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A fascinating account of the life of one of the most famous women of the Victorian era.

Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental disorders with a considerable overlap in their genetic etiology. We dissected their shared and distinct genetic architecture by cross-disorder analyses of large data sets, including samples with information on comorbid diagnoses. We identified seven loci shared by the disorders and the first five genome-wide significant loci differentiating the disorders. All five differentiating loci showed opposite allelic directions in the two disorders separately as well as significant associations with variation in other traits e.g. educational attainment, items of neuroticism and regional brain volume. Integration with brain transcriptome data identified and prioritized several significantly associated genes. Genetic correlation of the shared liability across ASD-ADHD was strong for other psychiatric phenotypes while the ASD-ADHD differentiating liability correlated most strongly with cognitive traits. Polygenic score analyses revealed that individuals diagnosed with both ASD and ADHD are double-burdened with genetic risk for both disorders and show distinctive patterns of genetic association with other traits when compared to the ASD-only and ADHD-only subgroups. The results provide novel insights into the biological foundation for developing just one or both of the disorders and for driving the psychopathology discriminatively towards either ADHD or ASD.

BackgroundThere is evidence that autism spectrum disorders (ASDs) co-occur with bipolar disorder (BD) relatively frequently. Individuals with BD often report symptoms of mania and hypomania during adolescence, prior to the age of onset for BD. It is unknown whether these symptoms are associated with ASDs. We examined whether diagnoses of ASDs and autistic traits were associated with hypomania in a large, population-based Swedish twin sample.MethodsParental structured interviews assessed autistic traits, and were used to assign screening diagnoses of ASDs, when twins were aged 9 or 12 (N = 13 533 pairs). Parents then completed questionnaires assessing hypomania when the twins were aged 15 and 18 (N = 3852 pairs at age 15, and 3013 pairs at age 18). After investigating the phenotypic associations between these measures, we used the classical twin design to test whether genetic and environmental influences on autistic traits influence variation in adolescent hypomania.ResultsAutistic traits and ASD diagnoses in childhood were associated with elevated scores on the measures of adolescent hypomania. Twin analyses indicated that 6–9% of the variance in hypomania was explained by genetic influences that were shared with autistic traits in childhood. When repeating these analyses for specific autistic trait domains, we found a stronger association between social interaction difficulties and hypomania than for other autistic trait domains.ConclusionsThese results indicate a genetic link between autistic traits and hypomania in adolescence. This adds to the growing evidence base of genetic factors associated with ASDs showing links with psychiatric outcomes across childhood and into adulthood.

International audience; We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

Anxiety and depression are common mental health disorders and have a higher prevalence in females. They are modestly heritable, share genetic liability with other psychiatric disorders, and are highly heterogeneous. There is evidence that genetic liability to neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) is associated with anxiety and depression, particularly in females. We investigated sex differences in family history for neurodevelopmental and psychiatric disorders and neurodevelopmental genetic risk burden (indexed by ADHD polygenic risk scores (PRS) and rare copy number variants; CNVs) in individuals with anxiety and depression, also taking into account age at onset.We used two complementary datasets: 1) participants with a self-reported diagnosis of anxiety or depression (N=4,178, 65.5% female; mean age=41.5 years; N=1,315 with genetic data) from the National Centre for Mental Health (NCMH) cohort and 2) a clinical sample of 13,273 (67.6% female; mean age=45.2 years) patients with major depressive disorder (MDD) from the Psychiatric Genomics Consortium (PGC). We tested for sex differences in family history of psychiatric problems and presence of rare CNVs (neurodevelopmental and >500kb loci) in NCMH only and for sex differences in ADHD PRS in both datasets.In the NCMH cohort, females were more likely to report family history of neurodevelopmental and psychiatric disorders, but there were no robust sex differences in ADHD PRS or presence of rare CNVs. There was weak evidence of higher ADHD PRS in females compared to males in the PGC MDD sample, particularly in those with an early onset of MDD.These results do not provide strong evidence of sex differences in neurodevelopmental genetic risk burden in adults with anxiety and depression. This indicates that sex may not be a major index of neurodevelopmental genetic heterogeneity, that is captured by ADHD PRS and rare CNV burden, in adults with anxiety and depression.

BackgroundA recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE).MethodsThe discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8–40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses.ResultsWhen combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, β = 0.088, p = 0.02) but not for CE (R2 = 0.011, β = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10).ConclusionsWe detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.

There is increasing evidence that childhood Attention-Deficit Hyperactivity Disorder (ADHD) elevates risk of later depression, but the mechanisms behind this association are unclear. We investigated the relationship between childhood ADHD symptoms and late-adolescent depressive symptoms in a population cohort, and examined whether academic attainment and peer problems mediated this association. ALSPAC (Avon Longitudinal Study of Parents and Children) is an ongoing prospective longitudinal population-based UK cohort that has collected data since September 1990. 2950 individuals with data on parent-reported ADHD symptoms in childhood (7.5 years) and self-reported depressive symptoms in late adolescence (17.5 years) were included in analyses. 2161 individuals with additional data at age 16 years on parent-reported peer problems as an indicator of peer relationships and formal examination results (General Certificate of Secondary Education; GCSE) as an indicator of academic attainment were included in mediation analyses. Childhood ADHD symptoms were associated with higher depressive symptoms (b = 0.49, SE = 0.11, p

