Park Building Room 451, 12420 Parklawn Drive, Rockville, MD 20852, USA
  • , Adekunle OdunsiAffiliated withDepartment of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
  • , Friday OkonofuaAffiliated withDepartment of Obstetrics and Gynecology, Faculty of Medicine, University of Benin, Benin City, Nigeria
  • , Elena GrigorenkoAffiliated withDepartment of Psychology, Yale University, New Haven CT 06511, USA
  • , Leslie O. SchulzAffiliated withDepartment of Health Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA
    • , Batsheva Bonne-TamirAffiliated withDepartment of Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
    • , Ru-Band LuAffiliated withDepartment of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
    • , Josef ParnasAffiliated withCopenhagen University, Psychiatry Department, Hvidovre Hospital, Kettegard Alle 30, Hvidovre, Denmark
    • , Andrew J. PakstisAffiliated withDepartment of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005, USA
    • , Kenneth K. KiddAffiliated withDepartment of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005, USA

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Abstract.

Catechol-O-methyl transferase (COMT) catalyzes the first step in one of the major pathways in the degradation of catecholamines. The COMT gene on chromosome 22 has been considered a candidate gene for many neuropsychiatric disorders, in part because an exon 4 single nucleotide polymorphism (SNP) in COMT causes an amino acid substitution associated with significantly altered enzyme activity. This functional variant, detected as an NlaIII restriction site polymorphism (RSP), is polymorphic in populations from around the world. A four-site haplotype spanning 28 kb effectively encompasses COMT. This haplotype is comprised of two novel polymorphisms [a tetranucleotide short tandem repeat polymorphism (STRP) in intron 1 and a HindIII RSP at the 5′ end of COMT], the NlaIII site, and another previously published site – a BglI RSP at the 3′ end of the gene. Overall linkage disequilibrium (LD) for this haplotype is strong and significant in 32 population samples from around the world. Conditional probabilities indicate that, in spite of moderate to strong disequilibrium in most non-African populations, the NlaIII site, although often used for prediction, would not always be a reliable predictor of allelic variation at the other sites. Because other functional variation might exist, especially regulatory variation, these findings indicate that haplotypes would be more effective indicators of possible involvement of COMT in disease etiology.