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The longstanding association between the major histocompatibility complex (MHC) locus and schizophrenia (SZ) risk has recently been accounted for, partially, by structural variation at the complement component 4 (C4) gene. This structural variation generates varying levels of C4 RNA expression, and genetic information from the MHC region can now be used to predict C4 RNA expression in the brain. Increased predicted C4A RNA expression is associated with the risk of SZ, and C4 is reported to influence synaptic pruning in animal models.
Based on our previous studies associating MHC SZ risk variants with poorer memory performance, we tested whether increased predicted C4A RNA expression was associated with reduced memory function in a large (n = 1238) dataset of psychosis cases and healthy participants, and with altered task-dependent cortical activation in a subset of these samples.
We observed that increased predicted C4A RNA expression predicted poorer performance on measures of memory recall (p = 0.016, corrected). Furthermore, in healthy participants, we found that increased predicted C4A RNA expression was associated with a pattern of reduced cortical activity in middle temporal cortex during a measure of visual processing (p < 0.05, corrected).
These data suggest that the effects of C4 on cognition were observable at both a cortical and behavioural level, and may represent one mechanism by which illness risk is mediated. As such, deficits in learning and memory may represent a therapeutic target for new molecular developments aimed at altering C4’s developmental role.
Schizophrenia is a highly heritable disorder, linked to several structural abnormalities of the brain. More specifically, previous findings have suggested that increased gyrification in frontal and temporal regions are implicated in the pathogenesis of schizophrenia.
The current study included participants at high familial risk of schizophrenia who remained well (n = 31), who developed sub-diagnostic symptoms (n = 28) and who developed schizophrenia (n = 9) as well as healthy controls (HC) (n = 16). We first tested whether individuals at high familial risk of schizophrenia carried an increased burden of trait-associated alleles using polygenic risk score analysis. We then assessed the extent to which polygenic risk was associated with gyral folding in the frontal and temporal lobes.
We found that individuals at high familial risk of schizophrenia who developed schizophrenia carried a significantly greater burden of risk-conferring variants for the disorder compared to those at high risk (HR) who developed sub-diagnostic symptoms or remained well and HC. Furthermore, within the HR cohort, there was a significant and positive association between schizophrenia polygenic risk score and bilateral frontal gyrification.
These results suggest that polygenic risk for schizophrenia impacts upon early neurodevelopment to confer greater gyral folding in adulthood and an increased risk of developing the disorder.
Objectives: This study examined whether children with distinct brain disorders show different profiles of strengths and weaknesses in executive functions, and differ from children without brain disorder. Methods: Participants were children with traumatic brain injury (N=82; 8–13 years of age), arterial ischemic stroke (N=36; 6–16 years of age), and brain tumor (N=74; 9–18 years of age), each with a corresponding matched comparison group consisting of children with orthopedic injury (N=61), asthma (N=15), and classmates without medical illness (N=68), respectively. Shifting, inhibition, and working memory were assessed, respectively, using three Test of Everyday Attention: Children’s Version (TEA-Ch) subtests: Creature Counting, Walk-Don’t-Walk, and Code Transmission. Comparison groups did not differ in TEA-Ch performance and were merged into a single control group. Profile analysis was used to examine group differences in TEA-Ch subtest scaled scores after controlling for maternal education and age. Results: As a whole, children with brain disorder performed more poorly than controls on measures of executive function. Relative to controls, the three brain injury groups showed significantly different profiles of executive functions. Importantly, post hoc tests revealed that performance on TEA-Ch subtests differed among the brain disorder groups. Conclusions: Results suggest that different childhood brain disorders result in distinct patterns of executive function deficits that differ from children without brain disorder. Implications for clinical practice and future research are discussed. (JINS, 2017, 23, 529–538)
There is now a well-established link between childhood adversity (CA) and schizophrenia. Similar structural abnormalities to those found in schizophrenia including alterations in grey-matter volume have also been shown in those who experience CA.
We examined whether global estimates of cortical thickness or surface area were altered in those familial high-risk subjects who had been referred to a social worker or the Children's Panel compared to those who had not.
We found that the cortical surface area of those who were referred to the Children's Panel was significantly smaller than those who had not been referred, but cortical thickness was not significantly altered. There was also an effect of social work referral on cortical surface area but not on thickness.