Objective Genomic discoveries should be investigated in generalizable child psychiatric samples in order to justify and inform studies that will evaluate their use for specific clinical purposes. In youth consecutively referred for neuropsychiatric evaluation, we examined 1) the convergent and discriminant validity of attention-deficit/hyperactivity disorder (ADHD) polygenic risk scores (PRSs) in relation to DSM-based ADHD phenotypes; 2) the association of ADHD PRSs with phenotypes beyond ADHD that share its liability and have implications for outcome; and 3) the extent to which youth with high ADHD PRSs manifest a distinctive clinical profile. Method Participants were 433 youth, ages 7–18 years, from the Longitudinal Study of Genetic Influences on Cognition. We used logistic/linear regression and mixed effects models to examine associations with ADHD-related polygenic variation from the largest ADHD genome-wide association study to date. We replicated key findings in 5,140 adult patients from a local health system biobank. Results Among referred youth, ADHD PRSs were associated with ADHD diagnoses, cross-diagnostic ADHD symptoms and academic impairment (odds ratios ∼1.4; R2 values ∼2%–3%), as well as cross-diagnostic variation in aggression and working memory. In adults, ADHD PRSs were associated with ADHD and phenotypes beyond the condition that have public health implications. Finally, youth with a high ADHD polygenic burden showed a more severe clinical profile than youth with a low burden (β coefficients ∼.2). Conclusion Among child and adolescent outpatients, ADHD polygenic risk was associated with ADHD and related phenotypes as well as clinical severity. These results extend the scientific foundation for studies of ADHD polygenic risk in the clinical setting and highlight directions for further research.

Background: Psychiatric disorders show phenotypic as well as genetic overlaps. Factor analyses of child and adult psychopathology have found that phenotypic overlaps can be largely explained by a latent general factor that reflects general liability to psychopathology. We investigated whether shared genetic liability across disorders would be reflected in associations between multiple different psychiatric polygenic risk scores (PRS) and a 'general psychopathology' factor in childhood. Methods: The sample was a UK, prospective, population-based cohort (ALSPAC), including data on psychopathology at ages 7 (N=8161) and 13 (N=7017) years. PRS were generated from large published genome-wide association studies. Results: A general psychopathology factor was associated with both schizophrenia PRS and attention-deficit/hyperactivity disorder (ADHD) PRS, whereas there was no strong evidence of association for major depressive disorder (MDD) and autism spectrum disorder PRS. Schizophrenia and MDD PRS also showed association with a specific emotional problems factor and ADHD PRS were associated with a specific neurodevelopmental factor. Conclusions: Our findings suggest that common variant genetic liability to schizophrenia and ADHD may contribute to shared genetic risks across childhood psychiatric diagnoses at least partly via association with a 'general psychopathology' factor, whereas genetic liability for MDD appears to contribute more specifically to an emotional factor in childhood.

Background Many psychiatric disorders show gender differences in prevalence. Recent studies suggest that female patients diagnosed with anxiety and depression carry more genetic risks related to attention-deficit hyperactivity disorder (ADHD) compared with affected males. Aims In this register-based study, we aimed to test whether female patients who received clinical diagnoses of anxiety, depressive, bipolar and eating disorders are at higher familial risk for ADHD and other neurodevelopmental disorders, compared with diagnosed male patients. Method We analysed data from a record-linkage of several Swedish national registers, including 151 025 sibling pairs from 103 941 unique index individuals diagnosed with anxiety, depressive, bipolar or eating disorders, as well as data from 646 948 cousin pairs. We compared the likelihood of having a relative diagnosed with ADHD/neurodevelopmental disorders in index males and females. Results Female patients with anxiety disorders were more likely than affected males to have a brother with ADHD (odd ratio (OR) = 1.13, 95% CI 1.05–1.22). Results for broader neurodevelopmental disorders were similar and were driven by ADHD diagnoses. Follow-up analyses revealed similar point estimates for several categories of anxiety disorders, with the strongest effect observed for agoraphobia (OR = 1.64, 95% CI 1.12–2.39). No significant associations were found in individuals with depressive, bipolar or eating disorders, or in cousins. Conclusions These results provide modest support for the possibility that familial/genetic risks for ADHD may show gender-specific phenotypic expression. Alternatively, there could be gender-specific biases in diagnoses of anxiety and ADHD. These factors could play a small role in the observed gender differences in prevalence of ADHD and anxiety.

BackgroundRecent case-control genetic studies of attention deficit hyperactivity disorder (ADHD) have implicated common and rare genetic risk alleles, highlighting the polygenic and complex aetiology of this neurodevelopmental disorder. Studies of other neurodevelopmental disorders, such as autism spectrum disorder (ASD), Tourette disorder, developmental delay/intellectual disability, and schizophrenia indicate that identification of specific risk alleles and additional insights into disorder biology can be gained by studying non-inherited de novo variation. In this study, we aimed to identify large de novo copy number variants (CNVs) in children with ADHD.MethodsChildren with a confirmed diagnosis of ADHD and their parents were genotyped and included in this sample. We used PennCNV to call large (>200kb) CNVs and identified those calls that were present in the proband and absent in both biological parents.ResultsIn 305 parent-offspring trios, we detected 14 de novo CNVs in 13 probands, giving a mutation rate of 4.6% and a per individual rate of 4.3%. This rate is higher than published reports in controls and similar to those observed for ASD, schizophrenia and Tourette disorder. We also identified de novo mutations at 4 genomic loci (15q13.1-13.2 duplication, 16p13.11 duplication, 16p12.2 deletion and 22q11.21 duplication) that have previously been implicated in other neurodevelopmental disorders, two of which (16p13.11 and 22q11.21) have also been implicated in case-control ADHD studies.ConclusionsOur study complements ADHD case-control genomic analyses and demonstrates the need for larger parent-offspring trio genetic studies to gain further insights into the complex aetiology of ADHD.

