Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Changing activities and different resistance to proteolytic activity of two forms of glutamine synthetase in wheat leaves during senescence

Leaves of field-grown wheat (Triticum aestivum) were collected at different stages. Two forms of glutamine synthetase (GS I and GS II) were separated on diethylamino ethyl cellulose columns with a linear NaCl gradient. GS II was the predominant form in young leaves (85-92% of total activity). The activity of GS II decreased earlier than that of GS I during senescence, and therefore the ratio GS I/GS II changed in favour of GS I. Total glutamine synthetase was inactivated more rapidly in senescing leaves (high caseolytic activity) than in extracts of young leaves (low caseolytic activity). A more rapid inactivation of GS II than of GS I was found when extracts were pre-incubated at 30°C and then applied to a diethylamino ethyl cellulose column, suggesting that GS I was less susceptible to proteolysis than GS II. GS II is assumed to be located in the chloroplasts and GS I in the cytoplasm. Besides subcellular localization, the different stability may contribute to the changing ratio GS I/GS II.Des feuilles de Blé (Triticum aestivum) cultivé aux champs ont été récoltées à différents stades de développement et de senescence. Deux formes de la glutamine synthétase ( GS I et GS II ) ont été isolées sur diethylamino ethyl cellulose à gradient NaCl linéaire. GS II est la forme prédominante dans les jeunes feuilles (85-92% de l'activité totale). Au cours de la senescence, l'activité GS II diminue plus rapidement que l'activité GS I, entraînant un changement du rapport GS I/GS II. La glutamine synthétase totale est inactivée plus rapidement dans les extraits de feuilles sénescent es ( activité caséolytique élevée ) que dans les extraits de jeunes feuilles ( activité caséolytique faible ). Une inactivation plus rapide de la GS II que de la GS I est observée si les extraits sont préincubés au préalable à 30°C et ensuite appliques d la diethylamino ethyl cellulose, suggérant que la GS I est moins susceptible d la protéolyse que la GS II. La GS II semble être localisée dans les chloroplastes et la GS I dans le cytoplasme. En plus de la localisation subcellulaire, la différente stabilité des deux formes semble contribuer au changement du rapport GS I/GS II

Inactivation of N-assimilating enzymes and proteolytic activities in wheat leaf extracts: Effect of pyridine nucleotides and of adenylates

Nitrate reductase was protected from inactivation in wheat leaf extracts by NADH, while NADPH was less effective. NAD, NADP or adenylates did not affect nitrate reductase inactivation in vitro. Glutamine synthetase was more stable than nitrate reductase and was protected from inactivation by ATP. ADP, AMP or pyridine nucleotides had no or only a minor effect on the decrease of glutamine synthetase activity in extracts. The caseolytic activity extracted from senescing leaves was slightly decreased by NADH and NADPH but this effect was not sufficient to explain the stabilization of nitrate reductase by NADH. Oxidized pyridine nucleotides and adenylates had no major effect on the caseolytic activity under the conditions used

Nitrogen-metabolizing Enzymes from Bean Leaves (Phaseolus vulgaris L.): Stability «in vitro» and Susceptibility to Proteolysis

The inactivation «in vitro» was investigated for four enzymes involved in nitrogen metabolism. Nitrate reductase (EC 1.6.6.1) was very unstable in extracts of bean leaves. Glutamine synthetase (EC 6.3.1.2) and glutamate synthase (EC 1.4.7.1) showed intermediate stabilities, and glutamate dehydrogenase (EC 1.4.1.2) proved to be very stable. Inactivation of both nitrate reductase and glutamine synthetase was accelerated in extracts from young leaves after addition of trypsin, chymotrypsin, extract from senescing leaves, or extract from cotyledons of germinating seeds. Glutamate synthase inactivation remained unchanged in presence of peptide hydrolases, while glutamate dehydrogenase was slowly inactivated by trypsin and chymotrypsin, but not by cotyledon or leaf extract. The inactivating factor from cotyledons and from leaves was precipitable with ammonium sulfate, heat labile and excluded by Sephadex G-25. The relative resistance to proteolysis was similar for nitrate reductase, glutamine synthetase and glutamate dehydrogenase, regardless of the peptide hydrolase source. Nitrate reductase was always the least stable and glutamate dehydrogenase the most stable of the three enzymes mentioned. It remains open by which factor(s) glutamate synthase was inactivated. Stability of glutamine synthetase decreased with age of the extracted leaves, and no increase in total endopeptidase activity was observed. Enzyme inactivation was delayed after addition of caScin or of heat inactivated extract. It appears likely that quality and quantity of other proteins present in the extract influence the inactivation of a particular enzyme

Analysis Of Demonstration Low Speed Wind Tunnel Test Data, M-DAW technical Note, WP4 task 4.10

Pressure distribution analysis is given for the M-DAW low speed wind tunnel tests with the model XO3D1. Low speeds were performed in the KKK-DNW (July 2003) with the reference tip devices and in the ETW (November 2005) using the novel downward pointed winglet and the Küchemann tip. For the low speed ETW take-off configuration tests, results are compared between the downward pointing winglet and the reference Küchemann tip device. In addition, ETW and DNW-KKK test results for the take-off configuration with Küchemann tip are compared. ETW low speed test results for the clean X03D1 with the downward pointing winglet are compared to (Elsa) Navier-Stokes results obtained by ONERA using the N-47 configuratio