A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers

Multiphenotype genome-wide association studies (GWAS) may reveal pleiotropic genes, which would remain undetected using single phenotype analyses. Analysis of large pedigrees offers the added advantage of more accurately assessing trait heritability, which can help prioritise genetically influenced phenotypes for GWAS analysis. In this study we performed a principal component analysis (PCA), heritability (h2) estimation and pedigree-based GWAS of 37 cardiovascular disease -related phenotypes in 330 related individuals forming a large pedigree from the Norfolk Island genetic isolate. PCA revealed 13 components explaining >75% of the total variance. Nine components yielded statistically significant h2 values ranging from 0.22 to 0.54 (P<0.05). The most heritable component was loaded with 7 phenotypic measures reflecting metabolic and renal dysfunction. A GWAS of this composite phenotype revealed statistically significant associations for 3 adjacent SNPs on chromosome 1p22.2 (P<1x10-8). These SNPs form a 42kb haplotype block and explain 11% of the genetic variance for this renal function phenotype. Replication analysis of the tagging SNP (rs1396315) in an independent US cohort supports the association (P = 0.000011). Blood transcript analysis showed 35 genes were associated with rs1396315 (P<0.05). Gene set enrichment analysis of these genes revealed the most enriched pathway was purine metabolism (P = 0.0015). Overall, our findings provide convincing evidence for a major pleiotropic effect locus on chromosome 1p22.2 influencing risk of renal dysfunction via purine metabolism pathways in the Norfolk Island population. Further studies are now warranted to interrogate the functional relevance of this locus in terms of renal pathology and cardiovascular disease risk.

Effects of severity of threshing damage on seed quality of Gatton panic Panicum maximum)

Different degrees of severity of threshing were imposed during combine-harvesting of seed of Gatton panic, a cultivar of Panicum maximum , to determine effects of degree of threshing damage on subsequent properties of seed. Threshing cylinder peripheral speeds and concave clearances covering the normal range employed commercially were varied experimentally in the harvest of 2 crops grown in north Queensland. Harvested seed was dried and cleaned, then stored under ambient conditions. The extent of physical damage was measured, and samples were tested at intervals for viability, germination, dormancy and seedling emergence from soil in a glasshouse and in the field over the 2 seasons following harvest. Physical damage increased as peripheral rotor speed rose and (though less markedly) as concave clearance was reduced. As the level of damage increased, viability was progressively reduced, life expectancy was shortened, and dormancy was broken. When the consequences were measured as seedling emergence from soil, the adverse effects on viability tended to cancel out the benefits of dormancy-breaking, leaving few net differences attributable to the degree of threshing severity. We concluded that there would be no value in trying to manipulate the quality of seed produced for normal commercial use through choice of cylinder settings, but that deliberate light or heavy threshing could benefit special-purpose seed, destined, respectively, for long-term storage or immediate use.

Identification and characterization of non-pathogenic Fusarium oxysporum capable of increasing and decreasing Fusarium wilt severity

Fusarium wilt of banana is a potentially devastating disease throughout the world. Options for control of the causal organism, Fusarium oxysporum f.sp. cubense (Foc) are limited. Suppressive soil sites have previously been identified where, despite the presence of Foc, Fusarium wilt does not develop. In order to understand some aspects of this disease suppression, endophytic Fusarium oxysporum isolates were obtained from banana roots. These isolates were genetically characterized and compared with an isolate of Fusarium oxysporum previously identified as being capable of suppressing Fusarium wilt of banana in glasshouse trials. Three additional isolates were selected for glasshouse trials to assess suppression of Fusarium wilt in two different cultivars of banana, Cavendish and Lady Finger. One isolate (BRIP 29089) was identified as a potential biocontrol organism, reducing the disease severity of Fusarium wilt in Lady Finger and Cavendish cultivars. Interestingly, one isolate (BRIP 45952) increased Fusarium wilt disease severity on Cavendish. The implications of an isolate of Fusarium oxysporum, non-pathogenic on banana, increasing disease severity and the potential role of non-pathogenic isolates of Fusarium oxysporum in disease complexes are discussed.