In youth, ADHD is more commonly diagnosed in males than females, but higher male-to-female ratios are found in clinical versus population-based samples, suggesting a sex bias in the process of receiving a clinical diagnosis of ADHD. This study investigated sex differences in the severity and presentation of ADHD symptoms, conduct problems, and learning problems in males and females with and without clinically diagnosed ADHD. We then investigated whether the predictive associations of these symptom domains on being diagnosed and treated for ADHD differed in males and females. Parents of 19,804 twins (50.64% male) from the Swedish population completed dimensional assessments of ADHD symptoms and co-occurring traits (conduct and learning problems) when children were aged 9 years. Children from this population sample were linked to Patient Register data on clinical ADHD diagnosis and medication prescriptions. At the population level, males had higher scores for all symptom domains (inattention, hyperactivity/impulsivity, conduct, and learning problems) compared to females, but similar severity was seen in clinically diagnosed males and females. Symptom severity for all domains increased the likelihood of receiving an ADHD diagnosis in both males and females. Prediction analyses revealed significant sex-by-symptom interactions on diagnostic and treatment status for hyperactivity/impulsivity and conduct problems. In females, these behaviours were stronger predictors of clinical diagnosis (hyperactivity/impulsivity: OR 1.08, 95% CI 1.01, 1.15; conduct: OR 1.43, 95% CI 1.09, 1.87), and prescription of pharmacological treatment (hyperactivity/impulsivity: OR 1.24, 95% CI 1.02, 1.50; conduct: OR 2.20, 95% CI 1.05, 4.63). Females with ADHD may be more easily missed in the ADHD diagnostic process and less likely to be prescribed medication unless they have prominent externalising problems. Electronic supplementary material The online version of this article (10.1007/s00787-018-1211-3) contains supplementary material, which is available to authorized users.

Copy number variants (CNVs) are associated with psychiatric conditions in clinical populations. The relationship between rare CNV burden and neuropsychiatric traits in young, general populations is underexplored. A total of 6,807 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) were studied. CNVs were inferred from single nucleotide polymorphism-array data using PennCNV. After excluding children with known candidate CNVs for schizophrenia (SCZ), rare (

IMPORTANCE: Subsyndromal hypomanic symptoms are relatively common in the general population and are linked to the onset of bipolar disorder. Little is known about their etiology and whether this is shared with the etiology of bipolar disorder or other mental illnesses. OBJECTIVE: To examine the genetic and environmental architecture of hypomanic symptoms in a nonclinical youth sample and compare estimates at varying severity levels and their association with diagnosed bipolar disorder. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used phenotypic and genetic data from the Child and Adolescent Twin Study in Sweden and included individuals with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis of psychiatric disorders from national registries for residents of Sweden. Associations between hypomania and polygenic risk scores for bipolar disorder, major depressive disorder and schizophrenia were also investigated. Analysis began November 2018 and ended October 2021. MAIN OUTCOMES AND MEASURES: Hypomanic symptoms were assessed using the parent-rated Mood Disorders Questionnaire when the twins were aged 18 years. Bipolar disorder diagnosis and/or lithium prescription were ascertained from national registries for residents of Sweden. Polygenic risk scores for psychiatric disorders were calculated using independent discovery genetic data. RESULTS: A total of 8568 twin pairs aged 18 years (9381 [54.7%] female) were included in the study. The hypomania heritability estimate was 59% (95% CI, 52%-64%) for male individuals and 29% (95% CI, 16%-44%) for female individuals. Unique environmental factors accounted for 41% (95% CI, 36%-47%) of the hypomania variance in male individuals and 45% (95% CI, 40%-50%) in female individuals. Shared environmental factors were only detected for female individuals and explained 26% (95% CI, 13%-38%) of the variance. The heritability estimates were fairly consistent across different hypomania severity groups. Moderate genetic (0.40; 95% CI, 0.21-0.58) and shared environmental (0.41; 95% CI, 0.03-0.75) correlations between hypomania and diagnosed bipolar disorder were found. Hypomania was significantly associated with the polygenic risk scores for schizophrenia (β = 0.08; SE = 0.026; P = .002) and major depressive disorder (β = 0.09; SE = 0.027; P = .001) but not bipolar disorder (β = 0.017; SE = 0.03; P = 0.57) (bipolar disorder I [β = 0.014; SE = 0.029; P = .64] or bipolar disorder II [β = 0.045; SE = 0.027; P = .10]). CONCLUSIONS AND RELEVANCE: Higher heritability for hypomania was found for male compared with female individuals. The results highlight the shared etiologies between hypomanic symptoms, bipolar disorder, major depression, and schizophrenia in youths. Future research should focus on identifying specific shared genetic and environmental factors. These findings support a possible dimensional model of bipolar disorder, with hypomania representing a continuous trait underlying the disorder.

The field of hospice and palliative medicine continues to grow, attracting recent graduates as well as more senior physicians looking for career changes. Unfortunately, there is little, if any, training in most residencies regarding the home hospice visit, and there are not enough fellowship-trained physicians to fill the available positions. A systematic review of the literature was made for the years 2000 to 2016 to identify articles which provided practical, clinical guidelines for the physician home hospice visit. No single article provided this needed information. Thus, the authors formulated these guidelines based on the literature and their experiences to aid the home hospice physician—as well as other providers who may work with the physician—to understand the physician’s role in the home hospice visit.

