Site-directed genotype screening for elimination of antinutritional saponins in quinoa seeds identifies TSARL1 as a master controller of saponin biosynthesis selectively in seeds.

Climate change may result in a drier climate and increased salinization, threatening agricultural productivity worldwide. Quinoa (Chenopodium quinoa) produces highly nutritious seeds and tolerates abiotic stresses such as drought and high salinity, making it a promising future food source. However, the presence of antinutritional saponins in their seeds is an undesirable trait. We mapped genes controlling seed saponin content to a genomic region that includes TSARL1. We isolated desired genetic variation in this gene by producing a large mutant library of a commercial quinoa cultivar and screening the library for specific nucleotide substitutions using droplet digital PCR. We were able to rapidly isolate two independent tsarl1 mutants, which retained saponins in the leaves and roots for defence, but saponins were undetectable in the seed coat. We further could show that TSARL1 specifically controls seed saponin biosynthesis in the committed step after 2,3-oxidosqualene. Our work provides new important knowledge on the function of TSARL1 and represents a breakthrough for quinoa breeding.

In-session gaming as a tool in treating adolescent problematic gaming.

For some adolescent gamers, playing online games may become problematic, impairing functioning in personal, family, and other life domains. Parental and family factors are known to influence the odds that adolescents may develop problematic gaming (PG), negative parenting and conflictual family dynamics increasing the risk, whereas positive parenting and developmentally supportive family dynamics protecting against PG. This suggests that a treatment for adolescent PG should not only address the gaming behaviors and personal characteristics of the youth, but also the parental and family domains. An established research-supported treatment meeting these requirements is multidimensional family therapy (MDFT), which we adapted for use as adolescent PG treatment. We report here on one adaptation, applying in-session gaming. In-session demonstration of the "problem behavior" is feasible and informative in PG. In the opening stage of therapy, we use in-session gaming to establish an alliance between the therapist and the youth. By inviting them to play games, the therapist demonstrates that they are taken seriously, thus boosting treatment motivation. Later in treatment, gaming is introduced in family sessions, offering useful opportunities to intervene in family members' perspectives and interactional patterns revealed in vivo as the youth plays the game. These sessions can trigger strong emotions and reactions from the parents and youth and give rise to maladaptive transactions between the family members, thus offering ways to facilitate new discussions and experiences of each other. The insights gained from the game demonstration sessions aid the therapeutic process, more so than mere discussion about gaming.

Multidimensional family therapy reduces problematic gaming in adolescents: A randomised controlled trial.

BACKGROUND AND AIMS: Social variables including parental and family factors may serve as risk factors for Internet Gaming Disorder (IGD) in adolescents. An IGD treatment programme should address these factors. We assessed two family therapies - multidimensional family therapy (MDFT) and family therapy as usual (FTAU) - on their impact on the prevalence of IGD and IGD symptoms. METHODS: Eligible for this randomised controlled trial comparing MDFT (N = 12) with FTAU (N = 30) were adolescents of 12-19 years old meeting at least 5 of the 9 DSM-5 IGD criteria and with at least one parent willing to participate in the study. The youths were recruited from the Centre Phénix-Mail, which offers outpatient adolescent addiction care in Geneva. Assessments occurred at baseline and 6 and 12 months. RESULTS: Both family therapies decreased the prevalence of IGD across the one-year period. Both therapies also lowered the number of IGD criteria met, with MDFT outperforming FTAU. There was no effect on the amount of time spent on gaming. At baseline, parents judged their child's gaming problems to be important whereas the adolescents thought these problems were minimal. This discrepancy in judgment diminished across the study period as parents became milder in rating problem severity. MDFT better retained families in treatment than FTAU. DISCUSSION AND CONCLUSIONS: Family therapy, especially MDFT, was effective in treating adolescent IGD. Improvements in family relationships may contribute to the treatment success. Our findings are promising but need to be replicated in larger study. TRIAL REGISTRATION NUMBER: ISRCTN 11142726.

