Evaluation of genetic association of the INK4 locus with primary open angle glaucoma in East Indian population

INK4 locus at chromosome 9p21 has been reported to be associated with primary open angle glaucoma (POAG) and its subtypes along with the associated optic disc parameters across the populations of European, Japanese and African ancestries. The locus encodes three tumor suppressor genes namely CDKN2A, ARF, CDKN2B and a long non-coding RNA CDKN2B-AS1 (also known as ANRIL). Here, we report association study of 34 SNPs from INK4 locus with POAG in a population of Indo-European ancestry from the eastern part of India (350 patients and 354 controls). With 81% power to detect genetic association we observed only nominal association of rs1011970 (uncorrected p = 0.048) with POAG and rs10120688 (uncorrected p = 0.048) in patients without a high intra-ocular pressure (IOP<21 mm of Hg) compared to controls. This study, in contrast to the previous reports, suggests lack of significant genetic association of INK4 locus with POAG in East Indian population which needs to be replicated in larger studies in diverse world populations

Fusion transcripts in normal human cortex increase with age and show distinct genomic features for single cells and tissues

Fusion transcripts can contribute to diversity of molecular networks in the human cortex. In this study, we explored the occurrence of fusion transcripts in normal human cortex along with single neurons and astrocytes. We identified 1305 non-redundant fusion events from 388 transcriptomes representing 59 human cortices and 329 single cells. Our results indicate while the majority of fusion transcripts in human cortex are intra-chromosomal (85%), events found in single neurons and astrocytes were primarily inter-chromosomal (80%). The number of fusions in single neurons was significantly higher than that in single astrocytes (p <0.05), indicating fusion as a possible contributor towards transcriptome diversity in neuronal cells. The identified fusions were largely private and 4 specific recurring events were found both in cortex and in single neurons but not in astrocytes. We found a significant increase in the number of fusion transcripts in human brain with increasing age both in single cells and whole cortex (p <0.0005 and <0.005, respectively). This is likely one of the many possible contributors for the inherent plasticity of the adult brain. The fusion transcripts in fetal brain were enriched for genes for long-term depression; while those in adult brain involved genes enriched for long-term potentiation pathways. Our findings demonstrate fusion transcripts are naturally occurring phenomenon spanning across the health-disease continuum, and likely contribute to the diverse molecular network of human brain

Association of early life stress and cognitive performance in patients with schizophrenia and healthy controls

As core symptoms of schizophrenia, cognitive deficits contribute substantially to poor outcomes. Early life stress (ELS) can negatively affect cognition in patients with schizophrenia and healthy controls, but the exact nature of the mediating factors is unclear. Therefore, we investigated how ELS, education, and symptom burden are related to cognitive performance. The sample comprised 215 patients with schizophrenia (age, 42.9 ± 12.0 years; 66.0 % male) and 197 healthy controls (age, 38.5 ± 16.4 years; 39.3 % male) from the PsyCourse Study. ELS was assessed with the Childhood Trauma Screener (CTS). We used analyses of covariance and correlation analyses to investigate the association of total ELS load and ELS subtypes with cognitive performance. ELS was reported by 52.1 % of patients and 24.9 % of controls. Independent of ELS, cognitive performance on neuropsychological tests was lower in patients than controls (p < 0.001). ELS load was more closely associated with neurocognitive deficits (cognitive composite score) in controls (r = −0.305, p < 0.001) than in patients (r = −0.163, p = 0.033). Moreover, the higher the ELS load, the more cognitive deficits were found in controls (r = −0.200, p = 0.006), while in patients, this correlation was not significant after adjusting for PANSS. ELS load was more strongly associated with cognitive deficits in healthy controls than in patients. In patients, disease-related positive and negative symptoms may mask the effects of ELS-related cognitive deficits. ELS subtypes were associated with impairments in various cognitive domains. Cognitive deficits appear to be mediated through higher symptom burden and lower educational level

Interferon-driven brain phenotype in a mouse model of RNaseT2 deficient leukoencephalopathy

Solid state NMR/Biophysical Organic Chemistr

Gene-rich large deletions are overrepresented in POAG patients of Indian and Caucasian origins