Background The high burden of infectious disease and associated antimicrobial use likely contribute to the emergence of antimicrobial resistance in remote Australian Aboriginal communities. We aimed to develop and apply context-specific tools to audit antimicrobial use in the remote primary healthcare setting. Methods We adapted the General Practice version of the National Antimicrobial Prescribing Survey (GP NAPS) tool to audit antimicrobial use over 2–3 weeks in 15 remote primary healthcare clinics across the Kimberley region of Western Australia (03/2018–06/2018), Top End of the Northern Territory (08/2017–09/2017) and far north Queensland (05/2018–06/2018). At each clinic we reviewed consecutive clinic presentations until 30 presentations where antimicrobials had been used were included in the audit. Data recorded included the antimicrobials used, indications and treating health professional. We assessed the appropriateness of antimicrobial use and functionality of the tool. Results We audited the use of 668 antimicrobials. Skin and soft tissue infections were the dominant treatment indications (WA: 35%; NT: 29%; QLD: 40%). Compared with other settings in Australia, narrow spectrum antimicrobials like benzathine benzylpenicillin were commonly given and the appropriateness of use was high (WA: 91%; NT: 82%; QLD: 65%). While the audit was informative, non-integration with practice software made the process manually intensive. Conclusions Patterns of antimicrobial use in remote primary care are different from other settings in Australia. The adapted GP NAPS tool functioned well in this pilot study and has the potential for integration into clinical care. Regular stewardship audits would be facilitated by improved data extraction systems.

There is little evidence about barriers to pain management or their relationships with pain outcomes of hospice patients with cancer. The purpose of the study was to determine the barriers reported by hospice patients with cancer and their caregivers and the relationships with demographic characteristics and the patients’ pain. In this cross-sectional study, we used selected baseline data from an ongoing randomized clinical trial of patient and lay caregiver dyads receiving home-level hospice care. Participants used an Internet-enabled tablet to complete the valid, reliable measures of pain intensity, pain management barriers (Barriers Questionnaire 13 items [BQ-13]), and demographic characteristics. The responses indicate that the 2 areas of highest concern (mean scores >3) to both patients and caregivers were “pain means disease progression” and “constipation.” Additionally, 3 other areas of highest concern (mean scores >3) to caregivers were “addiction” pain medicine causing “one to do embarrassing things” and “confusion.” The mean BQ-13 scores ranged from 0.2 to 4.9 and averaged 2.6 ± 0.9 for the patients and ranged from 0.5 to 4.7 and averaged 2.7 ± 0.9 for the caregivers. Mean barrier scores remain high and were not different between patients and their caregivers or significantly related to the patients’ pain intensity. However, there were differences in race, ethnic, and hospice setting in the barrier scores. Patients with Hispanic heritage reported higher barrier scores than non-Hispanic patients. Together, these findings not only support prior research findings but also contribute new insights about pain intensity and pain barriers that are relevant to hospices serving minorities with cancer.

Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology.

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

L’histoire des collections provenant de Russie meridionale dans les musees occidentaux demeure un sujet peu traite. En France, les musees du Louvre et d’Archeologie nationale a Saint-Germain-en-Laye integrent un mobilier archeologique provenant de ces regions essentiellement a la faveur des « devolutions » de la guerre de Crimee (1853-1856), ainsi que de l’achat d’une riche collection privee d’antiques, celle de Pierre Messaksoudy. Nous revenons ici sur les circonstances ayant preside a l’entree de ce patrimoine dans les musees francais et aux peripeties qui en accompagnent l’acquisition.

Neurodevelopmental problems (NPs) are more common in males, whereas anxiety and depression are more common in females. Rare copy number variants (CNVs) have been implicated in neurodevelopmental disorders. The aim of this study was to characterize the relationship between rare CNVs with NPs, anxiety, and depression in a childhood population sample, as well as to examine sex‐specific effects. We analyzed a sample of N = 12,982 children, of whom 5.3% had narrowly defined NPs (clinically diagnosed), 20.9% had broadly defined NPs (based on validated screening measures, but no diagnosis), and 3.0% had clinically diagnosed anxiety or depression. Rare ( 500 kb), type, and putative relevance to NPs. We tested for association of CNV categories with outcomes and examined sex‐specific effects. Medium deletions (OR[CI] = 1.18[1.05–1.33], p = .0053) and large duplications (OR[CI] = 1.45[1.19–1.75], p = .00017) were associated with broadly defined NPs. Large deletions (OR[CI] = 1.85[1.14–3.01], p = .013) were associated with narrowly defined NPs. There were no significant sex differences in CNV burden in individuals with NPs. Although CNVs were not associated with anxiety/depression in the whole sample, in individuals diagnosed with these disorders, females were more likely to have large CNVs (OR[CI] = 3.75[1.45–9.68], p = .0064). Rare CNVs are associated with both narrowly and broadly defined NPs in a general population sample of children. Our results also suggest that large, rare CNVs may show sex‐specific phenotypic effects.

Background Attention deficit hyperactivity disorder (ADHD) is more commonly diagnosed in males than in females. A growing body of research suggests that females with ADHD might be underdiagnosed or receive alternative diagnoses, such as anxiety or depression. Other lines of reasoning suggest that females might be protected from developing ADHD, requiring a higher burden of genetic risk to manifest the disorder. Methods We tested these two hypotheses, using common variant genetic data from two population‐based cohorts. First, we tested whether females and males diagnosed with anxiety or depression differ in terms of their genetic risk for ADHD, assessed as polygenic risk scores (PRS). Second, we tested whether females and males with ADHD differed in ADHD genetic risk burden. We used three different diagnostic definitions: registry‐based clinical diagnoses, screening‐based research diagnoses and algorithm‐based research diagnoses, to investigate possible referral biases. Results In individuals with a registry‐based clinical diagnosis of anxiety or depression, females had higher ADHD PRS than males [OR(CI) = 1.39 (1.12–1.73)] but there was no sex difference for screening‐based [OR(CI) = 1.15 (0.94–1.42)] or algorithm‐based [OR(CI) = 1.04 (0.89–1.21)] diagnoses. There was also no sex difference in ADHD PRS in individuals with ADHD diagnoses that were registry‐based [OR(CI) = 1.04 (0.84–1.30)], screening‐based [OR(CI) = 0.96 (0.85–1.08)] or algorithm‐based [OR(CI) = 1.15 (0.78–1.68)]. Conclusions This study provides genetic evidence that ADHD risk may be more likely to manifest or be diagnosed as anxiety or depression in females than in males. Contrary to some earlier studies, the results do not support increased ADHD genetic risk in females with ADHD as compared to affected males.