Linking parental mediation practices to adolescents' problematic online screen use: A systematic literature review.

BACKGROUND AND AIMS: To remedy problematic Internet use (PIU) and problematic online gaming (POG) in adolescents, much is expected from efforts by parents to help youths to contain their screen use. Such parental mediation can include (a) refraining from acting, (b) co-viewing or co-gaming with the teen, (c) active mediation, and (d) restrictive mediation. We evaluated if parental mediation practices are linked to PIU and POG in adolescents. METHODS: For a systematic literature review, we searched for publications presenting survey data and relating parental mediation practices to levels of PIU and/or POG in adolescents. The review's selection criteria were met by 18 PIU and 9 POG publications, reporting on 81.002 and 12.915 adolescents, respectively. We extracted data on gaming problems, mediation interventions, study design features, and sample characteristics. RESULTS: No type of parental mediation was consistently associated with lower or elevated problematic screen use rates in the adolescents. Refraining from parental mediation tended to aggravate screen use problems, whereas active mediation (talking to the teen) may mitigate such problems in PIU, but less clearly in POG. The link of restrictive mediation with problematic screen use varied from positive to negative, possibly depending on type of restriction. In both PIU and POG, family cohesion was related to lower rates of the problem behavior concerned and family conflict to higher rates. DISCUSSION AND CONCLUSIONS: Parental mediation practices may affect problematic screen use rates for better or worse. However, research of higher quality, including observations of parent-teen interactions, is needed to confirm the trends noted and advance the critical issue of the possible association between PIU, POG, and family interactions.

Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum.

There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.

Associations Between Autoimmune Diseases and Attention-Deficit/Hyperactivity Disorder: A Nationwide Study.

OBJECTIVE: Recent studies have suggested that autoimmune diseases and immune activation play a part in the pathogenesis of different neurodevelopmental disorders. This study investigated the association between a personal history and a family history of autoimmune disease and the risk of developing attention-deficit/hyperactivity disorder (ADHD). METHOD: A cohort was formed of all singletons born in Denmark from 1990 to 2007, resulting in a study population of 983,680 individuals followed from 1995 to 2012. Information on autoimmune diseases was obtained from the Danish National Hospital Register. Individuals with ADHD were identified through the Danish National Hospital Register and the Danish Psychiatric Central Register. RESULTS: In total, 23,645 children were diagnosed with ADHD during the study period. Autoimmune disease in the individual was associated with an increased risk of ADHD by an incidence rate ratio of 1.24 (95% CI 1.10-1.40). The primary analyses associated maternal autoimmune disease with ADHD in the offspring (incidence rate ratio 1.12, 95% CI 1.06-1.19), whereas a paternal history of autoimmune diseases was not significantly associated with ADHD in the offspring. In exploratory analyses, an increased risk of ADHD was observed for children with a family history of thyrotoxicosis, type 1 diabetes, autoimmune hepatitis, psoriasis, and ankylosing spondylitis. CONCLUSION: A personal history and a maternal history of autoimmune disease were associated with an increased risk of ADHD. The previously reported association between type 1 diabetes and ADHD was confirmed. In addition, specific parental autoimmune diseases were associated with ADHD in offspring.

Does Schizophrenia in Offspring Increase the Risk of Developing Alzheimer's Dementia.

BACKGROUND/AIMS: Prior studies have consistently found a higher risk of dementia in individuals with schizophrenia, but whether this is due to a common etiology between the disorders remains obscure. We wanted to elucidate this association by investigating whether schizophrenia in offspring increases the risk of Alzheimer's dementia. METHODS: All individuals born between 1930 and 1953 were identified through national registers and followed from their 50th birthday until the date of Alzheimer's dementia, death or end of the study. Regressions were performed to evaluate the association between offspring with schizophrenia and Alzheimer's dementia. RESULTS: Individuals with offspring with schizophrenia did not have an increased risk of Alzheimer's dementia [incidence rate ratio (IRR), 0.97; 95% CI, 0.88-1.07] compared to individuals with offspring without psychiatric contact. This finding remained stable when evaluating early-onset (IRR, 1.10; 95% CI, 0.91-1.31) and late-onset Alzheimer's dementia (IRR, 0.92; 95% CI, 0.88-1.07). Similar findings were made for vascular and unspecified dementia. CONCLUSION: The finding of no familial coaggregation between schizophrenia and Alzheimer's dementia may suggest that no common etiology between the disorders exists. This may indicate that the excess risk of dementia in individuals with schizophrenia is a by-product of the higher rates of somatic comorbidity and adverse health risk factors among these individuals.

