Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders

Press release - Commonwealth-State agreement on urban transport

Context: There is evidence of linkage to a schizophrenia susceptibility locus on chromosome 8p21-22 found by several family linkage studies.Objectives: To fine map and identify a susceptibility gene for schizophrenia on chromosome 8p22 and to investigate the effect of this genetic susceptibility on an endophenotype of abnormal brain structure using magnetic resonance imaging.Design: Fine mapping and identification of a chromosome 8p22 susceptibility gene was carried out by finding linkage disequilibrium between genetic markers and schizophrenia in multiply affected families, a case-control sample, and a trio sample. Variation in brain morphology associated with pericentriolar material 1 (PCM1) alleles was examined using voxel-based morphometry and statistical parametric mapping with magnetic resonance imaging.Setting and Patients: A family sample of 13 large families multiply affected with schizophrenia, 2 schizophrenia case-control samples from the United Kingdom and Scotland, and a sample of schizophrenic trios from the United States containing parents and 1 affected child with schizophrenia.Main Outcome Measures: Tests of transmission disequilibrium between PCM1 locus polymorphisms and schizophrenia using a family sample and tests of allelic association in case-control and trio samples. Voxel-based morphometry using statistical parametric mapping.Results: The family and trio samples both showed significant transmission disequilibrium between marker D85261 in the PCM1 gene locus and schizophrenia. The case-control sample from the United Kingdom also found significant allelic association between PCM1 gene markers and schizophrenia. Voxel-based morphometry of cases who had inherited a PCM1 genetic susceptibility showed a significant relative reduction in the volume of orbitofrontal cortex gray matter in comparison with patients with non-PCM1-associated schizophrenia, who, by contrast, showed gray matter volume reduction in the temporal pole, hippocampus, and inferior temporal cortex.Conclusions: The PCM1 gene is implicated in susceptibility to schizophrenia and is associated with orbitofrontal gray matter volumetric deficits

Improving Genetic Prediction by Leveraging Genetic Correlations Among Human Diseases and Traits

Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7 for height to 47 for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait. © 2018 The Author(s)

Variability in Working Memory Performance Explained by Epistasis vs Polygenic Scores in the ZNF804A Pathway

Importance: We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. Objectives To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. Design, Setting, and Participants: Patients with psychosis (n = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition. We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). Main Outcomes and Measures: Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. Results: Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4.8% (P = .11 and .001, respectively) but did not explain additional variation in control participants. Conclusions and Relevance: These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score

The influence of fibrous feed added to diets for gilts

Соответствующие исследования проводились на свиноматках крупной белой польской порода разделенных на 2 группы. Животные обеих групп получали комбикорм ПР Стандарт в соответствии с американскими нормами NRC - 1973, причем к рациону для опытной группы прибавляли сухую размельченную кукурузную солому в количестве 0,7 или 1,8 кг в зависимости от периода беременности и лактации. Эта солома содержала 25% сырого волокна и таким образом повышала уровень последнего до 10% сухого вещества во всем суточном рационе. Репродуктивные признаки, здоровье и витальность свиноматок, а также их потомства до отъема на 28-ой день жизни не зависели от прибавки волокнистого корма. Изменения веса тела свиноматок были обусловлены в высшей степени их дифференцированным кормлением, особенно в отношении привесов в период беременности, лактационным потерям и общей ретенции. Переваримость сырого белка, сырого жира и экстрактивных безазотистых веществ не подвергались ухудшению в связи с повышением уровня волокна в рационах беременных и кормящих свиноматок. Прибавка сухой кукурузной соломы приводила к продлению периода откорма, в связи с чем снижалась вероятность объедания более слабых беременных свиноматок содержимых в группах. Такого рода косм обеспечивал лучшую наполненность пищеварительного тракта животных вызывая ощущение сытости. В опытной группе свиноматок установлено, что подстилка не поедалась животными, а во время родов и лактации животные вели себя спокойнее, что может оказывать некоторое влияние на сокращение смертности потомства.The experiment was carried out on 36 Large White gilts allocated to two groups. Both groups of the animals were fed with a standard mash, according to the NRC recommendations (1973). In the experimental group the basal diet was supplied with corn stover meal as fibrous feed. Pregnant and lactating gilts received 0.7 or 1.8 kg of this feed, respectively. That increased the crude fibre level in rations to 10% in dry matter. The supplementation of diets with fibrous feed did not have any influence on reproductivity indices of gilts such as litter size and live weight of piglets weaned at 28 days of life. Changes of live weight were more dependent on the addition of fibrous feed, particularly significant differences appeared in weight gains during gestation, lactation losses and total retention. Digestibilities of crude protein, ether extract and NFE were not affected by the crude fibre level in the diets. The addition of corn stover meal extended the consumption time. This could decrease the probability of the sponging upon weaker pregnant gilts managed in a bigger group. Corn stover meal allows to better filling of alimentary tract and assures the feeling of the satiety. Due to that the animals bahaved more quietly during reproductive cycle and this could result in a restriction of mortality among piglets

Effects of linseed and oat in antibiotic-free diets on the gut health, mucosal integrity and performance of piglets

The aim of the study was to determine the effects of 10% linseed meal (FM) and 15% hulled oat meal (HOM) in antibiotic-free diets on clinical health, performance, faecal Escherichia coli shedding, haematological indices and gut morphology of weaned piglets (n=48) before and after exposure to a controlled infection with enterotoxigenic E. coli K88 (ETEC). It was observed that both plants improved (