Risk for emerging bipolar disorder,variants, and symptoms in children with attention deficit hyperactivity disorder,now grown up

AIM: To determine the prevalence of bipolar disorder (BD) and sub-threshold symptoms in children with attention deficit hyperactivity disorder (ADHD) through 14 years’ follow-up, when participants were between 21-24 years old.METHODS: First, we examined rates of BD type I and II diagnoses in youth participating in the NIMH-funded Multimodal Treatment Study of ADHD (MTA). We used the diagnostic interview schedule for children (DISC), administered to both parents (DISC-P) and youth (DISCY). We compared the MTA study subjects with ADHD (n = 579) to a local normative comparison group (LNCG, n = 289) at 4 different assessment points: 6, 8, 12, and 14 years of follow-ups. To evaluate the bipolar variants, we compared total symptom counts (TSC) of DSM manic and hypomanic symptoms that were generated by DISC in ADHD and LNCG subjects. Then we sub-divided the TSC into pathognomonic manic (PM) and non-specific manic (NSM) symptoms. We compared the PM and NSM in ADHD and LNCG at each assessment point and over time. We also evaluated the irritability as category A2 manic symptom in both groups and over time. Finally, we studied the irritability symptom in correlation with PM and NSM in ADHD and LNCG subjects.RESULTS: DISC-generated BD diagnosis did not differ significantly in rates between ADHD (1.89%) and LNCG 1.38%). Interestingly, no participant met BD diagnosis more than once in the 4 assessment points in 14 years. However, on the symptom level, ADHD subjects reported significantly higher mean TSC scores: ADHD 3.0; LNCG 1.7; P < 0.001. ADHD status was associated with higher mean NSM: ADHD 2.0 vs LNCG 1.1; P < 0.0001. Also, ADHD subjects had higher PM symptoms than LNCG, with PM means over all time points of 1.3 ADHD; 0.9 LNCG; P = 0.0001. Examining both NSM and PM, ADHD status associated with greater NSM than PM. However, Over 14 years, the NSM symptoms declined and changed to PM over time (df 3, 2523; F = 20.1; P < 0.0001). Finally, Irritability (BD DSM criterion-A2) rates were significantly higher in ADHD than LNCG (χ² = 122.2, P < 0.0001), but irritability was associated more strongly with NSM than PM (df 3, 2538; F = 43.2; P < 0.0001).CONCLUSION: Individuals with ADHD do not appear to be at significantly greater risk for developing BD, but do show higher rates of BD symptoms, especially NSM. The greater linkage of irritability to NSM than to PM suggests caution when making BD diagnoses based on irritability alone as one of 2 (A-level) symptoms for BD diagnosis, particularly in view of its frequent presentation with other psychopathologies.     

The Relationship of Attention-Deficit/Hyperactivity Disorder With Posttraumatic Stress Disorder: A Two-Sample Mendelian Randomization and Population-Based Sibling Comparison Study

BackgroundAttention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship.MethodsLinkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (r_g) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons).ResultsADHD and PTSD had consistent r_g (r_g range, 0.43–0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (β = 0.367; 95% CI, 0.186–0.552; p = 7.68 × 10^?5). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10^?4, p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98–3.53).ConclusionsOur findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.     

Genetic Overlap Between Measures of Hyperactivity/Inattention and Mood in Children and Adolescents

ObjectiveEvidence suggests that there is substantial comorbidity between attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder in childhood and adolescence. This study aims to investigate the degree to which etiological factors are shared between the symptoms of these significantly heritable disorders.MethodA twin study design was used to determine to what extent the covariation between the traits of ADHD and depression is genetically or environmentally mediated, based on parental reports. A general community sample of 645 twin pairs aged 5 to 17 years from the Cardiff Study of All Wales and North England Twins project took part in the study. Parent-rated measures of hyperactivity/inattention (Abbreviated Conners Hyperactivity subscale) and depression (Short Mood and Feelings Questionnaire).ResultsPhenotypes derived from the scales were significantly correlated in both boys and girls. Bivariate structural equation modeling revealed a large overlap in underlying genetic factors (boys, r_A = 0.77; girls, r_A = 0.67) along with a smaller influence of nonshared environment.ConclusionsThese findings suggest that there are common genes conferring liability to both hyperactive/inattentive and depressive traits in children and adolescents. This has implications for future molecular genetic research into ADHD and major depressive disorder. Additionally, it indicates that the comorbid clinical presentation of these disorders may reflect a common genetic pathway. J. Am. Acad. Child Adolesc. Psychiatry, 2009;48(11):1094–1101.     

