26 research outputs found
Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder
This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu).Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P<1x10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (GWS, p < 5x10-8) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene-sets including regulation of insulin secretion and endocannabinoid signaling. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD.This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch
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A Molecular Approach to Understanding Plant Response to Global Climate Change in a Californian Grassland Ecosystem
Global warming affects the climate in multiple ways from increased temperature to altered rainfall pattern. Understanding the effect of these climatic changes on different ecosystems is paramount. We are currently investigating the coordinated responses to climate change of soil microorganisms and plants from a Californian grassland ecosystem through a multidisciplinary project. Our aim is to link the different responses, scaling from gene expression to ecosystem function. Here we discuss some aspects of the plants response at the molecular level. Our experimental setup reproduced a Californian annual grassland ecosystem in climate-controlled greenhouses. A total of 152 mesocosms were filled with three horizons of natural soil packed to specific bulk density and instrumented to follow precisely the plant growth conditions. Seeds, collected from the grassland, were dispersed on the mesocosms to generate monocultures of Avena barbata (the dominant species in many California grasslands), or mixed communities including five additional grasses and two forbs. Leaf and root samples were collected at the peak of the growing season from A. barbata plants grown under low, ambient and high precipitation treatments and in two different soil types. The availability of genomic sequences for A. barbata was limited and only a few cDNA have been cloned and sequenced previously. We used genomic data from other grass species to design PCR primers in order to amplify specific sequences in our focal species. Using the PCR cloning approach we have sequenced target genes and subsequently studied their expression using real-time RT-PCR. The target genes were selected for their key role in both nitrogen and carbon metabolism. Preliminary data suggests that, at the time of sample collection, plants grown under low precipitation treatments were subjected to mild water stress. Under these conditions, ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) gene expression was shown to decline by 40%. The expression of nitrate reductase (Nia) and chloroplastic glutamine synthetase (GS2) was maintained suggesting that nitrate was still available to the plants for uptake. The decline in ADP-glucose pyrophosphorylase (AGPS) expression may indicate that less carbon was available for storage in the form of starch. At high precipitation, the levels of Nia and Rubisco mRNAs decreased while those of GS2 and AGPS were maintained. Under these conditions, the soil pools of nitrate and ammonium were lower compared to the ambient conditions, which could explain the pattern of expression seen for Nia and Rubisco. Furthermore, the up-regulation of the cytosolic GS isoform may indicate a greater need for nitrogen remobilisation in the leaf, which is consistent with a lower nitrogen supply. These results will be integrated with ongoing studies of leaf metabolite levels, plant physiology and ecosystem function to understand the potential significance of genomic responses to climate change