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Takaki Tanifuji,1 Satoshi Okazaki,1 Ikuo Otsuka,1 Tadasu Horai,1 Yutaka Shinko,1 Saehyeon Kim,1 Ichiro Sora,1 Akitoyo Hishimoto1,2 1Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan; 2Department of Psychiatry, Yokohama City University Graduate School of Medicine, Yokohama, JapanCorrespondence: Akitoyo HishimotoDepartment of Psychiatry, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama, 236-0004, JapanTel +81-45-787-2667Fax +81-45-783-2540Email hishipon@yokohama-cu.ac.jpBackground: Monoamine oxidase-A (MAO-A) decomposes dopamine and serotonin, and decreased MAO-A expression increases monoamine levels and is related to the pathophysiology of schizophrenia. Previous studies have reported that variable number of tandem repeats (VNTR), namely, upstream (u)VNTR, and some single nucleotide polymorphisms (SNPs) in the MAOA gene are associated with schizophrenia.Methods: We investigated the two VNTRs and their related SNPs (rs6323 and rs1137070) in the MAOA gene promoter in 859 patients with schizophrenia and 826 healthy controls. Distal (d)VNTR and uVNTR were genotyped with fluorescence-based fragment polymerase chain reaction assays, and rs6323 and rs1137070 with TaqMan SNP genotyping assays.Results: Neither the genotype nor allelic frequency of the VNTRs or SNPs showed significant differences between the schizophrenia and control groups. On the other hand, analysis of the dVNTR-uVNTR-rs6323-rs1137070 haplotype showed significant association for nine repeats (9R)-3R-T-C in female patients (corrected p = 0.0006, odds ratio [confidence interval] = 2.17 [1.446– 3.257]).Conclusion: Our findings provide novel evidence that MAOA gene polymorphisms are associated with an increased risk of developing schizophrenia in females.Keywords: haplotype, monoamine oxidase A, polymorphism, schizophrenia, variable number of tandem repeats

Takashi Hirata, Akitoyo Hishimoto, Ikuo Otsuka, Satoshi Okazaki, Shuken Boku, Atsushi Kimura, Tadasu Horai, Ichiro Sora Department of Psychiatry, Kobe University Graduate School of Medicine, Kusunoki-cho, Chuo-ku, Kobe, Japan Background: Life expectancy is 10–20 years lower in patients with schizophrenia than in the general population. In addition, men with schizophrenia have an earlier age at onset, more pronounced deficit symptoms, poorer course, and poorer response to antipsychotic medications than women. Recent studies have indicated that loss of chromosome Y (LOY) in peripheral blood is associated with an increased risk of all-cause mortality. In order to elucidate the pathophysiology of male-specific features, we investigated the association between LOY and schizophrenia. Materials and methods: The present study included 360 Japanese men (146 patients with schizophrenia vs 214 controls). The relative amount of Y chromosome was defined as the ratio of chromosome Y to chromosome X (Y/X ratio) based on the fluorescent signal of co-amplified short sequences from the Y-X homologous amelogenin genes (AMELY and AMELX). Results: There was no significant difference in the frequency of LOY between the schizophrenia and control groups. However, longer duration of illness was associated with LOY after controlling for age and smoking status in the schizophrenia group (P=0.007, OR =1.11 [95% CI =1.03–1.19]). Conclusion: According to our results, schizophrenia may not have a remarkable effect on blood LOY; however, LOY may be associated with disease course in patients with schizophrenia. Keywords: loss of chromosome Y, schizophrenia, disease duration

Tadasu Horai,1 Akitoyo Hishimoto,1 Ikuo Otsuka,1 Tatsuhiro So,2 Kentaro Mouri,1 Naofumi Shimmyo,1 Shuken Boku,1 Noriaki Okishio,3 Ichiro Sora1 1Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan; 2So Mental Clinic, Kobe, Japan; 3Hyogo Mental Health Center, Kobe, Japan Background: Alcohol dependence induces low bone mineral density (BMD), predicting osteoporosis, while low and moderate alcohol consumption may even increase BMD. In recent years, undercarboxylated osteocalcin (ucOC) and tartrate-resistant acid phosphatase-5b (TRACP-5b), bone turnover markers, have gained special interest as useful indicators of low BMD. However, it remains unclear whether other alcohol-related variables (eg, duration of abstinence and continuous drinking) are linked to aberrant BMD. In addition, no previous study has investigated whether ucOC or TRACP-5b is clinically useful to predict low BMD not only in the general population, but also in alcohol-dependent subjects.Patients and methods: We recruited 275 male alcohol-dependent subjects and collected information about their drinking habits, comorbid diseases, smoking history and walking exercise behavior. BMD in each subject was determined by ultrasonography. Serum liver enzymes (AST, ALT, ALP, ChE, γ-GTP and LDH), ucOC and TRACP-5b were measured in all subjects. T-scores were calculated according to BMD for all subjects.Results: The mean T-scores of our subjects were negatively shifted compared to the general population (-0.75±1.36 SD). We divided our subjects into a normal BMD group (n=137) and a low BMD group (n=138) according to their T-scores (T-score ≥-1 SD, normal BMD; T-score

Naofumi Shimmyo,1 Akitoyo Hishimoto,1 Ikuo Otsuka,1 Satoshi Okazaki,1 Shuken Boku,1 Kentaro Mouri,1 Tadasu Horai,1 Motonori Takahashi,2 Yasuhiro Ueno,2 Osamu Shirakawa,3 Ichiro Sora1 1Department of Psychiatry, 2Division of Legal Medicine, Department of Community Medicine and Social Health Science, Kobe University Graduate School of Medicine, Kobe, 3Department of Neuropsychiatry, Kindai University Faculty of Medicine, Osaka, Japan Background: Numerous studies suggest that inflammation plays a key role in suicidal behavior. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has received increasing attention in depression research. However, no study has investigated whether MIF has genetic involvement in completed suicide. In this study, we sought to explore the relationship between two functional polymorphisms on the MIF gene promoter (MIF-794CATT5–8 microsatellite and MIF-173G/C single-nucleotide polymorphism [SNP]) and completed suicide by using one of the largest samples of suicide completers ever reported.Methods: The subjects comprised 602 suicide completers and 728 healthy controls. We genotyped MIF-794CATT5–8 microsatellite by polymerase chain reaction–based size discrimination assay and MIF-173G/C SNP by TaqMan® SNP genotyping assay. The allele-, genotype-, or haplotype-based association analyses between the suicide completers and the controls were carried out with the χ2 test, the Cochran–Armitage trend test, or Fisher’s exact test.Results: Analyses of allele or genotype frequency distributions of the polymorphisms studied here did not reveal any significant differences between the suicide completers and the controls. Haplotype analysis also revealed no association with completed suicide.Conclusion: To our knowledge, this is the first study that has examined the genetic association between MIF and completed suicide. Our results suggest that the effects of MIF-794CATT5–8 microsatellite and MIF-173G/C SNP on the MIF gene promoter might not contribute to the genetic risk of completed suicide in the Japanese population. Keywords: MIF, suicide, microsatellite, SNP, haplotype, promoter region