Psychiatric traits related to categorically-defined psychiatric disorders are heritable and present to varying degrees in the general population. In this study, we test the hypothesis that genetic risk factors associated with psychiatric disorders are also associated with continuous variation in milder population traits. We combine a contemporary twin analytic approach with polygenic risk score (PRS) analyses in a large population-based twin sample. Questionnaires assessing traits of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), learning difficulties, tic disorders (TD), obsessive-compulsive disorder (OCD), anxiety, major depressive disorder (MDD), mania and psychotic experiences were administered to a large, Swedish twin sample. Individuals with clinical psychiatric diagnoses were identified using the Swedish National Patient Register. Joint categorical/continuous twin modeling was used to estimate genetic correlations between psychiatric diagnoses and continuous traits. PRS for psychiatric disorders were calculated based on independent discovery genetic data. The association between PRS for each disorder and related continuous traits was tested. We found mild to strong genetic correlations between psychiatric diagnoses and corresponding traits (ranging from .31-.69) in the twin analyses. There was also evidence of association between PRS for ASD, ADHD, TD, OCD, anxiety, MDD and schizophrenia with related population traits. These results indicate that genetic factors which predispose to psychiatric disorders are also associated with milder variation in characteristic traits throughout the general population, for many psychiatric phenotypes. This finding supports the conceptualization of psychiatric disorders as the extreme ends of continuous traits.

Genetic influences play a significant role in risk for psychiatric disorders, prompting numerous endeavors to further understand their underlying genetic architecture. In this paper, we summarize and review evidence from traditional twin studies and more recent genome-wide molecular genetic analyses regarding two important issues that have proven particularly informative for psychiatric genetic research. First, emerging results are beginning to suggest that genetic risk factors for some (but not all) clinically diagnosed psychiatric disorders or extreme manifestations of psychiatric traits in the population share genetic risks with quantitative variation in milder traits of the same disorder throughout the general population. Second, there is now evidence for substantial sharing of genetic risks across different psychiatric disorders. This extends to the level of characteristic traits throughout the population, with which some clinical disorders also share genetic risks. In this review, we summarize and evaluate the evidence for these two issues, for a range of psychiatric disorders. We then critically appraise putative interpretations regarding the potential meaning of genetic correlation across psychiatric phenotypes. We highlight several new methods and studies which are already using these insights into the genetic architecture of psychiatric disorders to gain additional understanding regarding the underlying biology of these disorders. We conclude by outlining opportunities for future research in this area.

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls that identifies five genome-wide significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), seven additional loci shared with other traits are identified at equally strict significance levels. Dissecting the polygenic architecture we find both quantitative and qualitative polygenic heterogeneity across ASD subtypes, in contrast to what is typically seen in other complex disorders. These results highlight biological insights, particularly relating to neuronal function and corticogenesis and establish that GWAS performed at scale will be much more productive in the near term in ASD, just as it has been in a broad range of important psychiatric and diverse medical phenotypes.

Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder, with common genetic risk variants implicated in the clinical diagnosis and symptoms of ADHD. However, given evidence of comorbidity and genetic overlap across neurodevelopmental and externalizing conditions, it remains unclear whether these genetic risk variants are ADHD-specific. The aim of this study was to evaluate the associations between ADHD genetic risks and related neurodevelopmental and externalizing conditions, and to quantify the extent to which any such associations can be attributed to a general genetic liability towards psychopathology. We derived ADHD polygenic risk scores (PRS) for 13,460 children aged 9 and 12 years from the Child and Adolescent Twin Study in Sweden, using results from an independent meta-analysis of genome-wide association studies of ADHD diagnosis and symptoms. Associations between ADHD PRS, a latent general psychopathology factor, and six latent neurodevelopmental and externalizing factors were estimated using structural equation modelling. ADHD PRS were statistically significantly associated with elevated levels of inattention, hyperactivity/impulsivity, autistic traits, learning difficulties, oppositional-defiant, and conduct problems (standardized regression coefficients=0.07-0.12). Only the association with specific hyperactivity/impulsivity remained significant after accounting for a general psychopathology factor, on which all symptoms loaded positively (standardized mean loading=0.61, range=0.32-0.91). ADHD PRS simultaneously explained 1% (p-valuep-value

This essay demonstrates the importance of the little-known poet William Lauder to the literary culture of mid-sixteenth-century Scotland and compares his work to that of his contemporaries, David Lyndsay and Richard Maitland. It argues that Lauder’s mirror for princes, Ane Compendious and breve Tractate, Concernyng þe Office and dewtie of Kyngis, printed in 1556, combines elements of the Older Scots advisory tradition with Protestant reformist thinking. The essay compares this political ‘tractate’ to Lauder’s post-Reformation devotional poetry, which is less confident in secular authority but nevertheless adopts the interest in advice giving and adapts it to the spiritual lives of Lauder’s readers. These poems demand high standards of moral and ethical reform from their readers, and the audience’s wider engagement with scriptural texts. In encouraging reading, self-reform, and self-understanding, the poems in turn urge their audience to strive for social justice and order in the creation of a godly society.