Genetic factors underlying the bidirectional relationship between autoimmune and mental disorders – Findings from a Danish population-based study

BackgroundPrevious studies have indicated the bidirectionality between autoimmune and mental disorders. However, genetic studies underpinning the co-occurrence of the two disorders have been lacking. In this study, we examined the potential genetic contribution to the association between autoimmune and mental disorders and investigated the genetic basis of overall autoimmune disease.MethodsWe used diagnostic information from patients with seven autoimmune diseases and six mental disorders from the Danish population-based case-cohort sample (iPSYCH2012). We explored the epidemiological association using survival analysis and modelled the effect of polygenic risk scores (PRSs) on autoimmune and mental diseases. Genetic factors were investigated using GWAS and imputed HLA alleles in the iPSYCH cohort.ResultsOf 64,039 individuals, a total of 43,902 (68.6%) were diagnosed with mental disorders and 1383 (2.2%) with autoimmune diseases. There was a significant comorbidity between the two disease classes (P = 2.67 × 10⁻⁷, OR = 1.38, 95%CI = 1.22–1.56), with an overall bidirectional association, wherein individuals with autoimmune diseases had an increased risk of subsequent mental disorders (HR = 1.13, 95%CI: 1.07–1.21, P = 7.95 × 10⁻⁵) and vice versa (HR = 1.27, 95%CI = 1.16–1.39, P = 8.77 × 10⁻¹⁵). Adding PRSs to these adjustment models did not have an impact on the associations. PRSs for autoimmune diseases were only slightly associated with increased risk of mental disorders (HR = 1.01, 95%CI: 1.00–1.02, p = 0.038), whereas PRSs for mental disorders were not associated with autoimmune diseases overall. Our GWAS highlighted 12 loci on chromosome 6 (minimum P = 2.74 × 10⁻³⁶, OR = 1.80, 95% CI: 1.64–1.96), which were implicated in gene regulation through bioinformatic functional analyses, thereby identifying new candidate genes for overall autoimmune disease. Moreover, we observed 20 human leukocyte antigen (HLA) alleles strongly associated, either positively or negatively, with overall autoimmune disease, but we did not find significant evidence of their associations with overall mental disorders. A GWAS of a comorbid diagnosis of an autoimmune disease and a mental disorder identified a genome-wide significant locus on chromosome 7 as well (P = 1.43 × 10⁻⁸, OR = 10.65, 95%CI = 3.21–35.36).ConclusionsOur findings confirm the overall comorbidity and bidirectionality between autoimmune diseases and mental disorders and identify HLA genes which are significantly associated with overall autoimmune disease. Additionally, we identified several new candidate genes for overall autoimmune disease and ranked them based on their association with the investigated diseases.     

The relative contribution of common and rare genetic variants to ADHD

Attention deficit hyperactivity disorder (ADHD) is highly heritable. Genome-wide molecular studies show an increased burden of large, rare copy-number variants (CNVs) in children with ADHD compared with controls. Recent polygenic risk score analyses have also shown that en masse common variants are enriched in ADHD cases compared with population controls. The relationship between these common and rare variants has yet to be explored. In this study, we tested whether children with ADHD with (N=60) a large (>500 kb), rare (<1% frequency) CNV differ by polygenic risk scores for ADHD to children with ADHD without such CNVs (N=421). We also compared ADHD polygenic scores in ADHD children with and without CNVs with a group of population controls (N=4670; of whom N=397 had CNVs). The results show that children with ADHD with large, rare CNVs have lower polygenic scores than children without such CNVs (odds ratio (OR)=0.73, P=0.023). Although ADHD children without CNVs had higher scores than controls (OR=1.18, P=0.0031), this difference was not observed for ADHD children with CNVs (OR=0.86, P=0.27). These results are consistent with a polygenic liability threshold model of ADHD with both common and rare variants involved.     

