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First-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes.
We conducted, using two different samples for discovery (n = 336 controls and 649 siblings of patients with psychotic disorder) and replication (n = 1208 controls and 1106 siblings), an analysis of association between PRS on the one hand and psychopathological and cognitive intermediate phenotypes of schizophrenia on the other in a sample at average genetic risk (healthy controls) and a sample at higher than average risk (healthy siblings of patients). Two subthreshold psychosis phenotypes, as well as a standardised measure of cognitive ability, based on a short version of the WAIS-III short form, were used. In addition, a measure of jumping to conclusion bias (replication sample only) was tested for association with PRS.
In both discovery and replication sample, evidence for an association between PRS and subthreshold psychosis phenotypes was observed in the relatives of patients, whereas in the controls no association was observed. Jumping to conclusion bias was similarly only associated with PRS in the sibling group. Cognitive ability was weakly negatively and non-significantly associated with PRS in both the sibling and the control group.
The degree of endophenotypic expression of schizophrenia polygenic risk depends on having a sibling with psychotic disorder, suggestive of underlying gene–environment interaction. Cognitive biases may better index genetic risk of disorder than traditional measures of neurocognition, which instead may reflect the population distribution of cognitive ability impacting the prognosis of psychotic disorder.
Rare copy number variants (CNVs) are associated with risk of neurodevelopmental disorders characterised by varying degrees of cognitive impairment, including schizophrenia, autism spectrum disorder and intellectual disability. However, the effects of many individual CNVs in carriers without neurodevelopmental disorders are not yet fully understood, and little is known about the effects of reciprocal copy number changes of known pathogenic loci.
We aimed to analyse the effect of CNV carrier status on cognitive performance and measures of occupational and social outcomes in unaffected individuals from the UK Biobank.
We called CNVs in the full UK Biobank sample and analysed data from 420 247 individuals who passed CNV quality control, reported White British or Irish ancestry and were not diagnosed with neurodevelopmental disorders. We analysed 33 pathogenic CNVs, including their reciprocal deletions/duplications, for association with seven cognitive tests and four general measures of functioning: academic qualifications, occupation, household income and Townsend Deprivation Index.
Most CNVs (24 out of 33) were associated with reduced performance on at least one cognitive test or measure of functioning. The changes on the cognitive tests were modest (average reduction of 0.13 s.d.) but varied markedly between CNVs. All 12 schizophrenia-associated CNVs were associated with significant impairments on measures of functioning.
CNVs implicated in neurodevelopmental disorders, including schizophrenia, are associated with cognitive deficits, even among unaffected individuals. These deficits may be subtle but CNV carriers have significant disadvantages in educational attainment and ability to earn income in adult life.
The value of the nosological distinction between non-affective and affective psychosis has frequently been challenged. We aimed to investigate the transdiagnostic dimensional structure and associated characteristics of psychopathology at First Episode Psychosis (FEP). Regardless of diagnostic categories, we expected that positive symptoms occurred more frequently in ethnic minority groups and in more densely populated environments, and that negative symptoms were associated with indices of neurodevelopmental impairment.
This study included 2182 FEP individuals recruited across six countries, as part of the EUropean network of national schizophrenia networks studying Gene–Environment Interactions (EU-GEI) study. Symptom ratings were analysed using multidimensional item response modelling in Mplus to estimate five theory-based models of psychosis. We used multiple regression models to examine demographic and context factors associated with symptom dimensions.
A bifactor model, composed of one general factor and five specific dimensions of positive, negative, disorganization, manic and depressive symptoms, best-represented associations among ratings of psychotic symptoms. Positive symptoms were more common in ethnic minority groups. Urbanicity was associated with a higher score on the general factor. Men presented with more negative and less depressive symptoms than women. Early age-at-first-contact with psychiatric services was associated with higher scores on negative, disorganized, and manic symptom dimensions.
Our results suggest that the bifactor model of psychopathology holds across diagnostic categories of non-affective and affective psychosis at FEP, and demographic and context determinants map onto general and specific symptom dimensions. These findings have implications for tailoring symptom-specific treatments and inform research into the mood-psychosis spectrum.