Cortical surface area increases post-natally more than cortical thickness. Our findings suggest that CA can influence structural changes in the brain and it is likely to have a greater impact on cortical surface area than on cortical thickness.
Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene–environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.
The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.
PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10−6). SLEs and CT were also associated with MDD status (p = 2.19 × 10−4 and p = 5.12 × 10−20, respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.
CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene–environment interactions in complex traits.
A segment of the debate surrounding the commercialization and use of glyphosate-resistant (GR) crops focuses on the theory that the implementation of these traits is an extension of the intensification of agriculture that will further erode the biodiversity of agricultural landscapes. A large field-scale study was initiated in 2006 in the United States on 156 different field sites with a minimum 3-yr history of GR-corn, -cotton or -soybean in the cropping system. The impact of cropping system, crop rotation, frequency of using the GR crop trait, and several categorical variables on seedbank weed population density and diversity was analyzed. The parameters of total weed population density of all species in the seedbank, species richness, Shannon's H′ and evenness were not affected by any management treatment. The similarity between the seedbank and aboveground weed community was more strongly related to location than management; previous year's crops and cropping systems were also important while GR trait rotation was not. The composition of the weed flora was more strongly related to location (geography) than any other parameter. The diversity of weed flora in agricultural sites with a history of GR crop production can be influenced by several factors relating to the specific method in which the GR trait is integrated (cropping system, crop rotation, GR trait rotation), the specific weed species, and the geographical location. Continuous GR crop, compared to fields with other cropping systems, only had greater species diversity (species richness) of some life forms, i.e., biennials, winter annuals, and prostrate weeds. Overall diversity was related to geography and not cropping system. These results justify further research to clarify the complexities of crops grown with herbicide-resistance traits to provide a more complete characterization of their culture and local adaptation to the weed seedbank.
Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability).
For investigating familiality, we used 691 families with 2–5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software.
Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity.
AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.
Nitrous oxide (N2O) emissions associated with urine nitrogen (N) deposition during grazing are a major component of greenhouse gas emissions from domestic livestock. The present study investigated the relationship between urine N loading rate and the efficacy of a nitrification inhibitor, dicyandiamide (DCD), on cumulative N2O emissions from a grassland soil in Ireland over 80 and 360-day periods in 2009/10 and 2010/11. A diminishing curvilinear relationship between urine N rate and cumulative N2O emissions was observed in both years. Despite this increase in cumulative N2O emissions, the emission factor (EF3) for N2O decreased with increasing urine N rate from, on average, 0·24 to 0·10% (urine applied at 300 and 1000 kg N/ha, respectively), during an 80-day measurement period. This was probably the result of a factor other than N, such as carbon (C), limiting the production of N2O. The efficacy of DCD varied with urine N loading rate, and inter-annual variability in efficacy was also observed. Dicyandiamide was effective at reducing N2O production for 50–80 days after urine application, which accounted for the major period of elevated daily flux. However, DCD was ineffective at reducing N2O production after this period, which was likely a result of its removal from the soil via degradation and leaching.
The current study investigated the coupling of groundwater and surface water nitrogen (N) dynamics over 3 years, and considered intensive agricultural land-management influences over this period where the risk of N loss to water was considered high. Groundwater N (as nitrate) was monitored monthly in different strata and zones in four hillslopes, two in each of two agricultural catchments of c. 10 km2, and stream water N flux was monitored sub-hourly in the catchment outlets. Field nutrient sources were connected to surface water via groundwater; the groundwater along hillslopes was seen to be influenced spatially and temporally by management, geology and weather as observed in the concentration variability of nitrate in groundwater. Based on spatio-temporal averages of nitrate-N concentration, groundwater status was considered good (at least below a maximum acceptable concentration (MAC) of 11·3 mg/l). However, zones coincident with land-use change (ploughing and reseeding, typical of a management event in intensive landscapes), showed high spatio-temporal variability in nitrate-N concentration, exceeding the MAC temporarily, before recovering. This spatio-temporal variability highlighted the need for insight into these differences when interpreting groundwater quality data from a limited number of basin-scale sampling points and occasions. In both catchments the 3-year mean nitrate-N concentration in stream water was similar to the spatio-temporal mean concentration in groundwater. The magnitude and variability of loads, however, were more related to changes in annual runoff rather than changes in annual groundwater nitrate-N status. In one wet year, nitrate-N loads exceeded 48 kg/ha from an Arable catchment and 45 kg/ha from a grassland catchment (close to double the loss in a dry year).