Candidate system analysis in ADHD: Evaluation of nine genes involved in dopaminergic neurotransmission identifies association with DRD1

Abstract

Objectives. Several pharmacological and genetic studies support the involvement of the dopamine neurotransmitter system in the aetiology of attention-deficit hyperactivity disorder (ADHD). Based on this information we evaluated the contribution to ADHD of nine genes involved in dopaminergic neurotransmission (DRD1, DRD2, DRD3, DRD4, DRD5, DAT1, TH, DBH and COMT). Methods. We genotyped a total of 61 tagging single nucleotide polymorphisms (SNPs) in a sample of 533 ADHD patients (322 children and 211 adults), 533 sex-matched unrelated controls and additional 196 nuclear ADHD families from Spain. Results. The single- and multiple-marker analysis in both population and family-based approaches provided preliminary evidence for the contribution of DRD1 to combined-type ADHD in children (P = 8.8e-04; OR = 1.50 (1.18–1.90) and P = 0.0061; OR = 1.73 (1.23–2.45)) but not in adults. Subsequently, we tested positive results for replication in an independent sample of 353 German families with combined-type ADHD children and replicated the initial association between DRD1 and childhood ADHD (P = 8.4e-05; OR = 3.67 (2.04–6.63)). Conclusions: The replication of the association between DRD1 and ADHD in two European cohorts highlights the validity of our finding and supports the involvement of DRD1 in childhood ADHD.     

A Shared Genetic Propensity Underlies Experiences of Bullying Victimization in Late Childhood and Self-Rated Paranoid Thinking in Adolescence

Background: Bullying is a risk factor for developing psychotic experiences (PEs). Whether bullying is associated with particular PEs, and the extent to which genes and environments influence the association, are unknown. This study investigated which specific PEs in adolescence are associated with earlier bullying victimization and the genetic and environmental contributions underlying their association. Method: Participants were 4826 twin pairs from a longitudinal community-based twin study in England and Wales who reported on their bullying victimization at the age of 12 years. Measures of specific PEs (self-rated Paranoia, Hallucinations, Cognitive disorganization, Grandiosity, Anhedonia, and parent-rated Negative Symptoms) were recorded at age of 16 years. Results: Childhood bullying victimization was most strongly associated with Paranoia in adolescence (r = .26; P < .01), with weaker associations with Hallucinations, Cognitive Disorganization, parent-rated Negative Symptoms (r = .12–.20; P < .01), Grandiosity (r = .04; P < .05), and Anhedonia (r = .00, n.s.). Bivariate twin model-fitting demonstrated that bullying victimization and Paranoia were both heritable (35% and 52%, respectively) with unique environmental influences (39% and 48%, respectively), and bullying victimization showed common environmental influences (26%). The association between bullying victimization and Paranoia operated almost entirely via genetic influences (bivariate heritability = 93%), with considerable genetic overlap (genetic correlation = .55). Conclusion: In contrast to the assumed role of bullying victimization as an environmental trigger, these data suggest that bullying victimization in late childhood is particularly linked to self-rated Paranoia in adolescence via a shared genetic propensity. Clinically, individuals with a history of bullying victimization are predicted to be particularly susceptible to paranoid symptoms.Key words: bullying victimization, psychotic experiences, twin study, paranoia     

Functional genomics indicate that schizophrenia may be an adult vascular-ischemic disorder

In search for the elusive schizophrenia pathway, candidate genes for the disorder from a discovery sample were localized within the energy-delivering and ischemia protection pathway. To test the adult vascular-ischemic (AVIH) and the competing neurodevelopmental hypothesis (NDH), functional genomic analyses of practically all available schizophrenia-associated genes from candidate gene, genome-wide association and postmortem expression studies were performed. Our results indicate a significant overrepresentation of genes involved in vascular function (P<0.001), vasoregulation (that is, perivascular (P<0.001) and shear stress (P<0.01), cerebral ischemia (P<0.001), neurodevelopment (P<0.001) and postischemic repair (P<0.001) among schizophrenia-associated genes from genetic association studies. These findings support both the NDH and the AVIH. The genes from postmortem studies showed an upregulation of vascular-ischemic genes (P=0.020) combined with downregulated synaptic (P=0.005) genes, and ND/repair (P=0.003) genes. Evidence for the AVIH and the NDH is critically discussed. We conclude that schizophrenia is probably a mild adult vascular-ischemic and postischemic repair disorder. Adult postischemic repair involves ND genes for adult neurogenesis, synaptic plasticity, glutamate and increased long-term potentiation of excitatory neurotransmission (i-LTP). Schizophrenia might be caused by the cerebral analog of microvascular angina.     