PURPOSE: Large copy number variations (CNV) can contribute to increased burden for neurodegenerative diseases. In this study, we analyzed the genome-wide burden of large CNVs > 100 kb in primary open angle glaucoma (POAG), a neurodegenerative disease of the eye that is the largest cause of irreversible blindness. METHODS: Genome-wide analysis of CNVs > 100 kb were analyzed in a total of 1720 individuals, including an Indian cohort (347 POAG cases and 345 controls) and a Caucasian cohort (624 cases and 404 controls). All the CNV data were obtained from experiments performed on Illumina 660W-Quad (infinium) arrays. RESULTS: We observed that for both the populations CNVs > 1 Mb was significantly enriched for gene-rich regions unique to the POAG cases (P 1 Mb (39 calls) in patients influenced 125 genes while in controls 31 such CNVs influenced only 5 genes with no overlap. In both cohorts we observed 1.9-fold gene enrichment in patients for deletions compared to duplications, while such a bias was not observed in controls (0.3-fold). Overall duplications > 1 Mb were more than deletions (Del/Dup = 0.82) confirming that the enrichment of gene-rich deletions in patients was associated with the disease. Of the 39 CNVs > 1 Mb from Indian patients, 28 (72%) also were implicated in other neurodegenerative disorders, like autism, schizophrenia, sensorineural hearing loss, and so forth. We found one large duplication encompassing CNTN4 gene in Indian and Caucasian POAG patients that was absent in the controls. CONCLUSIONS: To our knowledge, our study is the first report on large CNV bias for gene-rich regions in glaucomatous neurodegeneration, implicating its impact across populations of contrasting ethnicities. We identified CNTN4 as a novel candidate gene for POAG

The Role of micrornas in the course of servere mental disorders.

Background Illnesses from the schizophrenia-to-bipolar spectrum have a highly variable course. Determinants of these different individual trajectories have been of particular interest to scholars during the past century. Beyond rudimentary understanding, however, different course types have been difficult to delineate in categorical disease phenotypes. We have therefore embarked upon a project in which we seek to delineate different course types in a large longitudinal sample of deeply phenotyped patients suffering from disorders of the schizophrenia-to-bipolar continuum. With respect to biology, a dysregulation of microRNAs, small non-coding RNA molecules that flexibly influence transcription, in mental disorders is increasingly recognized. To combine both of these novel approaches, we plan investigate the role of microRNAs in different course types identified using longitudinal cluster analysis. Methods Longitudinal clustering Participants were selected from an ongoing longitudinal, multi-site study (www.kfo241.de, www.PsyCourse.de). Patients with a DSM-IV diagnosis of the schizophrenia-to-bipolar spectrum were comprehensively phenotyped at four time-points over a period of 18 months. A set of longitudinally measured variables on current psychopathology, medication adherence, substance use, cognitive performance, level of psychosocial functioning and various questionnaires was analyzed using factor analysis for mixed data followed by longitudinal cluster analyses. This resulted in the identification of distinct subpopulations of patients, each being heterogeneous in terms of diagnostic composition. MicroRNA sequencing So far, we have compared four different methods to isolate blood borne small non-coding RNAs for RNA-sequencing. By this we were able to establish SOPs for the reliable analysis of circulating small non-coding RNAs in longitudinal cohorts. Results We will present results of our research project at the meeting. Discussion We will discuss our research project at the meeting. &nbsp

H3 acetylation selectively promotes basal progenitor proliferation and neocortex expansion.

Increase in the size of human neocortex―acquired in evolution―accounts for the unique cognitive capacity of humans. This expansion reflects the evolutionarily enhanced proliferative ability of basal progenitors (BPs), including the basal radial glia and basal intermediate progenitors (bIPs) in mammalian cortex, which may have been acquired through epigenetic alterations in BPs. However, how the epigenome in BPs differs across species is not known. Here, we report that histone H3 acetylation is a key epigenetic regulation in bIP amplification and cortical expansion. Through epigenetic profiling of sorted bIPs, we show that histone H3 lysine 9 acetylation (H3K9ac) is low in murine bIPs and high in human bIPs. Elevated H3K9ac preferentially increases bIP proliferation, increasing the size and folding of the normally smooth mouse neocortex. H3K9ac drives bIP amplification by increasing expression of the evolutionarily regulated gene, Trnp1, in developing cortex. Our findings demonstrate a previously unknown mechanism that controls cortical architecture