title: Biological effects of COMT haplotypes and psychosis risk in 22q11.2 deletion syndrome.
abstract: BACKGROUND
  22q11.2 deletion syndrome (22q11.2DS) is the most common genetic syndrome associated with schizophrenia. The catechol-O-methyltransferase (COMT) gene is located in the obligatory deletion region, and possible associations between COMT variants and neuropsychiatric manifestations in 22q11.2DS have been reported. The purpose of the current study was to evaluate the effect of COMT hemizygosity and molecular haplotypes on gene expression and enzyme activity and its association with psychotic symptoms in 22q11.2DS.
  
  
  METHODS
  Lymphoblast samples were drawn from 53 individuals with 22q11.2DS and 16 typically developing control subjects. We measured COMT messenger (m)RNA and protein expression and enzyme activity using standard procedures. The presence of a psychotic disorder and cognitive deficits were also evaluated using structured testing.
  
  
  RESULTS
  There was an approximately 50% reduction in COMT mRNA, protein, and enzyme activity levels in 22q11.2DS samples. Haplotype analysis revealed clear phenotypic differences between various Val-containing haplotypes on COMT-3' untranslated region extended mRNA, soluble COMT and membrane-bound proteins, and enzyme activity. The G variant of rs165599, a 3' untranslated region single nucleotide polymorphism, was associated with low levels of COMT expression and with the presence of psychosis and lower performance IQ scores in our 22q11.2DS sample. Finally, we demonstrate that the COMT rs74745580 "T" mutation is associated with absent soluble COMT expression and very low COMT activity in two 22q11.2DS individuals.
  
  
  CONCLUSIONS
  Our findings confirm a robust effect of COMT hemizygosity on COMT activity and show complex interactions of variants within the COMT gene that influence COMT biology and confound conclusions based on associations with the Val158Met genotype alone.
authors.affiliation: Behavioral Neurogenetics Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Gothelf
authors.affiliation: Departments of Psychiatry and Cell and Developmental Biology, School of Medicine, University of Colorado, Aurora, Colorado; Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Law
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; The Felsenstein Medical Research Center, Petah Tiqwa, Israel.
authors.forename: Amos
authors.initials: A
authors.lastname: Frisch
authors.affiliation: Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jingshan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Behavioral Neurogenetics Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Omer
authors.initials: O
authors.lastname: Zarchi
authors.affiliation: The Felsenstein Medical Research Center, Petah Tiqwa, Israel.
authors.forename: Elena
authors.initials: E
authors.lastname: Michaelovsky
authors.affiliation: Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
authors.forename: Renee
authors.initials: R
authors.lastname: Ren-Patterson
authors.affiliation: Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Lipska
authors.affiliation: The Felsenstein Medical Research Center, Petah Tiqwa, Israel.
authors.forename: Miri
authors.initials: M
authors.lastname: Carmel
authors.affiliation: Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kolachana
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; The Felsenstein Medical Research Center, Petah Tiqwa, Israel.
authors.forename: Abraham
authors.initials: A
authors.lastname: Weizman
authors.affiliation: Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; Lieber Institute for Brain Development, Johns Hopkins University Medical Campus; Departments of Psychiatry, Neurology, and Neuroscience and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: drweinberger@libd.org.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
mesh_terms: D000293:Adolescent; D000328:Adult; D002394:Catechol O-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D016009:Chi-Square Distribution; D002648:Child; D002872:Chromosome Deletion; D004062:DiGeorge Syndrome / Q000150:complications* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008715:Methionine / Q000235:genetics; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000150:complications* / Q000235:genetics*; D014633:Valine / Q000235:genetics; D055815:Young Adult
chemical_list: D008715:Methionine; D002394:Catechol O-Methyltransferase; D014633:Valine
keywords: COMT; DiGeorge; gene expression; haplotype; psychosis; velocardiofacial syndrome