This introductory chapter prefaces the subsequent collection of essays, dedicated to Professor Sally Mapstone. After an overview of the critical field and outline of the importance of kingship and Advice to Princes in the Older Scots literary tradition, the main body of the chapter first examines the centrality of advisory discourse in the poetry of Robert Henryson and William Dunbar, before analysing key scenes of royal reading and writing in Barbour’s Bruce, James I’s Kingis Quair, Walter Bower’s Scotichronicon, and John Shirley’s fulle lamentable cronicle of þe deþe and fals murdre of James Steward, last Kinge of Scottes. It explores both the signal relationship between themes of reading, writing, and rule, and the way in which such acts are transformed into self-consciously ethical activities. The second half of the chapter summarizes and draws together the essays that follow.

Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. We analyzed genome-wide common variants from the Psychiatric Genomics Consortium and iPSYCH Project (20,183 cases, 35,191 controls) and Swedish population-registry data (N=77,905 cases, N=1,874,637 population controls). We find strong genetic correlation for ADHD across sex and no mean difference in polygenic burden across sex. In contrast, siblings of female probands are at an increased risk of ADHD, compared to siblings of male probands. The results also suggest that females with ADHD are at especially high risk of comorbid developmental conditions. Overall, this study supports a greater familial burden of risk in females with ADHD and some clinical and etiological heterogeneity. However, autosomal common variants largely do not explain the sex bias in ADHD prevalence.

Background: Children with a diagnosis of attention-deficit hyperactivity disorder (ADHD) have lower cognitive ability and are at risk of adverse educational outcomes; ADHD genetic risks have been found to predict childhood cognitive ability and other neurodevelopmental traits in the general population; thus genetic risks might plausibly also contribute to cognitive ability later in development and to educational underachievement. Methods: We generated ADHD polygenic risk scores in the Avon Longitudinal Study of Parents and Children participants (maximum N: 6928 children and 7280 mothers) based on the results of a discovery clinical sample, a genome-wide association study of 727 cases with ADHD diagnosis and 5081 controls. We tested if ADHD polygenic risk scores were associated with educational outcomes and IQ in adolescents and their mothers. Results: High ADHD polygenic scores in adolescents were associated with worse educational outcomes at Key Stage 3 [national tests conducted at age 13–14 years; β = −1.4 (−2.0 to −0.8), P = 2.3 × 10−6), at General Certificate of Secondary Education exams at age 15–16 years (β = −4.0 (−6.1 to −1.9), P = 1.8 × 10−4], reduced odds of sitting Key Stage 5 examinations at age 16–18 years [odds ratio (OR) = 0.90 (0.88 to 0.97), P = 0.001] and lower IQ scores at age 15.5 [β = −0.8 (−1.2 to −0.4), P = 2.4 × 10−4]. Moreover, maternal ADHD polygenic scores were associated with lower maternal educational achievement [β = −0.09 (−0.10 to −0.06), P = 0.005] and lower maternal IQ [β = −0.6 (−1.2 to −0.1), P = 0.03]. Conclusions: ADHD diagnosis risk alleles impact on functional outcomes in two generations (mother and child) and likely have intergenerational environmental effects.

Attention Deficit Hyperactivity Disorder (ADHD) is a common, heritable childhood disorder that is more commonly diagnosed in males than females. Several family and molecular genetic studies suggest that females may require a higher burden of genetic risk to manifest the disorder, however the evidence for this effect is mixed and requires replication. Another possibility for the discrepancy in prevalence rate by sex is that females at high genetic risk for ADHD are routinely under-diagnosed with ADHD and instead this genetic risk manifests itself in other ways, e.g. through other diagnoses. To address these possibilities, we utilised Swedish whole population registry data and data on a subset of Swedish twins who were genotyped. In a sample of N=21,784 individuals, we found evidence that full siblings of females with diagnosed ADHD are at higher risk for an ADHD diagnosis than siblings of diagnosed males [OR=1.14 (1.11-1.18), p=1.5E-15]. However, we found no difference in ADHD polygenic risk scores (PRS) between males and females with traits of ADHD [N=1,226, OR=0.98 (0.87-1.11), p=0.70] or related neurodevelopmental disorders [N=2,719, OR=1.04 (0.96-1.13), p=0.32]. On the other hand, females diagnosed with anxiety had higher ADHD PRS than males with anxiety [N=265, OR=1.49 (1.13-1.98), p=0.0048], suggesting that genetic risk for ADHD may manifest differently in females. A replication of these analyses in a second sample will also be presented. The results of this study provide additional evidence for an increased genetic burden of ADHD risk in females diagnosed with ADHD and their relatives, although it would appear that common genetic variants may not play a substantial role. On the other hand, common variants related to ADHD appear to predispose females more than males to anxiety, which may partly explain the lower prevalence of ADHD seen in females.

