title: Association of copy number polymorphisms at the promoter and translated region of COMT with Japanese patients with schizophrenia.
abstract: Chromosome 22q11.2 deletion syndrome and genetic variations including single-nucleotide polymorphism (SNP) and copy number variation (CNV) in catechol-O-methyltransferase (COMT) situated at 22q11.2 remains controversial. Here, the genetic relationship between COMT and Japanese patients with schizophrenia was investigated by examining whether the SNPs correlated with schizophrenia based on a common disease-common variant hypothesis. Additionally, 22q11.2DS were screened based on a common disease-rare variant hypothesis; low-frequency CNVs situated at two COMT promoters and exons were investigated based on the low-frequency variants with an intermediate effect; and positive findings from the first stage were reconfirmed using a second-stage replication study including a larger sample size. Eight SNPs and 10 CNVs were investigated using Taqman SNP and CNV quantitative real-time polymerase chain reaction method. For the first-stage analysis, 513 unrelated Japanese patients with schizophrenia and 705 healthy controls were examined. For the second-stage replication study, positive findings from the first stage were further investigated using a larger sample size, namely 1,854 patients with schizophrenia and 2,137 controls. The first-stage analysis showed significant associations among schizophrenia, intronic SNP rs165774, CNV6 situated at promoter 1, CNV8 at exon 6, and CNV9 at exon 7. The second-stage study showed that intronic SNP rs165774 (χ(2)  = 8.327, P = 0.0039), CNV6 (χ(2)  = 19.66, P = 0.00005), and CNV8 (χ(2)  = 16.57, P = 0.00025) were significantly associated with schizophrenia. Large and rare CNVs as well as low-frequency CNVs and relatively small CNVs, namely <30 kb in COMT, may be genetic risk factors for schizophrenia.
authors: Department of Psychiatry, Juntendo University Schizophrenia Projects (JUSP), Juntendo University School of Medicine, Tokyo, Japan.
authors: Ryoko
authors: R
authors: Higashiyama
authors: Department of Psychiatry, Juntendo University Schizophrenia Projects (JUSP), Juntendo University School of Medicine, Tokyo, Japan.
authors: Tohru
authors: T
authors: Ohnuma
authors: Department of Psychiatry, Juntendo University Schizophrenia Projects (JUSP), Juntendo University School of Medicine, Tokyo, Japan.
authors: Yuto
authors: Y
authors: Takebayashi
authors: Department of Psychiatry, Juntendo University Schizophrenia Projects (JUSP), Juntendo University School of Medicine, Tokyo, Japan.
authors: Ryo
authors: R
authors: Hanzawa
authors: Department of Psychiatry, Juntendo University Schizophrenia Projects (JUSP), Juntendo University School of Medicine, Tokyo, Japan.
authors: Nobuto
authors: N
authors: Shibata
authors: Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
authors: Hidenaga
authors: H
authors: Yamamori
authors: Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
authors: Yuka
authors: Y
authors: Yasuda
authors: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Itaru
authors: I
authors: Kushima
authors: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Branko
authors: B
authors: Aleksic
authors: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
authors: Kenji
authors: K
authors: Kondo
authors: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
authors: Masashi
authors: M
authors: Ikeda
authors: Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.|Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan.
authors: Ryota
authors: R
authors: Hashimoto
authors: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
authors: Nakao
authors: N
authors: Iwata
authors: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Norio
authors: N
authors: Ozaki
authors: Department of Psychiatry, Juntendo University Schizophrenia Projects (JUSP), Juntendo University School of Medicine, Tokyo, Japan.
authors: Heii
authors: H
authors: Arai
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014176:Protein Biosynthesis; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000201:enzymology / Q000235:genetics*
chemical_list: D002394:Catechol O-Methyltransferase
keywords: 22q11.2; catechol-O-methyltransferase; copy number variation; schizophrenia; single-nucleotide polymorphism