Network-Based Analysis of Genetic Variants Associated with Hippocampal Volume in Alzheimer’S Disease: A Study of Adni Cohorts

Background: Alzheimer’s disease (AD) is a neurodegenerative disease that causes dementia. While molecular basis of AD is not fully understood, genetic factors are expected to participate in the development and progression of the disease. Our goal was to uncover novel genetic underpinnings of Alzheimer’s disease with a bioinformatics approach that accounts for tissue specificity. Findings: We performed genome-wide association studies (GWAS) for hippocampal volume in two Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts. We used these GWAS in a subsequent tissue-specific network-wide association study (NetWAS), which applied nominally significant associations in the initial GWAS to identify disease relevant patterns in a functional network for the hippocampus. We compared prioritized gene lists from NetWAS and GWAS with literature curated AD-associated genes from the Online Mendelian Inheritance in Man (OMIM) database. In the ADNI-1 GWAS, where we also observed an enrichment of low p-values, NetWAS prioritized disease-gene associations in accordance with OMIM annotations. This was not observed in the ADNI-2 dataset. We provide source code to replicate these analyses as well as complete results under permissive licenses. Conclusions: We performed the first analysis of hippocampal volume using NetWAS, which uses machine learning algorithms applied to tissue-specific functional interaction network to prioritize GWAS results. Our findings support the idea that tissue-specific networks may provide helpful context for understanding the etiology of common human diseases and reveal challenges that network-based approaches encounter in some datasets. Our source code and intermediate results files can facilitate the development of methods to address these challenges

Serials Spoken Here–Reports of Conferences, Institutes and Seminars

This quarter's column offers a report from the Acquisitions Institute at Timberline Lodge, held May 14–17, 2016, in Timberline Lodge, Oregon, and also provides coverage of multiple sessions from the Kraemer Copyright Conference, held June 6–7, 2016, in Colorado Springs, Colorado. Some reports are collected, as well, from the NASIG Annual Conference, held June 9–12, 2016, in Albuquerque, New Mexico, and the American Library Association (ALA) Annual Conference, held June 23–28, 2016, in Orlando, Florida. Lastly, there is a report from the International Federation of Library Associations and Institutions (IFLA) World Library and Information Congress, held August 13–19, 2016, in Columbus, Ohio. Topics covered include open access, linked data, copyright, text mining, e-resource management, and digitization

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

Proceedings of the 13th annual conference of INEBRIA

CITATION: Watson, R., et al. 2016. Proceedings of the 13th annual conference of INEBRIA. Addiction Science & Clinical Practice, 11:13, doi:10.1186/s13722-016-0062-9.The original publication is available at https://ascpjournal.biomedcentral.comENGLISH SUMMARY : Meeting abstracts.https://ascpjournal.biomedcentral.com/articles/10.1186/s13722-016-0062-9Publisher's versio

Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial

Purpose: To improve stratification of risk-adapted treatment for non-metastatic (M0), standard-risk medulloblastoma patients by prospective evaluation of biomarkers of reported biological or prognostic significance, alongside clinico-pathological variables, within the multi-center HIT-SIOP-PNET4 trial. Methods: Formalin-fixed paraffin-embedded tumor tissues were collected from 338 M0 patients (>4.0 years at diagnosis) for pathology review and assessment of the WNT subgroup (MBWNT) and genomic copy-number defects (chromosome 17, MYC/MYCN, 9q22 (PTCH1) and DNA ploidy). Clinical characteristics were reviewed centrally. Results: The favorable prognosis of MBWNT was confirmed, however better outcomes were observed for non-MBWNT tumors in this clinical risk-defined cohort compared to previous disease-wide clinical trials. Chromosome 17p/q defects were heterogeneous when assessed at the cellular copy-number level, and predicted poor prognosis when they occurred against a diploid (ch17(im)/diploid(cen)), but not polyploid, genetic background. These factors, together with post-surgical tumor residuum (R+) and radiotherapy delay, were supported as independent prognostic markers in multivariate testing. Notably, MYC and MYCN amplification were not associated with adverse outcome. In cross-validated survival models derived for the clinical standard-risk (M0/R0) disease group, (ch17(im)/diploid(cen); 14% of patients) predicted high disease-risk, while the outcomes of patients without (ch17(im)/diploid(cen)) did not differ significantly from MBWNT, allowing re-classification of 86% as favorable-risk. Conclusion: Biomarkers, established previously in disease-wide studies, behave differently in clinically-defined standard-risk disease. Distinct biomarkers are required to assess disease-risk in this group, and define improved risk-stratification models. Routine testing for specific patterns of chromosome 17 imbalance at the cellular level, and MBWNT, provides a strong basis for incorporation into future trials