Models for engaging public-private partnerships in civil infrastructure projects: A case of ‘having your cake and eating it too’?

Public-Private Partnerships (PPP) are established globally as an important mode of procurement and the features of PPP, not least of which the transfer of risk, appeal to governments and particularly in the current economic climate. There are many other advantages of PPP that are claimed as outweighing the costs of PPP and affording Value for Money (VfM) relative to traditionally financed projects or non-PPP. That said, it is the case that we lack comparative whole-life empirical studies of VfM in PPP and non-PPP. Whilst we await this kind of study, the pace and trajectory of PPP seem set to continue and so in the meantime, the virtues of seeking to improve PPP appear incontrovertible. The decision about which projects, or parts of projects, to offer to the market as a PPP and the decision concerning the allocation or sharing risks as part of engagement of the PPP consortium are among the most fundamental decisions that determine whether PPP deliver VfM. The focus in the paper is on latter decision concerning governments’ attitudes towards risk and more specifically, the effect of this decision on the nature of the emergent PPP consortium, or PPP model, including its economic behavior and outcomes. This paper presents an exploration into the extent to which the seemingly incompatible alternatives of risk allocation and risk sharing, represented by the orthodox/conventional PPP model and the heterodox/alliance PPP model respectively, can be reconciled along with suggestions for new research directions to inform this reconciliation. In so doing, an important step is taken towards charting a path by which governments can harness the relative strengths of both kinds of PPP model.

Cognitive Functioning in Young Adults with Depression, Anxiety Disorders, or Burnout Symptoms : Findings from a Population-based Sample

Background. Evidence of cognitive dysfunction in depressive and anxiety disorders is growing. However, the neuropsychological profile of young adults has received only little systematic investigation, although depressive and anxiety disorders are major public health problems for this age group. Available studies have typically failed to account for psychiatric comorbidity, and samples derived from population-based settings have also seldom been investigated. Burnout-related cognitive functioning has previously been investigated in only few studies, again all using clinical samples and wide age groups. Aims. Based on the information gained by conducting a comprehensive review, studies on cognitive impairment in depressive and anxiety disorders among young adults are rare. The present study examined cognitive functioning in young adults with a history of unipolar depressive or anxiety disorders in comparison to healthy peers, and associations of current burnout symptoms with cognitive functioning, in a population-based setting. The aim was also to determine whether cognitive deficits vary as a function of different disorder characteristics, such as severity, psychiatric comorbidity, age at onset, or the treatments received. Methods. Verbal and visual short-term memory, verbal long-term memory and learning, attention, psychomotor processing speed, verbal intelligence, and executive functioning were measured in a population-based sample of 21-35 year olds. Performance was compared firstly between participants with pure non-psychotic depression (n=68) and healthy peers (n=70), secondly between pure (n=69) and comorbid depression (n=57), and thirdly between participants with anxiety disorders (n=76) and healthy peers (n=71). The diagnostic procedure was based on the SCID interview. Fourthly, the associations of current burnout symptoms, measured with the Maslach Burnout Inventory General Survey, and neuropsychological test performance were investigated among working young adults (n=225). Results. Young adults with depressive or anxiety disorders, with or without psychiatric comorbidity, were not found to have major cognitive impairments when compared to healthy peers. Only mildly compromised verbal learning was found among depressed participants. Pure and comorbid depression groups did not differ in cognitive functioning, either. Among depressed participants, those who had received treatment showed more impaired verbal memory and executive functioning, and earlier onset corresponded with more impaired executive functioning. In anxiety disorders, psychotropic medication and low psychosocial functioning were associated with deficits in executive functioning, psychomotor processing speed, and visual short-term memory. Current burnout symptoms were associated with better performance in verbal working memory and verbal intelligence. However, lower examiner-rated social and occupational functioning was associated with problems in verbal attention, memory, and learning. Conclusions. Depression, anxiety disorders, or burnout symptoms may not be associated with major cognitive deficits among young adults derived from the general population. Even psychiatric comorbidity may not aggravate cognitive functioning in depressive or anxiety disorders among these young adults. However, treatment-seeking in depression was found to be associated with cognitive deficits, suggesting that these deficits relate to increased distress. Additionally, early-onset depression, found to be associated with executive dysfunction, may represent a more severe form of the disorder. In anxiety disorders, those with low symptom-related psychosocial functioning may have cognitive impairment. An association with self-reported burnout symptoms and cognitive deficits was not detected, but individuals with low social and occupational functioning may have impaired cognition.

