TY - JOUR
T1 - Population variation in linkage disequilibrium across the COMT gene considering promoter region and coding region variation
AU - DeMille, Mellissa M.C.
AU - Kidd, Judith
AU - Ruggeri, Valeria
AU - Palmatier, Meg A.
AU - Goldman, David
AU - Odunsi, Adekunle
AU - Okonofua, Friday
AU - Grigorenko, Elena
AU - Schulz, Leslie O.
AU - Bonne-Tamir, Betsheva
AU - Lu, Ru Band
AU - Parnas, Josef
AU - Pakstis, Andrew J.
AU - Kidd, Kenneth K.
N1 - Funding Information:
Acknowledgements This work was supported in part by NIH grants MH62495, AA09379, and GM57672 (to K.K.K.), NIH grant NS01795 (to M.A.P.), and by NSF grant SBR-9632509 (to J.R.K.). Support for sample collection was also provided by grants from the Alfred P. Sloan Foundation (to K.K.K. and J.R.K.), the National Science Council of Taiwan, NHRI-EX90-8939BP and NSC90-2314-B-016-081 (to R.-B.L.). Support was also provided by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases (to K.K.K.). We want to acknowledge and thank the following additional individuals for their help over the years in assembling the samples from the diverse populations: F.L. Black, L.L. Cavalli-Sforza, J. Friedlaender, Kenneth Kendler, William Knowler, Frank Oronsaye, Leena Peltonen, and Kenneth Weiss. Special thanks are due to the many hundreds of individuals who volunteered to give blood samples for studies such as this. Without such participation of individuals from diverse parts of the world we would be unable to obtain a true picture of the genetic variation in our species.
PY - 2002/12
Y1 - 2002/12
N2 - 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 trestriction 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.
AB - 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 trestriction 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.
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U2 - 10.1007/s00439-002-0809-0
DO - 10.1007/s00439-002-0809-0
M3 - Article
C2 - 12436243
AN - SCOPUS:0036941355
VL - 111
SP - 521
EP - 537
JO - Human Genetics
JF - Human Genetics
SN - 0340-6717
IS - 6
ER -