Comorbidity of schizophrenia and infection: a population-based cohort study.

PURPOSE: In this paper, we investigate the hypothesis that there is an overlap between infection and schizophrenia. Infections have been identified as a risk factor for schizophrenia, but the possible overlap between schizophrenia and infections remains unidentified so far. Here, we describe the use of the comorbidity index, a method for objectively integrating associations into a single measure estimating overlap. METHODS: Data were drawn from three population-based registers, the Civil Registration Register, the Danish Psychiatric Central Research Register, and the Danish National Hospital Register. We selected a cohort of 1,403,183 persons born in Denmark 1977-2002. RESULTS: Our results indicate that persons who have had a hospital contact with an infection (IRR 1.53, CI 1.46-1.61) are more likely to develop schizophrenia than persons who have not had such a contact. Persons who have had a diagnosis with schizophrenia are more likely to have had a hospital contact with an infection (IRR 1.73, 95 % CI 1.57-1.91) than persons who have had no schizophrenia diagnosis. A comorbidity index of 1.40 (95 % CI 1.34-1.46) was found, indicating an overlap between schizophrenia and infection. CONCLUSION: Our findings indicate that schizophrenia and infections overlap and that they share risk factors. The comorbidity index showed that the co-occurrence of schizophrenia and infection was 40 % higher than if the two disorders had occurred independently. Although the incidence of schizophrenia and infection was associated with each factor, the overlap could not be explained by urbanicity, parental history of psychiatric admission and infection.

Spouse with schizophrenia and risk of dementia.

Increased prevalence of lifestyle risk factors or shared etiology may underlie the association between schizophrenia and the subsequent risk of dementia. We explored the association between having a spouse with schizophrenia and the risk of dementia. We found a positive relationship between having a spouse with schizophrenia and vascular dementia in individuals without a mental disorder themselves but no association between having a spouse with schizophrenia and Alzheimer's dementia. As spouses share environmental risk factors and lifestyle, this might suggest that the excess risk of dementia in probands with schizophrenia could be ascribed to the unhealthy living environment among individuals with schizophrenia.

Infections as risk factor for autoimmune diseases - A nationwide study.

Viruses, bacteria and other infectious pathogens are the major postulated environmental triggers of autoimmunity. In the present nation-wide study we describe the association between infections and 29 autoimmune diseases. We used the Danish Civil Registration System to identify 4.5 million persons born between 1945 and 2000. Information on infections and autoimmune diseases was obtained from the Danish Hospital Register. The cohort was followed from 1977 to 2012. Incidence rate ratios for developing an autoimmune disease were estimated using poisson regression. We found an association between hospital admission for an infection and 29 autoimmune diseases. This study shows that infections are risk factors for a broad spectrum of autoimmune diseases in a dose-response and temporal manner, in agreement with the hypothesis that infections are an environmental risk factor contributing to the etiology of autoimmune diseases together with genetic factors.

Individual and combined effects of maternal anemia and prenatal infection on risk for schizophrenia in offspring.