Early detection of karyotype abnormalities, including aneuploidy, could aid producers in identifying animals which, for example, would not be suitable candidate parents. Genome-wide genetic marker data in the form of single nucleotide polymorphisms (SNPs) are now being routinely generated on animals. The objective of the present study was to describe the statistics that could be generated from the allele intensity values from such SNP data to diagnose karyotype abnormalities; of particular interest was whether detection of aneuploidy was possible with both commonly used genotyping platforms in agricultural species, namely the Applied BiosystemsTM AxiomTM and the Illumina platform. The hypothesis was tested using a case study of a set of dizygotic X-chromosome monosomy 53,X sheep twins. Genome-wide SNP data were available from the Illumina platform (11 082 autosomal and 191 X-chromosome SNPs) on 1848 male and 8954 female sheep and available from the AxiomTM platform (11 128 autosomal and 68 X-chromosome SNPs) on 383 female sheep. Genotype allele intensity values, either as their original raw values or transformed to logarithm intensity ratio (LRR), were used to accurately diagnose two dizygotic (i.e. fraternal) twin 53,X sheep, both of which received their single X chromosome from their sire. This is the first reported case of 53,X dizygotic twins in any species. Relative to the X-chromosome SNP genotype mean allele intensity values of normal females, the mean allele intensity value of SNP genotypes on the X chromosome of the two females monosomic for the X chromosome was 7.45 to 12.4 standard deviations less, and were easily detectable using either the AxiomTM or Illumina genotype platform; the next lowest mean allele intensity value of a female was 4.71 or 3.3 standard deviations less than the population mean depending on the platform used. Both 53,X females could also be detected based on the genotype LRR although this was more easily detectable when comparing the mean LRR of the X chromosome of each female to the mean LRR of their respective autosomes. On autopsy, the ovaries of the two sheep were small for their age and evidence of prior ovulation was not appreciated. In both sheep, the density of primordial follicles in the ovarian cortex was lower than normally found in ovine ovaries and primary follicle development was not observed. Mammary gland development was very limited. Results substantiate previous studies in other species that aneuploidy can be readily detected using SNP genotype allele intensity values generally already available, and the approach proposed in the present study was agnostic to genotype platform.
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.
Cull cows comprise about 44% of all cattle slaughtered at Irish meat factories in 2006; which was an increase of 6% from 2005. Between September and December 2006, 18% of cull cows failed to achieve P+3 carcass classification compared with 12% for the remainder of the year (DAF, 2006). There is a large proportion of cows slaughtered in November, which suggests that unfit (low bodyweight and condition score) cows are being presented for slaughter at the end of lactation without finishing prior to slaughter. Farmers who are finish feeding cull cows have an interest in alternative feeding regimes i.e. pasture and/or forage use for a more economical beef supply due to increasing concentrate costs, however present farm practice and culling decisions made by the dairy farmer often excludes this as a real possibility. The objective of this study was to compare days to slaughter, average daily gain, and final live and carcass of cull dairy cows subjected to four over-wintering strategies prior to a pasture based finishing diet.
Conventionally perennial ryegrass evaluations are conducted under simulated grazing studies to identify varieties with the best phenotypic performance. However, cut-plot environments differ greatly to those experienced on commercial farms as varieties are not exposed to the same stress levels in test environments. It could be argued that plot-based testing regimes provide little direction to plant breeders in the development of advanced varieties. Varietal phenotypic performance needs to be quantified in ‘commercial’ situations. The objective of the current study was to evaluate the phenotypic performance of a range of perennial ryegrass varieties under commercial farm conditions. Monocultures of 11 Irish Recommended List perennial ryegrass varieties were sown on 66 commercial farms throughout Ireland where performance was evaluated over a 3-year period from 2013 to 2015, inclusive. A linear mixed model was used to quantify variety effects on grassland phenotypic performance characteristics. No significant variety effect was estimated for total, seasonal or silage herbage production. Despite the lack of variety effects, pairwise comparisons found significant performance differences between individual varieties. Grazed herbage yield is of primary importance and was shown to be correlated strongly with total production (0.71); Grazed herbage yield differed significantly by variety, with a range of 1927 kg dry matter (DM)/ha between the highest and lowest performing varieties. Sward quality (dry matter digestibility [DMD]) and density were influenced by variety with a range of 44 g/kg DM for DMD and 0.7 ground score units between the highest and lowest performing varieties. Results of the current study show that on-farm evaluation is effective in identifying the most suitable varieties for intensive grazing regimes, and the phenotypic variance identified among varieties performance for many traits should allow for improved genetic gain in areas such as DM production, persistence and grazing efficiency.