A segment of the debate surrounding the commercialization of genetically
engineered (GE) crops, such as glyphosate-resistant (GR) crops, focuses on
the theory that implementation of these traits is an extension of the
intensification of agriculture that will further erode the biodiversity of
agricultural landscapes. A large field-scale study was conducted in 2006 in
the United States on 156 different field sites with a minimum 3-yr history
of GR corn, cotton, or soybean in the cropping system. The impact of
cropping system, crop rotation, frequency of using the GR crop trait, and
several categorical variables on emerged weed density and diversity was
analyzed. Species richness, evenness, Shannon's H′, proportion of forbs,
erect growth habit, and C3 species diversity were all greater in
agricultural sites that lacked crop rotation or were in a continuous GR crop
system. Rotating between two GR crops (e.g., corn and soybean) or rotating
to a non-GR crop resulted in less weed diversity than a continuous GR crop.
The composition of the weed flora was more strongly related to location
(geography) than any other parameter. The diversity of weed flora in
agricultural sites with a history of GR crop production can be influenced by
several factors relating to the specific method in which the GR trait is
integrated (cropping system, crop rotation, GR trait rotation), the specific
weed species, and the geographical location. The finding that fields with
continuous GR crops demonstrated greater weed diversity is contrary to
arguments opposing the use of GE crops. These results justify further
research to clarify the complexities of crops grown with
herbicide-resistance traits, or more broadly, GE crops, to provide a more
complete characterization of their culture and local adaptation.
Schizophrenia is associated with various brain structural abnormalities, including reduced volume of the hippocampi, prefrontal lobes and thalami. Cannabis use increases the risk of schizophrenia but reports of brain structural abnormalities in the cannabis-using population have not been consistent. We used automated image analysis to compare brain structural changes over time in people at elevated risk of schizophrenia for familial reasons who did and did not use cannabis.
Magnetic resonance imaging (MRI) scans were obtained from subjects at high familial risk of schizophrenia at entry to the Edinburgh High Risk Study (EHRS) and approximately 2 years later. Differential grey matter (GM) loss in those exposed (n = 23) and not exposed to cannabis (n = 32) in the intervening period was compared using tensor-based morphometry (TBM).
Cannabis exposure was associated with significantly greater loss of right anterior hippocampal (pcorrected = 0.029, t = 3.88) and left superior frontal lobe GM (pcorrected = 0.026, t = 4.68). The former finding remained significant even after the exclusion of individuals who had used other drugs during the inter-scan interval.
Using an automated analysis of longitudinal data, we demonstrate an association between cannabis use and GM loss in currently well people at familial risk of developing schizophrenia. This observation may be important in understanding the link between cannabis exposure and the subsequent development of schizophrenia.
In 2010, a grower survey was administered to 1,299 growers in 22 states to determine changes in weed management in the United States from 2006 to 2009. The majority of growers had not changed weed management practices in the previous 3 yr; however, 75% reported using weed management practices targeted at glyphosate-resistant (GR) weeds. Growers were asked to rate their efforts at controlling GR weeds and rate the effectiveness of various practices for controlling/preventing GR weeds regardless of whether they were personally using them. Using the herbicide labeled rate, scouting fields, and rotating crops were among the practices considered by growers as most effective in managing GR weeds. Sixty-seven percent of growers reported effective management of GR weeds. Between the 2005 and 2010 Benchmark surveys, the frequency of growers using specific actions to manage GR weeds increased markedly. Although the relative effectiveness of practices, as perceived by growers, remained the same, the effectiveness rating of tillage and the use of residual and POST herbicides increased.