The Canadian 24-Hour Movement Guidelines and Psychological Distress among Adolescents: Les Directives canadiennes en matière de mouvement sur 24 heures et la détresse psychologique chez les adolescents

Objective:The Canadian 24-Hour Movement Guidelines for Children and Youth recommend at least 60 minutes of physical activity per day, 2 hours or less of recreational screen time per day, and 9 to 11 hours of sleep per night for 5 to 13 years old and 8 to 10 hours per night for 14 to 17 years old. This study examined the association between meeting these guidelines and psychological distress among adolescents.Methods:The present cross-sectional sample included 6,364 students aged 11 to 20 years from the 2017 Ontario Student Drug Use and Health Survey. This provincially representative school-based survey is based on a 2-stage cluster design. A confirmatory factor analysis (CFA) was first conducted to confirm the factor structure of the K6, and structural equation modeling adjusted for age, sex, ethnoracial background, subjective socioeconomic status, and body mass index z-score was used to investigate the association between meeting the 24-Hour Movement Guidelines and K6 factors among adolescents.Results:The CFA demonstrated that a 2-factor model (representing anxiety and depressive symptoms) of the K6 fit the data well. The anxiety and depression items demonstrated a composite reliability (Cronbach’s α) of 0.86 and 0.83, respectively, indicating a high level of internal consistency. Compared to meeting none of the recommendations, meeting all 3 movement behavior recommendations was associated with lower anxiety (β = −0.076; P = 0.028) and depressive symptoms (β = −0.067; P = 0.028). Meeting the screen time + sleep duration recommendations had the strongest association with anxiety (β = −0.157; P < 0.001) and depressive symptoms (β = −0.139; P < 0.001), followed by meeting the sleep duration recommendation only for both anxiety (β = −0.135; P < 0.001) and depressive symptoms (β = −0.106; P < 0.001).Conclusions:Meeting the 24-Hour Movement Guidelines was associated with lower anxiety and depressive symptoms among adolescents, and these associations appear mainly driven by meeting the sleep duration recommendation.     

Sexual maturation among youth with ADHD and the impact of stimulant medication

Objective

Evaluate the differences in achieving puberty between ADHD and non-ADHD participants and the effects of medication on that process among ADHD participants.

Procedure

A subset of participants with ADHD from the Multimodal Treatment study of ADHD (n = 342) were compared with respect to Tanner staging to participants from a comparison group without ADHD (n = 159) at the 36-month follow-up assessment. Further comparisons were made for Tanner stages and Auxology of the participants in the ADHD group who were always (n = 61), never (n = 56), newly (n = 74) and inconsistently (n = 116) treated with stimulants.

Results

No statistically significant differences in Tanner stages of sexual development were found between the ADHD and non-ADHD groups at the age of assessment (between 10 and 14 years of age) or among the ADHD medication subgroups, although a trend was observed for stimulant-associated delayed pubertal initiation using auxological analysis.

Conclusion

Children with or without ADHD did not differ in Tanner stages at the 3-year follow-up assessment, and exposure to stimulant medication does not appear to affect sexual development within this age range.     

Genome-wide association of mood-incongruent psychotic bipolar disorder

Mood-incongruent psychotic features (MICP) are familial symptoms of bipolar disorder (BP) that also occur in schizophrenia (SZ), and may represent manifestations of shared etiology between the major psychoses. In this study we have analyzed three large samples of BP with imputed genome-wide association data and have performed a meta-analysis of 2196 cases with MICP and 8148 controls. We found several regions with suggestive evidence of association (P<10^–6), although no marker met genome-wide significance criteria. The top associations were on chromosomes: 6q14.2 within the PRSS35/SNAP91 gene complex (rs1171113, P=9.67 × 10^–8); 3p22.2 downstream of TRANK/LBA1 (rs9834970, P=9.71 × 10^–8); and 14q24.2 in an intron of NUMB (rs2333194, P=7.03 × 10^–7). These associations were present in all three samples, and both rs1171113 and rs2333194 were found to be overrepresented in an analysis of MICP cases compared with all other BP cases. To test the relationship of MICP with SZ, we performed polygenic analysis using the Psychiatric GWAS Consortium SZ results and found evidence of association between SZ polygenes and the presence of MICP in BP cases (meta-analysis P=0.003). In summary, our analysis of the MICP phenotype in BP has provided suggestive evidence for association of common variants in several genes expressed in the nervous system. The results of our polygenic analysis provides support for a modest degree of genetic overlap between BP with MICP and SZ, highlighting that phenotypic correlations across syndromes may be due to the influence of polygenic risk factors.     