BACKGROUND: Maternal iron deficiency and infection during pregnancy have individually been associated with increased risk of schizophrenia in the offspring, but possible interactions between the two remain unidentified thus far. Therefore, we determined the individual and combined effects of maternal infection during pregnancy and prepartum anemia on schizophrenia risk in the offspring. METHODS: We conducted a population-based study with individual record linkage of the Danish Civil Registration System, the Danish Hospital Register, and the Central Danish Psychiatric Register. In a cohort of Danish singleton births 1,403,183 born between 1977 and 2002, 6729 developed schizophrenia between 1987 and 2012. Cohort members were considered as having a maternal history of anemia if the mother had received a diagnosis of anemia at any time during the pregnancy. Maternal infection was defined based on infections requiring hospital admission during pregnancy. RESULTS: Maternal anemia and infection were both associated with increased risk of schizophrenia in unadjusted analyses (1.45-fold increase for anemia, 95% CI: 1.14-1.82; 1.32-fold increase for infection, 95% CI: 1.17-1.48). The effect of maternal infection remained significant (1.16-fold increase, 95% CI: 1.03-1.31) after adjustment for possible confounding factors. Combined exposure to anemia and an infection increased the effect size to a 2.49-fold increased schizophrenia risk (95% CI: 1.29-4.27). The interaction analysis, however, failed to provide evidence for multiplicative interactions between the two factors. CONCLUSION: Our findings indicate that maternal anemia and infection have additive but not interactive effects, and therefore, they may represent two independent risk factors of schizophrenia.

The Association between Infections and General Cognitive Ability in Young Men - A Nationwide Study.

BACKGROUND: Infections and activated immune responses can affect the brain through several pathways that might also affect cognition. However, no large-scale study has previously investigated the effect of infections on the general cognitive ability in the general population. METHODS: Danish nationwide registers were linked to establish a cohort of all 161,696 male conscripts during the years 2006-2012 who were tested for cognitive ability, which was based on logical, verbal, numerical and spatial reasoning at a mean age of 19.4 years. Test scores were converted to a mean of 100.00 and with a standard deviation (SD) of 15. Data were analyzed as a cohort study with severe infections requiring hospitalization as exposure using linear regression. RESULTS: Adjusted effect sizes were calculated with non-exposure to severe infections as reference, ranging from 0.12 SD to 0.63 SD on general cognitive ability. A prior infection was associated with significantly lower cognitive ability by a mean of 1.76 (95%CI: -1.92 to -1.61; corresponding to 0.12 SD). The cognitive ability was affected the most by the temporal proximity of the last infection (P<0.001) and by the severity of infection measured by days of admission (P<0.001). The number of infections were associated with decreased cognitive ability in a dose-response relationship, and highest mean differences were found for ≥10 hospital contacts for infections (Mean: -5.54; 95%CI: -7.20 to -3.89; corresponding to 0.37 SD), and for ≥5 different types of infections (Mean: -9.44; 95%CI: -13.2 to -5.69; corresponding to 0.63 SD). Hospital contacts with infections had occurred in 35% of the individuals prior to conscription. CONCLUSIONS: Independent of a wide range of possible confounders, significant associations between infections and cognitive ability were observed. Infections or related immune responses might directly affect the cognitive ability; however, associated heritable and environmental factors might also account for the lowered cognitive ability.

Somatic diseases and conditions before the first diagnosis of schizophrenia: a nationwide population-based cohort study in more than 900 000 individuals.

OBJECTIVE: Schizophrenia is associated with excess physical comorbidity. Yet, to our knowledge, large studies are lacking on the associations with somatic diseases before the onset of schizophrenia. The authors conducted a nationwide study of the full spectrum of treated somatic diseases before the first diagnosis of schizophrenia. METHOD: Nationwide sample of the Danish population consisting of singletons (n = 954351) born 1977-1993 and followed from birth to 2009, during which period 4371 developed schizophrenia. Somatic diagnoses at all general hospital contacts (admitted or outpatient care at a somatic hospital) from 1977 to 2009 were used as exposures. The incidence rate ratio (IRR) of schizophrenia was calculated using Poisson regression adjusted for confounders. RESULTS: Among the 4371 persons who developed schizophrenia from 1992 to 2009, a total of 4180 (95.6%) persons had a previous somatic hospital contact. A history of any somatic hospital contact was associated with an elevated risk of schizophrenia (IRR = 2.04, 95% CI = 1.77-2.37). A wide range of somatic diseases and conditions were associated with an increased risk of schizophrenia, including epilepsy (IRR = 2.26, 95% CI = 1.93-2.62), nutritional or metabolic disorders (IRR = 1.57, 95% CI = 1.39-1.77), circulatory system diseases (IRR = 1.63, 95% CI= 1.38-1.92), and brain injury (IRR = 1.58, 95% CI = 1.45-1.72). CONCLUSIONS: A wide range of potential etiological factors could have contributed to the observed associations, including genetic or physiological overlaps between conditions, and interacting immunological, behavioral, and neurodevelopmental factors.