Fogorvosi Szemle 1914

This report provides a summary of a workshop organised by the EuropeanCommission-funded EarlyNutrition Project and the EarlyNutrition Academy.Accurate and reliable methods to assess body composition are needed inresearch on prenatal and early post-natal influences of nutrition onlater health because common surrogate measures of maternal and offspringadiposity (body fat content), such as body mass index (BMI), haverelatively poor predictive power for the risk of later disease. The keygoals of the workshop were to discuss approaches to assess growth andbody composition from pregnancy to adolescence, to summarise conclusionsand to prepare a framework for research in the EarlyNutrition Project.The participants concluded that there is a pressing need to harmonisethe methodologies for assessing body composition, recognising that eachhas advantages and limitations. Essential core measurements acrossstudies assessing early growth and body composition were identified,including weight, length, BMI, waist and mid-upper arm circumference,subscapular and triceps skinfold thicknesses, and bioelectricalimpedance analysis. In research settings with access to moresophisticated technologies, additional methods could include dual-energyX-ray absorptiometry, peripheral quantitative computed tomography,ultrasound assessment of regional body fat, magnetic resonance imaging(MRI), air displacement plethysmography (ADP), and deuterium dilution.These provide richer data to answer research questions in greater depthbut also increase costs. Where overall whole-body composition is theprimary outcome measure, ADP or tracer dilution should be used wheneverpossible. Where regional distribution of body fat is of greaterinterest, an imaging technique such as MRI is preferred

Sun Exposure across the Life Course Significantly Modulates Early Multiple Sclerosis Clinical Course

Background: Low vitamin D and/or sun exposure have been associated with increased risk of multiple sclerosis (MS) onset. However, comparatively, few studies have prospectively examined associations between these factors and clinical course.Objectives: To evaluate the association of sun exposure parameters and vitamin D levels with conversion to MS and relapse risk in a prospectively monitored cohort of 145 participants followed after a first demyelinating event up to 5-year review (AusLong Study).Methods: Sun exposure prior to and after onset measured by annual questionnaire; ultraviolet radiation (UVR) "load" estimated by location of residence over the life course and ambient UVR levels. Serum 25-hydroxyvitamin D [25(OH)D] concentrations measured at baseline, 2/3-year, and 5-year review. MS conversion and relapse assessed by neurologist assessment and medical record review.Results: Over two-thirds (69%) of those followed to 5-year review (100/145) converted to MS, with a total of 252 relapses. Higher pre-MS onset sun exposure was associated with reduced risk of MS conversion, with internal consistency between measures and dose-response relationships. Analogous associations were also seen with risk of relapse, albeit less strong. No consistent associations were observed between postonset sun exposure and clinical course, however. Notably, those who increased their sun exposure during follow-up had significantly reduced hazards of MS conversion and relapse. Serum 25(OH)D levels and vitamin D supplementation were not associated with conversion to MS or relapse hazard.Conclusion: We found that preonset sun exposure was protective against subsequent conversion to MS and relapses. While consistent associations between postonset sun exposure or serum 25(OH)D level and clinical course were not evident, possibly masked by behavior change, those participants who markedly increased their sun exposure demonstrated a reduced MS conversion and relapse hazard, suggesting beneficial effects of sun exposure on clinical course

CXCL8 (200 pg/ml) and CCL20 (500 pg/ml) affected osteoblast-to-osteoclast communication at day 14.

<p><b>(A)</b> CXCL8 (200 pg/ml) enhanced MCSF and IL-6 gene expression. <b>(B)</b> CCL20 (500 pg/ml) enhanced IL-6 gene expression. <b>(C)</b> CXCL8+CCL20 (20 pg/ml+50 pg/ml) enhanced IL-6, OPG, and CYR61 gene expression. <b>(D)</b> TNF-α (100 ng/ml) enhanced MCSF, IL-6, and OPG gene expression. <b>(E)</b> CXCL8 (200 pg/ml), CCL20 (500 pg/ml), CXCL8+CCL20 (20 pg/ml+50 pg/ml), and TNF-α (100 ng/ml) enhanced IL-6 production by osteoblasts. Values are median with 5–95 percentile range of treatment-over-control ratios from 3 experiments, n = 9. Significant effect of chemokines and TNF-α, *p<0.05, **p<0.01.</p