Post-school needs of young people with high-functioning Autism Spectrum Disorder

This study describes the post-school circumstances and service needs of older teenagers and adults with high-functioning Autism Spectrum Disorder, living in Queensland, Australia. The respondents were 95 parents. Results indicated that the majority of the young people lived in the family home and were unemployed. Of those who worked, 56% had unskilled jobs. They were estimated to spend a significant proportion of their time engaged in solitary, technology-based activities, and comparatively little time in employment or socialising. Parents rated employment support as the greatest service priority for their sons and daughters, followed by specialised support to assist with completing post-school education and training, assistance to support the transition from high school to adulthood, and social skills training.

Self-rating scales in the assessment of current and childhood symptoms of attention deficit hyperactivity disorder in adults

Objective: Attention deficit hyperactivity disorder (ADHD) is a life-long condition, but because of its historical status as a self-remitting disorder of childhood, empirically validated and reliable methods for the assessment of adults are scarce. In this study, the validity and reliability of the Wender Utah Rating Scale (WURS) and the Adult Problem Questionnaire (APQ), which survey childhood and current symptoms of ADHD, respectively, were studied in a Finnish sample. Methods: The self-rating scales were administered to adults with an ADHD diagnosis (n = 38), healthy control participants (n = 41), and adults diagnosed with dyslexia (n = 37). Items of the self-rating scales were subjected to factor analyses, after which the reliability and discriminatory power of the subscales, derived from the factors, were examined. The effects of group and gender on the subscales of both rating scales were studied. Additionally, the effect of age on the subscales of the WURS was investigated. Finally, the diagnostic accuracy of the total scores was studied. Results: On the basis of the factor analyses, a four-factor structure for the WURS and five-factor structure for the APQ had the best fit to the data. All of the subscales of the APQ and three of the WURS achieved sufficient reliability. The ADHD group had the highest scores on all of the subscales of the APQ, whereas two of the subscales of the WURS did not statistically differ between the ADHD and the Dyslexia group. None of the subscales of the WURS or the APQ was associated with the participant's gender. However, one subscale of the WURS describing dysthymia was positively correlated with the participant's age. With the WURS, the probability of a correct positive classification was .59 in the current sample and .21 when the relatively low prevalence of adult ADHD was taken into account. The probabilities of correct positive classifications with the APQ were .71 and .23, respectively. Conclusions: The WURS and the APQ can provide accurate and reliable information of childhood and adult ADHD symptoms, given some important constraints. Classifications made on the basis of the total scores are reliable predictors of ADHD diagnosis only in populations with a high proportion of ADHD and a low proportion of other similar disorders. The subscale scores can provide detailed information of an individual's symptoms if the characteristics and limitations of each domain are taken into account. Improvements are suggested for two subscales of the WURS.