Neonatal levels of inflammatory markers and later risk of schizophrenia.

BACKGROUND: There is a long-standing interest in investigating the impact of early-life immune abnormalities on later onset of psychosis. The aim of this study was to assess inflammatory marker levels in neonatal dried blood spots and their association with later risk of schizophrenia. METHODS: This nested case-control study included 995 cases and 980 control subjects. Cases were identified using the Danish Psychiatric Central Register. Control subjects of same age and sex were identified using the Danish Civil Registration System. Samples for the identified individuals were retrieved from the Danish Neonatal Screening Biobank. Concentrations of 17 inflammatory markers were measured in eluates from dried blood spots using a bead-based multiplex assay. Incidence rate ratios were calculated using conditional logistic regression. Principal component analysis was used to capture the overall variation in the inflammatory markers' concentrations. RESULTS: No significant differences were found for any of the analyzed interleukins. We did not find any association with schizophrenia for any of the other examined inflammatory markers. CONCLUSIONS: Our results suggest that persons who develop schizophrenia do not have higher or lower levels of the examined inflammatory markers at the time of birth. Our findings differ from the studies of maternal inflammatory changes during the antenatal period for which associations with schizophrenia have previously been demonstrated.

Obsessive-compulsive disorder as a risk factor for schizophrenia: a nationwide study.

IMPORTANCE: Despite a remarkable co-occurrence of obsessive-compulsive disorder (OCD) and schizophrenia, little is known about the clinical and etiological relationship of these 2 disorders. Exploring the degree to which these disorders share etiological factors might provide useful implications for clinicians, researchers, and those with the disorders. OBJECTIVES: To assess whether patients with OCD experience an enhanced risk of developing schizophrenia and schizophrenia spectrum disorders and to determine whether a family history of OCD constitutes a risk factor for schizophrenia and schizophrenia spectrum disorders. DESIGN, SETTING, AND PARTICIPANTS: Using individual data from longitudinal nationwide Danish registers, we conducted a prospective cohort study with 45 million person-years of follow-up. All survival analyses were adjusted for sex, age, calendar year, parental age, and place of residence at the time of birth. A total of 3 million people born between January 1, 1955, and November 30, 2006, were followed up from January 1, 1995, through December 31, 2012. During this period, 30 556 people developed schizophrenia or schizophrenia spectrum disorders. MAIN OUTCOMES AND MEASURES: The presence of a prior diagnosis of OCD and the risk of a first lifetime diagnosis of schizophrenia and a schizophrenia spectrum disorder assigned by a psychiatrist in a hospital, outpatient clinic, or emergency department setting. Incidence rate ratios (IRRs) and accompanying 95% confidence intervals are used as measures of relative risk. RESULTS: The presence of prior diagnosis of OCD was associated with an increased risk of developing schizophrenia (IRR = 6.90; 95% CI, 6.25-7.60) and schizophrenia spectrum disorders (IRR = 5.77; 95% CI, 5.33-6.22) later in life. Similarly, offspring of parents diagnosed as having OCD had an increased risk of schizophrenia (IRR = 4.31; 95% CI, 2.72-6.43) and schizophrenia spectrum disorders (IRR = 3.10; 95% CI, 2.17-4.27). The results remained significant after adjusting for family history of psychiatric disorders and the patient's psychiatric history. CONCLUSIONS AND RELEVANCE: A diagnosis of OCD was associated with higher rates of schizophrenia and schizophrenia spectrum disorders. The observed increase in risk suggests that OCD, schizophrenia, and schizophrenia spectrum disorders probably lay on a common etiological pathway.