Comorbid ADHD and DCD: examining cognitive functions using the WISC-IV

This study explored the cognitive performance of children with Attention Deficit/Hyperactivity Disorder (ADHD) and/or Developmental Coordination Disorder (DCD) using the Wechsler Intelligence Scale for Children-IV. Participants were 62 children with ages between 9 years 8 months and 12 years 7 months. These children were placed into one of the four groups: Comparison (n = 26), ADHD (n = 14), DCD (n = 11), and ADHD + DCD (n = 11) groups. The ADHD symptoms were assessed using the Australian Disruptive Behaviours Scale, and motor ability was assessed using the McCarron Assessment of Neuromuscular Development (MAND). Significantly poorer perceptual reasoning ability was seen in DCD and ADHD + DCD groups but not in the ADHD group. The findings provide evidence that a deficit in visuo-spatial ability may underlie DCD but not ADHD. These findings revealed different cognitive profiles for ADHD and/or DCD, thus the current study does not lend support to the common aetiology hypothesis in understanding the basis of ADHD and DCD comorbidity.     

A potential association of RNF219-AS1 with ADHD: Evidence from categorical analysis of clinical phenotypes and from quantitative exploration of executive function and white matter microstructure endophenotypes

AimsAttention‐deficit/hyperactivity disorder (ADHD) is a neuropsychiatric disorder of substantial heritability, yet emerging evidence suggests that key risk variants might reside in the noncoding regions of the genome. Our study explored the association of lncRNAs (long noncoding RNAs) with ADHD as represented at three different phenotypic levels guided by the Research Domain Criteria (RDoC) framework: (i) ADHD caseness and symptom dimension, (ii) executive functions as functional endophenotype, and (iii) potential genetic influence on white matter architecture as brain structural endophenotype.MethodsGenotype data of 107 tag single nucleotide polymorphisms (SNP) from 10 candidate lncRNAs were analyzed in 1040 children with ADHD and 630 controls of Chinese Han descent. Executive functions including inhibition and set‐shifting were assessed by STROOP and trail making tests, respectively. Imaging genetic analyses were performed in a subgroup of 33 children with ADHD and 55 controls using fractional anisotropy (FA).ResultsOne SNP rs3908461 polymorphism in RNF219‐AS1 was found to be significantly associated with ADHD caseness: with C‐allele detected as the risk genotype in the allelic model (P = 8.607E‐05) and dominant genotypic model (P = 9.628E‐05). Nominal genotypic effects on inhibition (p = 0.020) and set‐shifting (p = 0.046) were detected. While no direct effect on ADHD core symptoms was detected, mediation analysis suggested that SNP rs3908461 potentially exerted an indirect effect through inhibition function [B = 0.21 (SE = 0.12), 95% CI = 0.02‐0.49]. Imaging genetic analyses detected significant associations between rs3908461 genotypes and FA values in corpus callosum, left superior longitudinal fasciculus, left posterior limb of internal capsule, left posterior thalamic radiate (include optic radiation), and the left anterior corona radiate (P _{FWE corrected} < 0.05).ConclusionOur present study examined the potential roles of lncRNA in genetic etiological of ADHD and provided preliminary evidence in support of the potential RNF219‐AS1 involvement in the pathophysiology of ADHD in line with the RDoC framework.     

Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans

BackgroundSchizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world’s population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. MethodsWe performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. ResultsOur primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10^–30) and African American (P < .0005) participants in CSP #572. ConclusionsWe have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.     