An imagery-based road map to tackle maladaptive motivation in clinical disorders

There is now a widespread recognition of the importance of mental imagery in a range of clinical disorders (1). This provides the potential for a transdiagnostic route to integrate some aspects of these disorders and their treatment within a common framework. This opinion piece argues that we need to understand why imagery is such a central and recurring feature, if we are to progress theories of the origin and maintenance of disorders. This will aid us in identifying therapeutic techniques that are not simply targeting imagery as a symptom, but as a manifestation of an underlying problem. As papers in this issue highlight, imagery is a central feature across many clinical disorders, but has been ascribed varying roles. For example, the involuntary occurrence of traumatic memories is a diagnostic criterion for PTSD (2), and it has been suggested that multisensory imagery of traumatic events normally serves a functional role in allowing the individual to reappraise the situation (3), but that this re-appraisal is disabled by extreme affective responses. In contrast to the disabling flashbacks associated with PTSD, depressed adults who experience suicidal ideation often report “flash forward” imagery related to suicidal acts (4), motivating them to self-harm. Socially anxious individuals who engage in visual imagery about giving a talk in public become more anxious and make more negative predictions about future performance than others who engage in more abstract, semantic processing of the past event (5). People with Obsessive Compulsive Disorder (OCD) frequently report imagery of past adverse events, and imagery seems to be associated with severity (6). The content of intrusive imagery has been related to psychotic symptoms (7), including visual images of the catastrophic fears associated with paranoia and persecution. Imagery has been argued (8) to play a role in the maintenance of psychosis through negative appraisals of imagined voices, misattribution of sensations to external sources, by the induction of negative mood states that trigger voices, and through maintenance of negative schemas. In addiction and substance dependence, Elaborated Intrusion (EI) Theory (9, 10) emphasizes the causal role that imagery plays in substance use, through its role in motivating an individual to pursue goals directed toward achieving the pleasurable outcomes associated with substance use...

Radish leaves and radish roots: are we eating the right part for cancer prevention?

Radishes are most commonly consumed as a root vegetable, although radish leaves are occasionally used in salads and cooking. While both the radish root and shoot contain glucosinolates with anti-cancer potential, the glucosinolate profile of the root and the shoot are very different. Whereas the root contains mainly glucodehydroerucin (2.8 mol/gFW) (also known as glucoraphasatin), the main glucosinolate components of the shoot are glucoraphanin (2.8 mol/gFW) and glucoraphenin (2.1 mol/gFW). Upon hydrolysis, the latter glucosinolates produce sulforaphane and sulforaphene respectively, both potent inducers of mammalian phase 2 enzymes. Previously, radishes have been dismissed as having minimal anti-cancer potential based on studies with radish roots. However, depending on the cultivar, radish shoots can have up to 45 times the capacity of roots to induce phase 2 enzymes. In fact, shoots of a number of radish cultivars (eg. 'Black Spanish') have similar or greater anti-cancer potential than broccoli florets, a vegetable that has received considerable interest in this area.

The effect of rapid solidification on the order-disorder transformation in iron-based alloys

The effect of rapid solidification on the ordering reaction in Fe---Si and Fe---Al alloys has been reported. It is shown that rapid solidification can influence the ordering reaction in alloys with higher critical ordering temperatures. For ordering reactions at lower temperatures, the effect is similar to that of solid-state quenching. Different factors influencing the ordering reactions and domain structures during rapid solidification of iron-based alloys are discussed.

Early-onset depressive disorders,related mental health disorders and substance use-A prospective : longitudinal study of Finnish twins born 1983-1987