Perennial ryegrass and white clover (WC) have been shown to form compatible mixtures for pasture production under temperate climates. The inclusion of WC has the potential to enhance the performance of grass swards, but the extent of the improvement under contrasting grazing management strategies is unclear. Grazing rotation and fertilizer nitrogen (N) use have been identified as two major factors that can influence the performance of grass–clover swards. The objective of the current study was to examine the effect of differing grazing rotation lengths and the level of N application on the dry matter (DM) yield performance of grass–clover and grass-only swards as well as on WC productivity and persistency under animal grazing. Swards were managed by N application and grazing rotation length: High-N swards were managed on a 21-day grazing rotation (Man 1) and low-N swards were managed on a 30-day grazing rotation (Man 2). The four treatments were: 250 kg N/ha without WC (HN−C), 250 kg N/ha with WC (HN+C), 100 kg N/ha N without WC (LN−C) and 100 kg N/ha with WC (LN+C). There was a significant management × WC interaction over the 3 years for annual DM yield. The LN−C swards produced lower DM yield (−1917 kg DM/ha) than the swards of the other three treatments (11 167 kg DM/ha). Management had a significant effect on annual DM yield with Man 1 swards yielding 801 kg DM/ha more than Man 2 swards (10 288 kg DM/ha). The inclusion of WC yielded significantly more annual DM yield (+1009 kg DM/ha) than grass-only swards. Notably, LN+C produced the same annual total DM yield as swards under High N and a 21-day grazing rotation. Total WC DM yield and proportion across the year was altered significantly by management. Higher N fertilized swards at shorter grazing intervals had a lower WC DM yield (−1544 kg DM/ha) and proportion (−0·13). Dry matter yield of WC with low N application can be similar to that at high N levels if rotation length is used as a mechanism to determine grazing timing. Variations in WC productivity into the final year of the experiment indicate that persistence of significant contributions to DM yield by WC under low N at longer grazing intervals remains unclear after 3 years.
Traditionally, personalised nutrition was delivered at an individual level. However, the concept of delivering tailored dietary advice at a group level through the identification of metabotypes or groups of metabolically similar individuals has emerged. Although this approach to personalised nutrition looks promising, further work is needed to examine this concept across a wider population group. Therefore, the objectives of this study are to: (1) identify metabotypes in a European population and (2) develop targeted dietary advice solutions for these metabotypes. Using data from the Food4Me study (n 1607), k-means cluster analysis revealed the presence of three metabolically distinct clusters based on twenty-seven metabolic markers including cholesterol, individual fatty acids and carotenoids. Cluster 2 was identified as a metabolically healthy metabotype as these individuals had the highest Omega-3 Index (6·56 (sd 1·29) %), carotenoids (2·15 (sd 0·71) µm) and lowest total saturated fat levels. On the basis of its fatty acid profile, cluster 1 was characterised as a metabolically unhealthy cluster. Targeted dietary advice solutions were developed per cluster using a decision tree approach. Testing of the approach was performed by comparison with the personalised dietary advice, delivered by nutritionists to Food4Me study participants (n 180). Excellent agreement was observed between the targeted and individualised approaches with an average match of 82 % at the level of delivery of the same dietary message. Future work should ascertain whether this proposed method could be utilised in a healthcare setting, for the rapid and efficient delivery of tailored dietary advice solutions.
Individual response to dietary interventions can be highly variable. The phenotypic characteristics of those who will respond positively to personalised dietary advice are largely unknown. The objective of this study was to compare the phenotypic profiles of differential responders to personalised dietary intervention, with a focus on total circulating cholesterol. Subjects from the Food4Me multi-centre study were classified as responders or non-responders to dietary advice on the basis of the change in cholesterol level from baseline to month 6, with lower and upper quartiles defined as responder and non-responder groups, respectively. There were no significant differences between demographic and anthropometric profiles of the groups. Furthermore, with the exception of alcohol, there was no significant difference in reported dietary intake, at baseline. However, there were marked differences in baseline fatty acid profiles. The responder group had significantly higher levels of stearic acid (18 : 0, P=0·034) and lower levels of palmitic acid (16 : 0, P=0·009). Total MUFA (P=0·016) and total PUFA (P=0·008) also differed between the groups. In a step-wise logistic regression model, age, baseline total cholesterol, glucose, five fatty acids and alcohol intakes were selected as factors that successfully discriminated responders from non-responders, with sensitivity of 82 % and specificity of 83 %. The successful delivery of personalised dietary advice may depend on our ability to identify phenotypes that are responsive. The results demonstrate the potential use of metabolic profiles in identifying response to an intervention and could play an important role in the development of precision nutrition.