Genetic Risk for Conduct Disorder Symptom Subtypes in an ADHD Sample: Specificity to Aggressive Symptoms

ObjectiveRecent studies have suggested an association between candidate genes (i.e., COMT, SLC6A4) and conduct disorder (CD). However, it is not clear if these relations extend to CD within the context of attention-deficit/hyperactivity disorder (ADHD). Also, it is uncertain whether the risk is specific to aggressive symptoms or is a risk for CD generally. The aim of this study was to examine the role of the COMT and SLC6A4 genes in the risk for CD and its symptomatic subtypes in the context of ADHD.MethodWe examined subjects with ADHD (n = 444, age range 6–55 years) aggregated across four completed studies. Psychiatric diagnoses were determined by structured interviews. We tested the association between genotype and the diagnosis of CD and aggressive and covert symptom counts.ResultsThere was no significant association between variations in functional polymorphisms of either the COMT gene or the SLC6A4 gene and the risk for CD. The COMT gene was associated with increased aggressive CD symptoms but not covert CD symptoms. The SLC6A4 gene was not associated with either symptom subtype.ConclusionsThese findings contribute to our understanding of the genetic basis of antisocial behavior in the ADHD population and provide additional support for the notion that aggressive and covert CD symptom subtypes are etiologically distinct.     

Associations of DNA Methylation With Behavioral Problems,Gray Matter Volumes,and Negative Life Events Across Adolescence: Evidence From the Longitudinal IMAGEN Study

BackgroundNegative life events (NLEs) increase the risk for externalizing behaviors (EBs) and internalizing behaviors (IBs) in adolescence and adult psychopathology. DNA methylation associated with behavioral problems may reflect this risk and long-lasting effects of NLEs.MethodsTo identify consistent associations between blood DNA methylation and EBs or IBs across adolescence, we conducted longitudinal epigenome-wide association studies (EWASs) using data from the IMAGEN cohort, collected at ages 14 and 19 years (n = 506). Significant findings were validated in a separate subsample (n = 823). Methylation risk scores were generated by 10-fold cross-validation and further tested for their associations with gray matter volumes and NLEs.ResultsNo significant findings were obtained for the IB-EWAS. The EB-EWAS identified a genome-wide significant locus in a gene linked to attention-deficit/hyperactivity disorder (ADHD) (IQSEC1, cg01460382; p = 1.26 × 10^?8). Other most significant CpG sites were near ADHD-related genes and enriched for genes regulating tumor necrosis factor and interferon-γ signaling, highlighting the relevance of EB-EWAS findings for ADHD. Analyses with the EB methylation risk scores suggested that it partly reflected comorbidity with IBs in late adolescence. Specific to EBs, EB methylation risk scores correlated with smaller gray matter volumes in medial orbitofrontal and anterior/middle cingulate cortices, brain regions known to associate with ADHD and conduct problems. Longitudinal mediation analyses indicated that EB-related DNA methylation were more likely the outcomes of problematic behaviors accentuated by NLEs, and less likely the epigenetic bases of such behaviors.ConclusionsOur findings suggest that novel epigenetic mechanisms through which NLEs exert short and longer-term effects on behavior may contribute to ADHD.     

Composition of treatment alliance in bipolar disorder: A cross-sectional study of patients’ perspectives

BACKGROUNDTreatment alliance has an impact on several key patient outcomes in all psychiatric disorders, including bipolar disorder (BD). It has been suggested that the construct of treatment alliance is different among patients from routine psychiatric settings compared to psychotherapeutic settings. However, research on the composition of treatment alliance in psychiatric disorders, such as BD, is relatively limited.AIMTo determine whether a broader construct of treatment alliance was prevalent among outpatients with BD.METHODSThis is a cross-sectional study, conducted in the psychiatric unit of a multi-specialty hospital in north India over 12 mo (September 2018 to September 2019). A consecutive sample of 160 remitted adult outpatients with BD on mood stabilizers for at least a year were selected. The principal instrument to assess treatment alliance was the Working Alliance Inventory-client version (WAI-Client). Other potential constituents of the alliance explored were perceived trust in clinicians assessed by the Trust in Physicians (TRIP) scale, perceived support from clinicians assessed by the Psychosocial Care by Physicians (PCP) scale, and perceived treatment satisfaction assessed by the Patient Satisfaction Questionnaire (PSQ). Associations between scores on all scales were determined by correlational and multiple regression analyses. Exploratory factor analysis of combined items of all scales was conducted using a principal components analysis.RESULTSScores on all the three WAI-Client subscales were significantly correlated with each other (r = 0.66-0.81; P < 0.0001). The total TRIP scores were associated with the total WAI-Client scores (r = 0.28; P < 0.01). The total TRIP scores and the total PCP scores were also significantly associated with the WAI-Client scores on the Task subscale (r = 0.28-0.29; P < 0.01). The total TRIP scores were significantly associated with the total PSQ scores (r = 0.45; P < 0.0001). Factor analysis yielded two independent and coherent factors, which explained 69% of the variance in data. Factor-1 (“alliance and support”), which explained about 41% of the variance, was comprised of a combined WAI-Client goal-task-bond component as well as the PCP support items. Factor-2 (“trust and satisfaction”), which explained about 28% of the variance, consisted of all the TRIP trust and the PSQ treatment satisfaction items.CONCLUSIONA broader construct of treatment alliance in BD was found. Apart from collaborative components, this construct included patients’ perceptions regarding trust in clinicians, support from clinicians, and treatment satisfaction.     