Early-onset psychiatric illnesses effects scatter to academic achievements as well as functioning in familial and social environments. From a public health point of view, depressive disorders are the most significant mental health disorders that begin in adolescence. Using prospective and longitudinal design, this study aimed to increase the understanding of early-onset depressive disorders, related mental health disorders and developing substance use in a large population-derived sample of adolescent Finnish twins. The participants of this study, FinnTwin12, an ongoing longitudinal population-based study, came from Finnish families with twins born in 1983-87 (exhaustive of five birth cohorts, identified from Finland s Central Population Register). With follow-up ongoing at age 20-24, this thesis assessed adolescent mental health in the first three waves, starting from baseline age 11-12 to follow-ups at age 14 and 17½. Some 5600 twins participated in questionnaire assessments of a wide range of health related behaviors. Mental health was further assessed among an intensively studied subsample of 1852 adolescents, who completed also professionally administered interviews at age 14, which provided data for full DSM-IV/III-R (Diagnostic and Statistical Manual for Mental Health disorders, 4th and 3rd editions) diagnoses. The participation rates of the study were 87-92%. The results of the study suggest, that the diagnostic criteria for major depressive disorder (MDD) may not capture youth with clinically significant early-onset depressive conditions outside clinical settings. Milder cases of depression, namely adolescents fulfilling the diagnostic criteria for minor depressive disorder, a qualitatively similar condition to MDD with fewer symptoms are also associated with marked suicidal thoughts, plans and attempts, recurrences and a high degree of comorbidity. Prospectively and longitudinally, early-onset depressive disorders were of substantial importance in the context of other mental health disorders and substance use behaviors: These data from a large population-derived sample established a substantial overlap between early-onset depressive disorders and attention deficit hyperactivity disorder in adolescent females, both of them significantly predictive for development of substance use among girls. Only in females baseline DSM-IV ADHD symptoms were strong predictors of alcohol abuse and dependence and illicit drug use at age 14 and frequent alcohol use and illicit drug use at age 17.½ when conduct disorder and previous substance use were controlled for. Early-onset depressive disorders were also prospectively and longitudinally associated to daily smoking behavior, smokeless tobacco use, frequent alcohol use and illicit drug use and eating disorders. Analysis of discordant twins suggested that these predictive associations were independent of familial confounds, such as family income, structure and parental models. In sum, early-onset depressive disorders predict subsequent involvement of substance use and psychiatric morbidity. A heightened risk for substance use is substantial also among those depressed below categorical diagnosis of MDD. Whether early recognition and interventions among these young people hold potential for substance use prevention further in their lives has potential public health significance and calls for more research. Data from this population-derived sample with balanced representation of boys and girls, suggested that boys and girls with ADHD behaviors may differ from each other in their vulnerability to substance use and depressive disorders: the data suggest more adverse substance use outcome for girls that was not attenuated by conduct disorder or previous substance use. Further, the prospective associations of early-onset depressive disorders and future elevated levels of addictive substance use is not explained by familial factors supporting future substance use, which could have important implications for substance use prevention.

Genetic burden associated with varying degrees of disease severity in endometriosis

Endometriosis is primarily characterized by the presence of tissue resembling endometrium outside the uterine cavity and is usually diagnosed by laparoscopy. The most commonly used classification of disease, the revised American Fertility Society (rAFS) system to grade endometriosis into different stages based on disease severity (I to IV), has been questioned as it does not correlate well with underlying symptoms, posing issues in diagnosis and choice of treatment. Using two independent European genome-wide association (GWA) datasets and top-level classification of the endometriosis cases based on rAFS [minimal or mild (Stage A) and moderate-to-severe (Stage B) disease], we previously showed that Stage B endometriosis has greater contribution of common genetic variation to its aetiology than Stage A disease. Herein, we extend our previous analysis to four endometriosis stages [minimal (Stage I), mild (Stage II), moderate (Stage III) and severe (Stage IV) disease] based on the rAFS classification system and compared the genetic burden across stages. Our results indicate that genetic burden increases from minimal to severe endometriosis. For the minimal disease, genetic factors may contribute to a lesser extent than other disease categories. Mild and moderate endometriosis appeared genetically similar, making it difficult to tease them apart. Consistent with our previous reports, moderate and severe endometriosis showed greater genetic burden than minimal or mild disease. Overall, our results provide new insights into the genetic architecture of endometriosis and further investigation in larger samples may help to understand better the aetiology of varying degrees of endometriosis, enabling improved diagnostic and treatment modalities.

A mega-analysis of genome-wide association studies for major depressive disorder

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 x 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 x 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.

Genome-wide association study of major depressive disorder: New results, meta-analysis, and lessons learned

Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were: (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10), and; (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.