Background A recent genome-wide association analysis has identified specific susceptibility variants and a substantial polygenic component for Attention-Deficit/Hyperactivity Disorder (ADHD). Given that emerging risk variants are unlikely to track precisely with conventional diagnoses, whether these discoveries will have utility in clinical settings for improved diagnostics and risk stratification requires further study. Our overall goal is to establish the relevance of emerging psychiatric genetics findings to youth clinical samples. In the current study, we aimed to 1) confirm the convergent validity of ADHD polygenic risk with ADHD-related phenotypes in youth presenting for neuropsychiatric evaluation; and 2) determine the extent to which ADHD polygenic risk associates with phenotypes beyond ADHD that putatively share its underlying liability and have implications for functional outcome. Methods Participants were 470 youth, ages 7 to 18, consecutively referred for neuropsychiatric evaluation and genotyped on the Illumina Infinium PsychArray Beadchip. Diagnoses made subsequent to study enrollment reflected a range of psychopathology and comorbidity. We determined the burden of ADHD-related common variants in these patients at different significance thresholds from the ADHD PGC-iPSYCH meta-analysis. We then associated this polygenic risk with clinical phenotypes. First, we conducted univariate analyses relating ADHD polygenic risks scores (PRSs) to ADHD diagnoses (none/borderline/full) and symptoms, cognition, and dimensional ratings of aggression and mania. Second, we stratified youth by low, medium, and high ADHD polygenic burden and used a mixed modeling approach to determine whether risk strata associated with distinct multivariate clinical profiles. Third, we determined phenotypically distinct latent classes in these and other youth (N~900) based on eight dimensional measures of psychopathology and examined whether the ADHD-PRS discriminated among them. Results The ADHD-PRS predicted the ADHD diagnosis at seven discovery sample thresholds after correction for potential confounds and multiple testing. The strongest association occurred at discovery sample p Discussion In a multi-diagnostic clinical sample, ADHD polygenic risk showed convergent validity with ADHD phenotypes. Genotype- and phenotype-first analyses also indicated that ADHD polygenic burden associates with traits reflecting cognition and behavioral and emotional dysregulation that extend beyond ADHD and that have implications for functional outcome.

199 Background: The Commission on Cancer (CoC) Standard 3.2 requires distress screening and indicated action for cancer patients. NCCN and ASCO supportive care and age-related guidelines include patient reported concerns beyond distress. This study compares PHQ4 scores to other patient reported concerns. Methods: The Coleman Supportive Oncology Collaborative aggregated “best of” screening tools to assess patient reported needs and concerns aligned with CoC, NCCN and ASCO guidance. This supportive care screening tool was implemented at 8 sites from July 2015 thru July 2018. Analysis used chi squared test. Results: Most patients, 86% (10,635/12,295), reported one plus concerns and/or above threshold scores on PHQ4, PROMIS Pain, Fatigue or Physical Function. A chi squared comparison of patients with at least mild distress on PHQ4 to patients with no distress resulted in p values < .0001 for every screening category. Conclusions: Patients with a PHQ4 distress score of mild, moderate or severe also reported statistically significant levels of practical, family, physical, nutrition and treatment concerns. These patients also scored threshold levels for PROMIS Pain, Fatigue, and Physical Function. Screening only for distress without screening for other patient concerns may direct patients to services that do not address or focus on the underlying cause of the distress. [Table: see text]

33 Background: The Institute of Medicine and Commission on Cancer recommend systematic delivery of supportive oncology care for cancer patients. The CSOC is focused on quality improvement (QI) of supportive care across Chicago cancer centers (Weldon ASCO ’17). Supportive oncology includes distress, practical, family, physical, nutrition, pain, fatigue and care concerns. To support QI, cross-institution teams developed unique, relevant tools, methods, care delivery processes, patient handouts and online training. Methods: Ten centers (5 academic, 1 VA, 1 public, 2 safety net, 1 community) implemented supportive oncology screening and care delivery quality improvements. Centers collected data for relevant Quality Oncology Practice Initiative (QOPI) metrics. Analyses used simple frequencies and Fishers exact test. Results: Five of six QOPI measures were improved at statistically significant levels from 2014 to 2017, p < .00001. Improvements are more modest in 2016 & 2017 as 4 of the centers started this QI in 2017. Conclusions: The CSOC achieved significant improvements in supportive oncology screening and identifying and addressing patients’ needs and concerns. Additional work is needed to improve these measures to achieve the best quality of cancer care possible for every patient based on their needs and concerns. [Table: see text]

This study assesses the association of the genetic risk for psychiatric disorders with population traits of these disorders in Sweden., Key Points Question Are genetic risks for psychiatric disorders associated with subclinical population traits of these disorders? Findings Phenotype data were available for 13 923 twin pairs at 9 years of age, 5165 pairs at 15 years of age, and 4273 pairs at 18 years of age, and genetic data were available for 13 412 individuals. Genetic risk factors for psychiatric disorders were associated with risk factors for subclinical traits; polygenic risk scores for psychiatric disorders were also significantly associated with subclinical traits. Meaning The findings suggest that psychiatric disorders are associated with continuously distributed genetic risks throughout the general population., Importance Psychiatric traits associated with categorically defined psychiatric disorders are heritable and present to varying degrees in the general population. It is commonly assumed that diagnoses represent the extreme end of continuously distributed traits in the population, but this assumption has yet to be robustly tested for many psychiatric phenotypes. Objective To assess whether genetic risk factors associated with psychiatric disorders are also associated with continuous variation in milder population traits. Design, Setting, and Participants This study combined a novel twin analytic approach with polygenic risk score (PRS) analyses in a large population-based twin sample. Phenotypic and genetic data were available from the Child and Adolescent Twin Study in Sweden. Inpatient data were available for January 1, 1987, to December 31, 2014, and outpatient data for January 1, 2001, to December 31, 2013. The last day of follow-up was December 31, 2014. Data analysis was performed from January 1, 2017, to September 30, 2017. Main Outcomes and Measures Questionnaires that assessed traits of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), learning difficulties, tic disorders (TDs), obsessive-compulsive disorder (OCD), anxiety, major depressive disorder (MDD), mania, and psychotic experiences were administered to a large Swedish twin sample. Individuals with clinical psychiatric diagnoses were identified using the Swedish National Patient Register. Joint categorical/continuous twin modeling was used to estimate genetic correlations between psychiatric diagnoses and continuous traits. The PRSs for psychiatric disorders were calculated based on independent discovery genetic data. The association between PRSs for each disorder and associated continuous traits was tested. Results Phenotype data were available for 13 923 twin pairs (35.1% opposite sex and 31.7% same-sex females) at 9 years of age, 5165 pairs (36.9% opposite sex and 34.0% same-sex females) at 15 years of age, and 4273 pairs (36.5% opposite sex and 34.4% same-sex females) at 18 years of age. Genetic data were available for 13 412 individuals (50.2% females). Twin genetic correlations between numerous psychiatric diagnoses and corresponding traits ranged from 0.31 to 0.69. Disorder PRSs were associated with related population traits for ASD (β [SE] = 0.04 [0.01] at 9 years of age), ADHD (β [SE] = 0.27 [0.03] at 9 years of age), TDs (β [SE] = 0.02 [0.004] at 9 years of age), OCD (β [SE] = 0.13 [0.05] at 18 years of age), anxiety (β [SE] = 0.18 [0.08] at 9 years of age; β [SE] = 0.07 [0.02] at 15 years of age; and β [SE] = 0.40 [0.17] at 18 years of age), MDD (β [SE] = 0.10 [0.03] at 9 years of age; β [SE] = 0.11 [0.02] at 15 years of age; and β [SE] = 0.41 [0.10] at 18 years of age), and schizophrenia (β [SE] = 0.02 [0.01] at 18 years of age). Polygenic risk scores for depressive symptoms were associated with MDD diagnoses (odds ratio, 1.16; 95% CI, 1.02-1.32). Conclusions and Relevance These results suggest that genetic factors associated with psychiatric disorders are also associated with milder variation in characteristic traits throughout the general population for many psychiatric phenotypes. This study suggests that many psychiatric disorders are likely to be continuous phenotypes rather than the categorical entities currently defined in diagnostic manuals, which has strong implications for genetic research in particular.