A total economic merit index (Pasture Profit Index, PPI) for perennial ryegrass variety selection was developed to rank perennial ryegrass varieties (Lolium perenne L.) based on their economic potential for grass-based ruminant production systems. The key traits of importance identified were: spring, mid-season (April 11–August 10) and autumn dry matter (DM) yield, first and second cut silage DM yield, grass quality April to July (inclusive) and sward persistency. Variety persistency was quantified by determining the ground score (GS) change across years, which was associated with a yield threshold which triggered sward replacement. Each one-unit decline in GS was associated with a 1683 kg loss in DM yield. Data generated in the Irish recommended list trials for value for cultivation and use were analysed to quantify the relative performance of each variety for each of the aforementioned traits. A previously developed methodology to generate economic values was used with updated price assumptions to develop economic values, which were applied to the analysed performance data of individual varieties. These data were used to estimate the total economic merit of each variety. Thirty-nine varieties were ranked on total economic merit with the highest performing variety (Cv111) generating €213 per ha/year compared with Cv201, which was the lowest ranking variety generating −€31 per ha/year. Use of the PPI provides information to end users in relation to the economic merit of one variety over another, facilitating a more informed decision-making process at farm level.
To characterise clusters of individuals based on adherence to dietary recommendations and to determine whether changes in Healthy Eating Index (HEI) scores in response to a personalised nutrition (PN) intervention varied between clusters.
Food4Me study participants were clustered according to whether their baseline dietary intakes met European dietary recommendations. Changes in HEI scores between baseline and month 6 were compared between clusters and stratified by whether individuals received generalised or PN advice.
Individuals in cluster 1 (C1) met all recommended intakes except for red meat, those in cluster 2 (C2) met two recommendations, and those in cluster 3 (C3) and cluster 4 (C4) met one recommendation each. C1 had higher intakes of white fish, beans and lentils and low-fat dairy products and lower percentage energy intake from SFA (P<0·05). C2 consumed less chips and pizza and fried foods than C3 and C4 (P<0·05). C1 were lighter, had lower BMI and waist circumference than C3 and were more physically active than C4 (P<0·05). More individuals in C4 were smokers and wanted to lose weight than in C1 (P<0·05). Individuals who received PN advice in C4 reported greater improvements in HEI compared with C3 and C1 (P<0·05).
The cluster where the fewest recommendations were met (C4) reported greater improvements in HEI following a 6-month trial of PN whereas there was no difference between clusters for those randomised to the Control, non-personalised dietary intervention.
To characterise participants who dropped out of the Food4Me Proof-of-Principle study.
The Food4Me study was an Internet-based, 6-month, four-arm, randomised controlled trial. The control group received generalised dietary and lifestyle recommendations, whereas participants randomised to three different levels of personalised nutrition (PN) received advice based on dietary, phenotypic and/or genotypic data, respectively (with either more or less frequent feedback).
Seven recruitment sites: UK, Ireland, The Netherlands, Germany, Spain, Poland and Greece.
Adults aged 18–79 years (n 1607).
A total of 337 (21 %) participants dropped out during the intervention. At baseline, dropouts had higher BMI (0·5 kg/m2; P<0·001). Attrition did not differ significantly between individuals receiving generalised dietary guidelines (Control) and those randomised to PN. Participants were more likely to drop out (OR; 95 % CI) if they received more frequent feedback (1·81; 1·36, 2·41; P<0·001), were female (1·38; 1·06, 1·78; P=0·015), less than 45 years old (2·57; 1·95, 3·39; P<0·001) and obese (2·25; 1·47, 3·43; P<0·001). Attrition was more likely in participants who reported an interest in losing weight (1·53; 1·19, 1·97; P<0·001) or skipping meals (1·75; 1·16, 2·65; P=0·008), and less likely if participants claimed to eat healthily frequently (0·62; 0·45, 0·86; P=0·003).
Attrition did not differ between participants receiving generalised or PN advice but more frequent feedback was related to attrition for those randomised to PN interventions. Better strategies are required to minimise dropouts among younger and obese individuals participating in PN interventions and more frequent feedback may be an unnecessary burden.
Personalized or precision medicine is predicated on the assumption that the average response to treatment is not necessarily representative of the response of each individual. A commitment to personalized medicine demands an effort to bring evidence-based medicine and personalized medicine closer together. The use of relatively homogeneous groups, defined using a priori criteria, may constitute a promising initial step for developing more accurate risk-prediction models with which to advance the development of personalized evidence-based medicine approaches to heterogeneous syndromes such as schizophrenia. However, this can lead to a paradoxical situation in the field of psychiatry. Since there has been a tendency to loosely define psychiatric disorders as ones without a known aetiology, the discovery of an aetiology for psychiatric syndromes (e.g. 22q11.2 deletion syndrome in some cases of schizophrenia), while offering a path toward more precise treatments, may also lead to their reclassification away from psychiatry. We contend that psychiatric disorders with a known aetiology should not be removed from the field of psychiatry. This knowledge should be used instead to guide treatment, inasmuch as psychotherapies, pharmacotherapies and other treatments can all be valid approaches to mental disorders. The translation of the personalized clinical approach inherent to psychiatry into evidence-based precision medicine can lead to the development of novel treatment options for mental disorders and improve outcomes.
