Genetic underpinnings of left superior temporal gyrus thickness in patients with schizophrenia

<div><p></p><p><i>Objectives.</i> Schizophrenia is a highly disabling psychiatric disorder with a heterogeneous phenotypic appearance. We aimed to further the understanding of some of the underlying genetics of schizophrenia, using left superior temporal gyrus (STG) grey matter thickness reduction as an endophenoptype in a genome-wide association (GWA) study. <i>Methods.</i> Structural magnetic resonance imaging (MRI) and genetic data of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia were used to analyse the interaction effects between 1,067,955 single nucleotide polymorphisms (SNPs) and disease status on left STG thickness in 126 healthy controls and 113 patients with schizophrenia. We next used a pathway approach to detect underlying pathophysiological pathways that may be related to schizophrenia. <i>Results.</i> No SNP by diagnosis interaction effect reached genome-wide significance (5 × 10^–8) in our GWA study, but 10 SNPs reached <i>P</i>-values less than 10^–6. The most prominent pathways included those involved in insulin, calcium, PI3K-Akt and MAPK signalling. <i>Conclusions.</i> Our strongest findings in the GWA study and pathway analysis point towards an involvement of glucose metabolism in left STG thickness reduction in patients with schizophrenia only. These results are in line with recently published studies, which showed an increased prevalence of psychosis among patients with metabolic syndrome-related illnesses including diabetes.</p></div

Clinical evaluation of M-VAC (methotrexate, vinblastine, adriamycin and cisplatin) chemotherapy for advanced urothelial cancer

進行性尿路上皮癌27例に対してM-VAC療法を施行した。CR 2例(15.4%)を含め奏効率は, 44.4%と, 導入療法としては良好な成績であった。しかし, 再発および再燃が高率に認められ, 維持療法の確立が必要と考えられたM-VAC (methotrexate, vinblastine, adriamycin and cisplatin) chemotherapy was performed on 27 patients with advanced urothelial cancer. The patients included 20 with bladder cancer, 4 with upper urinary tract cancer and 3 with both lesions. Complete response (CR) was observed in 2 (7.4 +/- 9.9%) patients and partial response (PR) in 10 (37.0 +/- 18.2%) patients after the treatment, i.e., the overall objective response rate was 44.4 +/- 18.7%. The rate of relapse or recurrence in the patients with CR and PR was 100% and 90.0%, respectively. The mean duration of the response was 18.5 +/- 13.4 months and 10.7 +/- 10.9 months for CR and PR, respectively. The overall survival rate after one year was 30.2%. Bone marrow suppression was the most serious side effect. The white blood cell count became below 1, 000/microliters in 10 patients (36.7%). Among them, 4 patients suffered from sepsis. In conclusion, M-VAC chemotherapy was effective for induction therapy against advanced urothelial cancer, although the effective duration was short. Further maintenance therapy should be established

Effect of <i>NRGN</i> risk variant on brain function.

<p>Functional map illustrating increased neural activity in rs12541 TT homozygotes compared to C carriers. SSC, somatosensory cortex; CC, cingulate cortex. Results were cluster-corrected and z-values are represented according to the color code.</p

Effect of <i>NRGN</i> risk variant on cortical thickness and ACC volume.

<p>a) Cortical statistical map illustrating reduced cortical thickness for rs12807809 C carriers compared to TT homozygotes. The -log(CWP-value) is represented according to the color code. b) Boxplot showing mean and two standard errors of the standardized residuals for the effects of <i>NRGN</i> rs12807809 genotype on left rostal ACC volume controlled for intracranial volume, age, gender, diagnosis and scanner field strength.</p

Quantile-quantile plot for MCIC association results.

<p>The empirical and theoretical distributions are shown as dots and line, respectively.</p

Linkage disequilibrium (LD) plot of all MCIC main hits on chromosome 19.

<p>LD is given based on r² estimated using the current dataset. Each diamond indicates the pairwise magnitude of LD, with dark grey/black indicating strong LD (r²>0.8). Figure prepared with <i>HaploView</i> (Barrett et al. 2005).</p

Demographic variables of the MCIC sample.

<p>Means and standard deviations (SD) are given. HC = healthy control, SZ = patient with schizophrenia. Ethnicity was defined as described under Methods. WRAT3-RT = Wide Range Achievement Test 3 – Reading Test. Parental SES (socioeconomic status) was classified according to Hollingshead, and handedness determined using the Annett Scale of Hand Preference.</p>a<p>significantly different between HC and SZ on basis of Chi-Square (p<0.05).</p>b<p>significantly different between HC and SZ on basis of Welch (p<0.05).</p

Genome-wide association results for SNPs associated with hippocampal volume in the MCIC sample.

<p>SNP IDs with chromosome (CHR), basepair position (BP), minor (A1) and major allele (A2), minor allele frequency (MAF), regression coefficient (BETA), coefficient (STAT) and asymptotic p-value for t-statistic, and corresponding gene regions: <i>KIF26B</i> (kinesin family member 26B), <i>TRPM8</i> (transient receptor potential cation channel, subfamily M, member 8), <i>LOC283089</i> (uncharacterized), <i>NR2F6</i> (nuclear receptor subfamily 2, group F, member 6), <i>USHBP1</i> (Usher syndrome 1C binding protein 1), and <i>BABAM1</i> (BRISC and BRCA1 A complex member 1). For additional information see Table S3 in File S1.</p

Additional file 6 of Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude

Additional file 6. Table S5: “Genes mapped to DMP/DMR identified in at-birth samples of babies born in the latitude ≥ 50°N and some examples of their associations with biological functions”. Provides examples of known functional associations of genes mapped to significant CpG sites or differentially methylated regions identified in this study

Additional file 7 of Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude

Additional file 7. Table S6: “Season of birth-associated differentially methylated regions (DMRs) at birth in babies born in latitudes < 50°N”. Differentially methylated regions and mapped genes identified in the at-birth samples of babies born in latitudes < 50°N (lower latitude subgroup analysis). Table S7: “Season of birth associated with differentially methylated regions (DMRs) in children born in latitudes ≥ 50°N”