Children diagnosed with attention deficit disorder and their hospitalisations: population data linkage study

Examine the hospital admission risk in young children who are subsequently diagnosed with attention deficit hyperactivity disorder (ADHD). We conducted a population-based, record linkage study. Records of all non-Aboriginal children under 18 years who met the DSMIV/ICD10 criteria for ADHD and prescribed stimulant medication in Western Australia between 2003 and 2007 (n = 11,902) were linked to two other health data systems—the hospital morbidity data system and the midwives notification system (MNS). The non-ADHD reference population (n = 27,304) was randomly selected from the MNS. Compared with controls, children under 4 years who subsequently were diagnosed and treated for ADHD were 70 % [odds ratio (OR) 1.70; 95 % confidence intervals (CI) 1.62–1.77] more likely to be admitted to hospital under 4 years of age. There was an increased risk for injury or poison (OR 1.73; 95 % CI 1.59–1.88), respiratory disease (OR 1.49; 95 % CI 1.40–1.59), ear disease (OR 2.03; 95 % CI 1.86–2.21), infectious diseases (OR 1.68; 95 % CI 1.53–1.85) and neurological conditions (OR 2.03; 95 % CI 1.68–2.44). Admissions under 4 years of age for head injuries, burns, poisons, all other injuries, diseases of the tonsils and adenoids, asthma and early infections were all more common amongst children subsequently diagnosed with and treated for ADHD. There is significant early hospital morbidity for children subsequently diagnosed with ADHD. Multiple aetiologies and causal pathways need to be considered where some of these may include early infections, inflammatory conditions, epilepsy and injuries. Future studies should look at which of these conditions may be on the causal pathway or likely early markers for ADHD.     

Investigating Direct and Indirect Genetic Effects in Attention-Deficit/Hyperactivity Disorder Using Parent-Offspring Trios

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is highly heritable, but little is known about the relative effects of transmitted (i.e., direct) and nontransmitted (i.e., indirect) common variant risks. Using parent-offspring trios, we tested whether polygenic liability for neurodevelopmental and psychiatric disorders and lower cognitive ability is overtransmitted to ADHD probands. We also tested for indirect or genetic nurture effects by examining whether nontransmitted ADHD polygenic liability is elevated. Finally, we examined whether complete trios are representative of the clinical ADHD population.MethodsPolygenic risk scores (PRSs) for ADHD, anxiety, autism, bipolar disorder, depression, obsessive-compulsive disorder, schizophrenia, Tourette syndrome, and cognitive ability were calculated in UK control subjects (n = 5081), UK probands with ADHD (n = 857), their biological parents (n = 328 trios), and also a replication sample of 844 ADHD trios.ResultsADHD PRSs were overtransmitted and cognitive ability and obsessive-compulsive disorder PRSs were undertransmitted. These results were independently replicated. Overtransmission of polygenic liability was not observed for other disorders. Nontransmitted alleles were not enriched for ADHD liability compared with control subjects. Probands from incomplete trios had more hyperactive-impulsive and conduct disorder symptoms, lower IQ, and lower socioeconomic status than complete trios. PRS did not vary by trio status.ConclusionsThe results support direct transmission of polygenic liability for ADHD and cognitive ability from parents to offspring, but not for other neurodevelopmental/psychiatric disorders. They also suggest that nontransmitted neurodevelopmental/psychiatric parental alleles do not contribute indirectly to ADHD via genetic nurture. Furthermore, ascertainment of complete ADHD trios may be nonrandom, in terms of demographic and clinical factors.