Almost 1,650 corn, cotton, and soybean growers in 22 states participated in a 2010 telephone survey to determine their attitudes with regard to which weed species were most problematic in glyphosate-resistant (GR) crop production systems for corn, cotton, and soybean. The survey is a follow-up to a previous 2005 to 2006 survey that utilized a smaller set of growers from fewer states. In general, growers continued to estimate weed populations as low and few challenges have been created following adoption of GR cropping systems. Pigweed and foxtail species were dominant overall, whereas other species were more commodity and state specific. Corn, cotton, and soybean growers cited velvetleaf, annual morningglory, and waterhemp, respectively, as predominant weeds. Growers in the South region were more likely to report pigweed and waterhemp (Amaranthus spp.), whereas growers in the East and West reported horseweed. When growers were asked with which GR weeds they had experienced personally, horseweed was reported in all regions, but growers in the South more frequently reported pigweed, whereas growers in the East and West regions more frequently reported waterhemp. Comparisons with the previous 2005 survey indicated that more growers believed they were experiencing GR weeds and were more aware of specific examples in their state. In particular, the Amaranthus complex was of greatest concern in continuously cropped soybean and cotton.
A 2010 survey of 1,299 corn, cotton, and soybean growers was conducted to determine their attitudes and awareness regarding glyphosate-resistant (GR) weeds and resultant implications on weed management practices. An additional 350 growers included in the current study participated in a 2005 survey, and these answers were compared across time so that cross-sectional and longitudinal comparisons of responses could be made. Most growers surveyed in 2010 were aware of the potential for weeds to evolve resistance to glyphosate; however, many growers were not aware of glyphosate resistance in specific weeds in their county or state. Growers in the South were different from growers in other geographic regions and were significantly more aware of local cases of GR weeds. Awareness of GR weeds did not increase appreciably from 2005 to 2010, but the percentage who reported GR weeds as problematic was significantly higher. Grower reports of GR weeds on-farm in 2010 were up considerably from 2005, with growers in the South reporting significantly more instances than growers in other regions. Growers in the South were also more likely to consider glyphosate resistance a serious problem. Overall, 30% of growers did not consider GR weeds to be a problem. It appears that most growers received information about glyphosate resistance from farm publications, although in the South this percentage was less than for other geographic regions. Growers in the South received more information from universities and extension sources.
Approximately 1,300 growers from 22 states were surveyed during 2010 to determine herbicide use. Cropping systems included continuous glyphosate-resistant corn, cotton, and soybean, and various combinations of these crops and rotations with non–glyphosate-resistant crops. The most commonly used herbicide for both fall and spring applications was glyphosate followed by synthetic auxin herbicides. Herbicide application in spring was favored over application in the fall. The percentage of growers in a glyphosate-only system was as high as 69% for some cropping systems. Excluding glyphosate, the most frequently used herbicides included photosystem II, mitotic, and protoporphyrinogen oxidase inhibitors. A higher percentage of growers integrated herbicides other than glyphosate during 2010 compared with 2005. Extensive educational efforts have promoted resistance management by increasing the diversity of herbicides in glyphosate-resistant cropping systems. However, a considerable percentage of growers continued use of only glyphosate from the period of 2005 to 2010, and this practice most likely will continue to exert a high level of selection for evolved glyphosate-resistant weed species.
Recent data provide strong support for a substantial common polygenic contribution (i.e. many alleles each of small effect) to genetic susceptibility for schizophrenia and overlapping susceptibility for bipolar disorder.
To test hypotheses about the relationship between schizophrenia and psychotic types of bipolar disorder.
Using a polygenic score analysis to test whether schizophrenia polygenic risk alleles, en masse, significantly discriminate between individuals with bipolar disorder with and without psychotic features. The primary sample included 1829 participants with bipolar disorder and the replication sample comprised 506 people with bipolar disorder.
The subset of participants with Research Diagnostic Criteria schizoaffective bipolar disorder (n = 277) were significantly discriminated from the remaining participants with bipolar disorder (n = 1552) in both the primary (P = 0.00059) and the replication data-sets (P = 0.0070). In contrast, those with psychotic bipolar disorder as a whole were not significantly different from those with non-psychotic bipolar disorder in either data-set.
Genetic susceptibility influences at least two major domains of psychopathological variation in the schizophrenia–bipolar disorder clinical spectrum: one that relates to expression of a ‘bipolar disorder-like’ phenotype and one that is associated with expression of ‘schizophrenia-like’ psychotic symptoms.