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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.
Around 30% of individuals with schizophrenia remain symptomatic and significantly impaired despite antipsychotic treatment and are considered to be treatment resistant. Clinicians are currently unable to predict which patients are at higher risk of treatment resistance.
To determine whether genetic liability for schizophrenia and/or clinical characteristics measurable at illness onset can prospectively indicate a higher risk of treatment-resistant psychosis (TRP).
In 1070 individuals with schizophrenia or related psychotic disorders, schizophrenia polygenic risk scores (PRS) and large copy number variations (CNVs) were assessed for enrichment in TRP. Regression and machine-learning approaches were used to investigate the association of phenotypes related to demographics, family history, premorbid factors and illness onset with TRP.
Younger age at onset (odds ratio 0.94, P = 7.79 × 10−13) and poor premorbid social adjustment (odds ratio 1.64, P = 2.41 × 10−4) increased risk of TRP in univariate regression analyses. These factors remained associated in multivariate regression analyses, which also found lower premorbid IQ (odds ratio 0.98, P = 7.76 × 10−3), younger father's age at birth (odds ratio 0.97, P = 0.015) and cannabis use (odds ratio 1.60, P = 0.025) increased the risk of TRP. Machine-learning approaches found age at onset to be the most important predictor and also identified premorbid IQ and poor social adjustment as predictors of TRP, mirroring findings from regression analyses. Genetic liability for schizophrenia was not associated with TRP.
People with an earlier age at onset of psychosis and poor premorbid functioning are more likely to be treatment resistant. The genetic architecture of susceptibility to schizophrenia may be distinct from that of treatment outcomes.
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.
Studies involving clinically recruited samples show that genetic liability to schizophrenia overlaps with that for several psychiatric disorders including bipolar disorder, major depression and, in a population study, anxiety disorder and negative symptoms in adolescence.
We examined whether, at a population level, association between schizophrenia liability and anxiety disorders continues into adulthood, for specific anxiety disorders and as a group. We explored in an epidemiologically based cohort the nature of adult psychopathology sharing liability to schizophrenia.
Schizophrenia polygenic risk scores (PRSs) were calculated for 590 European-descent individuals from the Christchurch Health and Development Study. Logistic regression was used to examine associations between schizophrenia PRS and four anxiety disorders (social phobia, specific phobia, panic disorder and generalised anxiety disorder), schizophrenia/schizophreniform disorder, manic/hypomanic episode, alcohol dependence, major depression, and – using linear regression – total number of anxiety disorders. A novel population-level association with hypomania was tested in a UK birth cohort (Avon Longitudinal Study of Parents and Children).
Schizophrenia PRS was associated with total number of anxiety disorders and with generalised anxiety disorder and panic disorder. We show a novel population-level association between schizophrenia PRS and manic/hypomanic episode.
The relationship between schizophrenia liability and anxiety disorders is not restricted to psychopathology in adolescence but is present in adulthood and specifically linked to generalised anxiety disorder and panic disorder. We suggest that the association between schizophrenia liability and hypomanic/manic episodes found in clinical samples may not be due to bias.
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.
There is strong evidence that people born in winter and in spring have a small increased risk of schizophrenia. As this ‘season of birth’ effect underpins some of the most influential hypotheses concerning potentially modifiable risk exposures, it is important to exclude other possible explanations for the phenomenon.
Here we sought to determine whether the season of birth effect reflects gene-environment confounding rather than a pathogenic process indexing environmental exposure. We directly measured, in 136 538 participants from the UK Biobank (UKBB), the burdens of common schizophrenia risk alleles and of copy number variants known to increase the risk for the disorder, and tested whether these were correlated with a season of birth.
Neither genetic measure was associated with season or month of birth within the UKBB sample.
As our study was highly powered to detect small effects, we conclude that the season of birth effect in schizophrenia reflects a true pathogenic effect of environmental exposure.
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.
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.
It is postulated that knowledge of genotype may be more powerful than other types of personalised information in terms of motivating behaviour change. However, there is also a danger that disclosure of genetic risk may promote a fatalistic attitude and demotivate individuals. The original concept of personalised nutrition (PN) focused on genotype-based tailored dietary advice; however, PN can also be delivered based on assessment of dietary intake and phenotypic measures. Whilst dietitians currently provide PN advice based on diet and phenotype, genotype-based PN advice is not so readily available. The aim of this review is to examine the evidence for genotype-based personalised information on motivating behaviour change, and factors which may affect the impact of genotype-based personalised advice. Recent findings in PN will also be discussed, with respect to a large European study, Food4Me, which investigated the impact of varying levels of PN advice on motivating behaviour change. The researchers reported that PN advice resulted in greater dietary changes compared with general healthy eating advice, but no additional benefit was observed for PN advice based on phenotype and genotype information. Within Food4Me, work from our group revealed that knowledge of MTHFR genotype did not significantly improve intakes of dietary folate. In general, evidence is weak with regard to genotype-based PN advice. For future work, studies should test the impact of PN advice developed on a strong nutrigenetic evidence base, ensure an appropriate study design for the research question asked, and incorporate behaviour change techniques into the intervention.
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.
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.
Previous research has demonstrated that late and sequential applications of glyphosate and glufosinate can have adverse effects on glyphosate- and glufosinate-resistant canola. Similarly, imidazolinone (IMI)-resistant canola may be affected negatively by late applications of imidazolinone herbicides. Field trials were established across the Northern Great Plains region from 2010 to 2012 to examine the response of IMI-resistant canola yield, yield components, and seed quality to late and sequential applications of imazamox. Plots received either a single imazamox application at the two-leaf, six-leaf, bolt, or early bloom stages or sequential applications at the two-leaf followed by six-leaf, two-leaf followed by bolting, and two-leaf followed by early bloom stages; an unsprayed control was included for comparisons. Results indicated that in most site-years there was no effect of imazamox application timing on IMI-resistant canola yield, yield components, or seed quality. These results suggest that late and sequential applications of imazamox to IMI-resistant canola should have little effect on canola production, even if they are made beyond the recommended six-leaf stage. In situations where growers are forced to make late applications (beyond six leaves) to IMI-resistant canola, using solely imazamox appears to minimize adverse effects on seed yield and quality.
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 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.