16 research outputs found

    Examining the independent and joint effects of molecular genetic liability and environmental exposures in schizophrenia: results from the EUGEI study

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    Schizophrenia is a heritable complex phenotype associated with a background risk involving multiple common genetic variants of small effect and a multitude of environmental exposures. Early twin and family studies using proxy‐genetic liability measures suggest gene‐environment interaction in the etiology of schizophrenia spectrum disorders, but the molecular evidence is scarce. Here, by analyzing the main and joint associations of polygenic risk score for schizophrenia (PRS‐SCZ) and environmental exposures in 1,699 patients with a diagnosis of schizophrenia spectrum disorders and 1,542 unrelated controls with no lifetime history of a diagnosis of those disorders, we provide further evidence for gene‐environment interaction in schizophrenia. Evidence was found for additive interaction of molecular genetic risk state for schizophrenia (binary mode of PRS‐SCZ above 75% of the control distribution) with the presence of lifetime regular cannabis use and exposure to early‐life adversities (sexual abuse, emotional abuse, emotional neglect, and bullying), but not with the presence of hearing impairment, season of birth (winter birth), and exposure to physical abuse or physical neglect in childhood. The sensitivity analyses replacing the a priori PRS‐SCZ at 75% with alternative cut‐points (50% and 25%) confirmed the additive interaction. Our results suggest that the etiopathogenesis of schizophrenia involves genetic underpinnings that act by making individuals more sensitive to the effects of some environmental exposures

    Clustering schizophrenia genes by their temporal expression patterns aids functional interpretation

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    Background Schizophrenia is a highly heritable brain disorder with a typical symptom onset in early adulthood. The 2-hit hypothesis posits that schizophrenia results from differential early neurodevelopment, predisposing an individual, followed by a disruption of later brain maturational processes that trigger the onset of symptoms. Study design We applied hierarchical clustering to transcription levels of 345 genes previously linked to schizophrenia, derived from cortical tissue samples from 56 donors across the lifespan. We subsequently calculated clustered-specific polygenic risk scores for 743 individuals with schizophrenia and 743 sex- and age-matched healthy controls. Study results Clustering revealed a set of 183 genes that was significantly upregulated prenatally and downregulated postnatally and 162 genes that showed the opposite pattern. The prenatally upregulated set of genes was functionally annotated to fundamental cell cycle processes, while the postnatally upregulated set was associated with the immune system and neuronal communication. We found an interaction between the 2 scores; higher prenatal polygenic risk showed a stronger association with schizophrenia diagnosis at higher levels of postnatal polygenic risk. Importantly, this finding was replicated in an independent clinical cohort of 3233 individuals. Conclusions We provide genetics-based evidence that schizophrenia is shaped by disruptions of separable biological processes acting at distinct phases of neurodevelopment. The modeling of genetic risk factors that moderate each other’s effect, informed by the timing of their expression, will aid in a better understanding of the development of schizophrenia

    Nitrogen fertiliser recovery and yield response of greenhouse grown and fertigated tomato to root - Zone soil water tension [Fertigasyon teknigi ile serada yetiştirilen dornatesin, kök bölgesi topraksuyu tansiyonuna verim tepkisi ve azotlu gübre alimi]

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    Tomatoes were grown in a plastic greenhouse under 2 irrigation programmes and four N-fertiliser concentrations (0, 100, 150 and 200 mg N 1-1) of irrigation water. P and K concentrations were kept constant at 30 and 200 mg 1-1, respectively, for all N treatments. A drip irrigation system with single laterals centred between the plant rows, spaced 50 cm apart was used for irrigation as well as for feeding fertiliser solution (i.e. fertigation) during the experiment. Tensiometers, installed in 3 replicates at 45 cm soil depth and centred mid-way between 2 plants in rows, were used for irrigation scheduling. Two irrigation programmes, controlled through continuous monitoring of root-zone soil-water tension, were used as irrigation treatments. In one of the treatments, irrigation scheduling was based on a maximum soil-water tension of 50 kPa during the entire season. In the second treatment, soil-water tension to initiate irrigation was initially high (70 kPa), until fruit stetting, and it fell down to 50 kPa, later in the season. 15N labelled urea was used in one of the N-concentration treatments (150 mg N 1-1) to estimate tomato N-fertiliser recovery. The results showed that tomato yield was not influenced significantly by irrigation treatments, although the irrigation treatment of low soil-water tension (? 50 kPa), maintained throughout the season, gave higher yield. Exposing tomatoes to high soil water stress during the early growth stage, first 70 kPa then dropping to 50 kPa, promotes proportionally higher uptake of soil N, and thus reduces the recovery of applied N-fertiliser. However, when low soil water tension (?50 kPa) was maintained throughout the season, N-fertiliser recovery was 22.4% higher compared with when high soil water-tension prevailed until mid season. As for the effects of N concentration of the feeding solution, tomatoes showed a statistically significant (P ? 0.05) fruit-yield response to varying N concentrations. The feeding-solution-N concentration giving the highest tomato fruit yield was about 120 mg N 1-1 as estimated using a N-concentration yield-response function

    Estimating Exposome Score for Schizophrenia Using Predictive Modeling Approach in Two Independent Samples:The Results From the EUGEI Study

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    Exposures constitute a dense network of the environment: exposome. Here, we argue for embracing the exposome paradigm to investigate the sum of nongenetic “risk” and show how predictive modeling approaches can be used to construct an exposome score (ES; an aggregated score of exposures) for schizophrenia. The training dataset consisted of patients with schizophrenia and controls, whereas the independent validation dataset consisted of patients, their unaffected siblings, and controls. Binary exposures were cannabis use, hearing impairment, winter birth, bullying, and emotional, physical, and sexual abuse along with physical and emotional neglect. We applied logistic regression (LR), Gaussian Naive Bayes (GNB), the least absolute shrinkage and selection operator (LASSO), and Ridge penalized classification models to the training dataset. ESs, the sum of weighted exposures based on coefficients from each model, were calculated in the validation dataset. In addition, we estimated ES based on meta-analyses and a simple sum score of exposures. Accuracy, sensitivity, specificity, area under the receiver operating characteristic, and Nagelkerke’s R2 were compared. The ESMeta-analyses performed the worst, whereas the sum score and the ESGNB were worse than the ESLR that performed similar to the ESLASSO and ESRIDGE. The ESLR distinguished patients from controls (odds ratio [OR] = 1.94, P < .001), patients from siblings (OR = 1.58, P < .001), and siblings from controls (OR = 1.21, P = .001). An increase in ESLR was associated with a gradient increase of schizophrenia risk. In reference to the remaining fractions, the ESLR at top 30%, 20%, and 10% of the control distribution yielded ORs of 3.72, 3.74, and 4.77, respectively. Our findings demonstrate that predictive modeling approaches can be harnessed to evaluate the exposome
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