Hospital contacts with infection and risk of schizophrenia: a population-based cohort study with linkage of Danish national registers.

Infections and immune responses have been suggested to play an important role in the etiology of schizophrenia. Several studies have reported associations between maternal infections during pregnancy and the child's risk of schizophrenia; however, infection during childhood and adolescence unrelated to maternal infection during pregnancy has not been studied to nearly the same extent and the results are far from conclusive. Data were drawn from 2 population-based registers, the Danish Psychiatric Central Register and the Danish National Hospital Register. We used a historical population-based cohort design and selected all individuals born in Denmark between 1981 and 1996 (n = 843 390). We identified all individuals with a first-time hospital contact with schizophrenia from 1991 through 2010. Out of the 3409 individuals diagnosed with schizophrenia, a total of 1549 individuals had had a hospital contact with infection before their schizophrenia diagnosis (45%). Our results indicate that individuals who have had a hospital contact with infection are more likely to develop schizophrenia (relative risk [RR] = 1.41; 95% CI: 1.32-1.51) than individuals who had not had such a hospital contact. Bacterial infection was the type of infection that was associated with the highest risk of schizophrenia (RR = 1.63; 95% CI: 1.47-1.82). Our study does not exclude that a certain type of infection may have a specific effect; yet, it does suggest that schizophrenia is associated with a wide range of infections. This association may be due to inflammatory responses affecting the brain or genetic and environmental risk factors aggregating in families.

Population impact of familial and environmental risk factors for schizophrenia: a nationwide study.

Although several studies have examined the relative contributions of familial and environmental risk factors for schizophrenia, few have additionally examined the predictive power on the individual level and simultaneously examined the population impact associated with a wide range of familial and environmental risk factors. The authors present rate ratios (IRR), population-attributable risks (PAR) and sex-specific cumulative incidences of the following risk factors: parental history of mental illness, urban place of birth, advanced paternal age, parental loss and immigration status. We established a population-based cohort of 2,486,646million persons born in Denmark between 1 January 1955 and 31 December 1993 using Danish registers. We found that PAR associated with urban birth was 11.73%; PAR associated with one, respectively 2, parent(s) with schizophrenia was 2.67% and 0.12%. PAR associated with second-generation immigration was 0.70%. Highest cumulative incidence (CI=20.23%; 95% CI=18.10-22.62) was found in male offspring of 2 parents with schizophrenia. Cumulative incidences for male offspring or female offspring of a parent with schizophrenia were 9.53% (95% CI=7.71-11.79), and 4.89%, (95% CI 4.50-5.31). The study showed that risk factors with highest predictive power on the individual level have a relatively low population impact. The challenge in future studies with direct genetic data is to examine gene-environmental interactions that can move research beyond current approaches and seek to achieve higher predictive power on the individual level and higher population impact.

Implementation fidelity of Multidimensional Family Therapy in an international trial.

Implementation fidelity, a critical aspect of clinical trials research that establishes adequate delivery of the treatment as prescribed in treatment manuals and protocols, is also essential to the successful implementation of effective programs into new practice settings. Although infrequently studied in the drug abuse field, stronger implementation fidelity has been linked to better outcomes in practice but appears to be more difficult to achieve with greater distance from model developers. In the INternational CAnnabis Need for Treatment (INCANT) multi-national randomized clinical trial, investigators tested the effectiveness of Multidimensional Family Therapy (MDFT) in comparison to individual psychotherapy (IP) in Brussels, Berlin, Paris, The Hague, and Geneva with 450 adolescents with a cannabis use disorder and their parents. This study reports on the implementation fidelity of MDFT across these five Western European sites in terms of treatment adherence, dose and program differentiation, and discusses possible implications for international implementation efforts.