BackgroundThere is recent evidence of some degree of shared genetic susceptibility between adult schizophrenia and childhood attention-deficit hyperactivity disorder (ADHD) for rare chromosomal variants.AimsTo determine whether there is overlap between common alleles conferring risk of schizophrenia in adults with those that do so for ADHD in children.MethodWe used recently published Psychiatric Genome-wide Association Study (GWAS) Consortium (PGC) adult schizophrenia data to define alleles over-represented in people with schizophrenia and tested whether those alleles were more common in 727 children with ADHD than in 2067 controls.ResultsSchizophrenia risk alleles discriminated ADHD cases from controls (P = 1.04 × 104, R2 = 0.45%); stronger discrimination was given by alleles that were risk alleles for both adult schizophrenia and adult bipolar disorder (also derived from a PGC data-set) (P = 9.98 ×10−6, R2 × 0.59%).ConclusionsThis increasing evidence for a small, but significant, shared genetic susceptibility between adult schizophrenia and childhood ADHD highlights the importance of research work across traditional diagnostic boundaries.

OBJECTIVE Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. METHOD Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. RESULTS Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. CONCLUSIONS Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity. OBJECTIVE Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. METHOD Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. RESULTS Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. CONCLUSIONS Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.

This purpose of this article is to describe how we adhere to the Patient-Centered Outcomes Research Institute’s (PCORI) methodology standards relevant to the design and implementation of our PCORI-funded study, the PAIN RelieveIt Trial. We present details of the PAIN RelieveIt Trial organized by the PCORI methodology standards and components that are relevant to our study. The PAIN RelieveIt Trial adheres to four PCORI standards and 21 subsumed components. The four standards include standards for formulating research questions, standards associated with patient centeredness, standards for data integrity and rigorous analyses, and standards for preventing and handling missing data. In the past 24 months, we screened 2,837 cancer patients and their caregivers; 874 dyads were eligible; 223.5 dyads consented and provided baseline data. Only 55 patients were lost to follow-up—a 25% attrition rate. The design and implementation of the PAIN RelieveIt Trial adhered to PCORI’s methodology standards for research rigor.

Psychiatric disorders are highly heritable and polygenic, with numerous common genetic risk variants implicated. Twin and molecular genetic studies suggest that some clinically diagnosed psychiatric disorders (e.g. attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD)) share genetic risk with quantitative variation in milder traits of the same disorder throughout the general population. We utilized the latest emerging results from genome-wide association studies (GWAS) of 8 psychiatric disorders to test for genetic overlap across each of these clinically diagnosed psychiatric disorders and related continuously distributed population traits. GWAS summary statistics for 8 psychiatric phenotypes were used to derive polygenic risk scores (PRS) in a Swedish population of twins (N=13,472 individuals) with data available at ages 9, 12, 15 and 18 years (Child & Adolescent Twin Study in Sweden). We tested for association between PRS for a given psychiatric disorder with traits related to the same disorder, assessed using parent- and self-report questionnaires. After applying a false discovery rate to account for multiple testing, the results showed support for a significant association between PRS for psychiatric disorder with corresponding childhood population traits for the following phenotypes: ADHD (beta(SE)=0.278(0.0295), p=6.8E-20), ASD (beta(SE)=0.0366(0.0137), p=0.019), tic disorders (beta(SE)=0.0126(0.00387), p=0.0063), depression (beta(SE)=0.273(0.105), p=0.021), anxiety disorders (beta(SE)=0.202(0.0795), p=0.023), Obsessive Compulsive Disorder(OCD; beta(SE)=0.122(0.0447), p=0.019) and schizophrenia (beta(SE)=0.0561(0.0208), p=0.019). No association was seen for bipolar disorder PRS and adolescent mania symptoms. Results persisted after excluding individuals with relevant ICD diagnoses from analyses. This study provides evidence for shared genetic risks across clinical disorder and corresponding population traits assessed in childhood, for a range of psychiatric conditions. The results support the hypothesis that psychiatric disorders are the extreme ends of continuous distributions of population traits.