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1.
Neurosci Biobehav Rev ; 153: 105313, 2023 10.
Article in English | MEDLINE | ID: mdl-37451654

ABSTRACT

Attention-deficit/hyperactivity disorder (ADHD) co-occurs with many other psychiatric disorders and traits. In this review, we summarize and interpret the existing literature on the genetic architecture of these comorbidities based on hypothesis-generating approaches. Quantitative genetic studies indicate that genetic factors play a substantial role in the observed co-occurrence of ADHD with many different disorders and traits. Molecular genetic correlations derived from genome-wide association studies and results of studies based on polygenic risk scores confirm the general pattern but provide effect estimates that are smaller than those from twin studies. The identification of the specific genetic variants and biological pathways underlying co-occurrence using genome-wide approaches is still in its infancy. The first analyses of causal inference using genetic data support causal relationships between ADHD and comorbid disorders, although bidirectional effects identified in some instances point to complex relationships. While several issues in the methodology and inferences from the results are still to be overcome, this review shows that the co-occurrence of ADHD with many psychiatric disorders and traits is genetically interpretable.


Subject(s)
Attention Deficit Disorder with Hyperactivity , Humans , Attention Deficit Disorder with Hyperactivity/complications , Attention Deficit Disorder with Hyperactivity/epidemiology , Attention Deficit Disorder with Hyperactivity/genetics , Genome-Wide Association Study , Phenotype , Risk Factors , Multifactorial Inheritance/genetics
2.
Psychoneuroendocrinology ; 141: 105735, 2022 07.
Article in English | MEDLINE | ID: mdl-35447495

ABSTRACT

Stress initiates a cascade of (neuro)biological, physiological, and behavioral changes, allowing us to respond to a challenging environment. The human response to acute stress can be studied in detail in controlled settings, usually in a laboratory environment. To this end, many studies employ acute stress paradigms to probe stress-related outcomes in healthy and patient populations. Though valuable, these studies in themselves often have relatively limited sample sizes. We established a data-sharing and collaborative interdisciplinary initiative, the STRESS-NL database, which combines (neuro)biological, physiological, and behavioral data across many acute stress studies in order to accelerate our understanding of the human acute stress response in health and disease (www.stressdatabase.eu). Researchers in the stress field from 12 Dutch research groups of 6 Dutch universities created a database to achieve an accurate inventory of (neuro)biological, physiological, and behavioral data from laboratory-based human studies that used acute stress tests. Currently, the STRESS-NL database consists of information on 5529 individual participants (2281 females and 3348 males, age range 6-99 years, mean age 27.7 ±â€¯16 years) stemming from 57 experiments described in 42 independent studies. Studies often did not use the same stress paradigm; outcomes were different and measured at different time points. All studies currently included in the database assessed cortisol levels before, during and after experimental stress, but cortisol measurement will not be a strict requirement for future study inclusion. Here, we report on the creation of the STRESS-NL database and infrastructure to illustrate the potential of accumulating and combining existing data to allow meta-analytical, proof-of-principle analyses. The STRESS-NL database creates a framework that enables human stress research to take new avenues in explorative and hypothesis-driven data analyses with high statistical power. Future steps could be to incorporate new studies beyond the borders of the Netherlands; or build similar databases for experimental stress studies in rodents. In our view, there are major scientific benefits in initiating and maintaining such international efforts.


Subject(s)
Hydrocortisone , Databases, Factual , Female , Humans , Hydrocortisone/analysis , Male , Netherlands
3.
Eur Child Adolesc Psychiatry ; 30(1): 155-167, 2021 Jan.
Article in English | MEDLINE | ID: mdl-32246274

ABSTRACT

Environmental noise may play a role in the manifestation and severity of attention deficit/hyperactivity disorder (ADHD) symptoms, but evidence is limited. We investigated the cross-sectional associations between residential and school road traffic noise exposure and ADHD symptoms and diagnosis. The sample included n = 1710, 10-12-year-old children from the TRAILS study in The Netherlands. ADHD symptoms were measured using a DSM-IV based subscale from the Child Behavior Checklist. Children with diagnosed ADHD originated from the clinic-referred cohort. Road traffic noise (Lden) was estimated at the residence and school level, by model calculation. Risk ratios for ADHD symptoms and ADHD diagnoses, and regression coefficients for symptom severity were estimated separately and simultaneously for residential and school road traffic noise. Adjusted multinomial models with residential road traffic noise showed that residential noise was not associated with ADHD symptoms, but was associated with lower risks for ADHD diagnosis (RR = 0.93; 95% CI 0.89, 0.97). Similar associations were observed for models including school road traffic noise and models including both exposures. No clear exposure response relationship was observed for associations between residential or school noise and ADHD symptom severity. We found no evidence for a harmful association between road traffic noise and ADHD. Associations between noise and lower risks for ADHD were observed only in referred cases with a confirmed ADHD diagnosis and may be due to residual confounding or selection bias. Future studies should focus on residential and school noise exposure, and study associations with ADHD symptoms and diagnosis over time.