In western Canada, more money is spent on wild oat herbicides than on any other weed species, and wild oat resistance to herbicides is the most widespread resistance issue. A direct-seeded field experiment was conducted from 2010 to 2014 at eight Canadian sites to determine crop life cycle, crop species, crop seeding rate, crop usage, and herbicide rate combination effects on wild oat management and canola yield. Combining 2× seeding rates of early-cut barley silage with 2× seeding rates of winter cereals and excluding wild oat herbicides for 3 of 5 yr (2011 to 2013) often led to similar wild oat density, aboveground wild oat biomass, wild oat seed density in the soil, and canola yield as a repeated canola–wheat rotation under a full wild oat herbicide rate regime. Wild oat was similarly well managed after 3 yr of perennial alfalfa without wild oat herbicides. Forgoing wild oat herbicides in only 2 of 5 yr from exclusively summer annual crop rotations resulted in higher wild oat density, biomass, and seed banks. Management systems that effectively combine diverse and optimal cultural practices against weeds, and limit herbicide use, reduce selection pressure for weed resistance to herbicides and prolong the utility of threatened herbicide tools.
The objective of this experiment was to compare the effects of two concentrate feeding strategies offered with a grass silage and maize silage diet on the dry matter (DM) intake, milk production (MP) and estimated energy balance of autumn calved dairy cows. Over a 2-year period, 180 autumn calving Holstein Friesian cows were examined. Within year, cows were blocked into three MP sub-groups (n=9) (high (HMP), medium (MMP) and low (LMP)) based on the average MP data from weeks 3 and 4 of lactation. Within a block cows were randomly assigned to one of two treatments (n=54), flat rate (FR) concentrate feeding or feed to yield (FY) based on MP sub-group. Cows on the FR treatment were offered a fixed rate of concentrate (5.5 kg DM/cow per day) irrespective of MP sub-group. In the FY treatment HMP, MMP and LMP cows were allocated 7.3, 5.5 and 3.7 kg DM of concentrate, respectively. The mean concentrate offered to the FR and FY treatments was the same. On the FR treatment there was no significant difference in total dry matter intake (TDMI, 17.3 kg) between MP sub-groups. In the FY treatment, however, the TDMI of HMP-FY was 2.2 kg greater than MMP-FY, and 4.5 kg greater than LMP-FY (15.2 kg DM). The milk yield of LMP-FR was 3.5 kg less than the mean of the HMP-FR and MMP-FR treatments (24.5 kg). The milk yield of the HMP-FY treatment was 3.6 and 7.9 kg greater than the MMP-FY and LMP-FY treatments, respectively. The difference in MP between the HMP sub-groups was 2.6 kg, which translates to a response of 1.4 kg of milk per additional 1 kg of concentrate offered. There was no significant difference in MP between the two LMP sub-groups; however, MP increased 0.8 kg per additional 1 kg of concentrate offered between cows on the LMP-FR and LMP-FY treatments. The estimated energy balance was positive for cows on the LMP-FR treatment, but negative for cows on the other treatments. The experiment highlights the variation within a herd in MP response to concentrate, as cows with a lower MP potential are less responsive to additional energy input than cows with a greater MP potential. Cows with a greater MP capacity did not substitute additional concentrate for the basal forage, which indicates an additional demand for energy based on ability of individual cows to produce milk.
The interplay between the fat mass- and obesity-associated (FTO) gene variants and diet has been implicated in the development of obesity. The aim of the present analysis was to investigate associations between FTO genotype, dietary intakes and anthropometrics among European adults. Participants in the Food4Me randomised controlled trial were genotyped for FTO genotype (rs9939609) and their dietary intakes, and diet quality scores (Healthy Eating Index and PREDIMED-based Mediterranean diet score) were estimated from FFQ. Relationships between FTO genotype, diet and anthropometrics (weight, waist circumference (WC) and BMI) were evaluated at baseline. European adults with the FTO risk genotype had greater WC (AAv. TT: +1·4 cm; P=0·003) and BMI (+0·9 kg/m2; P=0·001) than individuals with no risk alleles. Subjects with the lowest fried food consumption and two copies of the FTO risk variant had on average 1·4 kg/m2 greater BMI (Ptrend=0·028) and 3·1 cm greater WC (Ptrend=0·045) compared with individuals with no copies of the risk allele and with the lowest fried food consumption. However, there was no evidence of interactions between FTO genotype and dietary intakes on BMI and WC, and thus further research is required to confirm or refute these findings.