Subject(s)
Attention Deficit Disorder with Hyperactivity/complications , Environmental Exposure/adverse effects , Noise, Transportation/adverse effects , Child , Cross-Sectional Studies , Female , Humans , Male
4.
J Abnorm Child Psychol ; 48(8): 1007-1021, 2020 08.
Article in English | MEDLINE | ID: mdl-32445103

ABSTRACT

Heightened reward sensitivity has been proposed as a risk factor for developing behavioral disorders whereas heightened punishment sensitivity has been related to the development of anxiety disorders in youth. Combining a cross-sectional (n = 696, mean age = 16.14) and prospective (n = 598, mean age = 20.20) approach, this study tested the hypotheses that an attentional bias for punishing cues is involved in the development of anxiety disorders and an attentional bias for rewarding cues in the development of behavioral disorders. A spatial orientation task was used to examine the relation between an attentional bias for punishing cues and an attentional bias for rewarding cues with anxiety and behavioral problems in a subsample of a large prospective population cohort study. Our study indicates that attentional biases to general cues of punishment and reward do not seem to be important risk factors for the development of anxiety or behavioral problems respectively. It might be that attentional biases play a role in the maintenance of psychological problems. This remains open for future research.


Subject(s)
Adolescent Behavior/psychology , Anxiety Disorders/psychology , Attentional Bias , Problem Behavior/psychology , Punishment/psychology , Reward , Adolescent , Cohort Studies , Cross-Sectional Studies , Cues , Female , Humans , Male , Netherlands , Prospective Studies , Reaction Time , Space Perception
5.
J Autism Dev Disord ; 50(8): 2973-2986, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32052317

ABSTRACT

We compared the presence of autistic and comorbid psychopathology and functional impairments in young adults who received a clinical diagnosis of Pervasive Developmental Disorders Not Otherwise Specified or Asperger's Disorder during childhood to that of a referred comparison group. While the Autism Spectrum Disorder group on average scored higher on a dimensional ASD self- and other-report measure than clinical controls, the majority did not exceed the ASD cutoff according to the Autism Diagnostic Observation Schedule. Part of the individuals with an ASD diagnosis in their youth no longer show behaviors that underscribe a clinical ASD diagnosis in adulthood, but have subtle difficulties in social functioning and a vulnerability for a range of other psychiatric disorders.


Subject(s)
Asperger Syndrome/epidemiology , Autism Spectrum Disorder/epidemiology , Autism Spectrum Disorder/psychology , Adolescent , Adult , Asperger Syndrome/diagnosis , Autism Spectrum Disorder/diagnosis , Child , Comorbidity , Female , Humans , Male , Mental Disorders , Young Adult
7.
Behav Genet ; 49(3): 270-285, 2019 05.
Article in English | MEDLINE | ID: mdl-30659475

ABSTRACT

We aimed to detect Attention-deficit/hyperactivity (ADHD) risk-conferring genes in adults. In children, ADHD is characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity and may persists into adulthood. Childhood and adulthood ADHD are heritable, and are thought to represent the clinical extreme of a continuous distribution of ADHD symptoms in the general population. We aimed to leverage the power of studies of quantitative ADHD symptoms in adults who were genotyped. Within the SAGA (Study of ADHD trait genetics in adults) consortium, we estimated the single nucleotide polymorphism (SNP)-based heritability of quantitative self-reported ADHD symptoms and carried out a genome-wide association meta-analysis in nine adult population-based and case-only cohorts of adults. A total of n = 14,689 individuals were included. In two of the SAGA cohorts we found a significant SNP-based heritability for self-rated ADHD symptom scores of respectively 15% (n = 3656) and 30% (n = 1841). The top hit of the genome-wide meta-analysis (SNP rs12661753; p-value = 3.02 × 10-7) was present in the long non-coding RNA gene STXBP5-AS1. This association was also observed in a meta-analysis of childhood ADHD symptom scores in eight population-based pediatric cohorts from the Early Genetics and Lifecourse Epidemiology (EAGLE) ADHD consortium (n = 14,776). Genome-wide meta-analysis of the SAGA and EAGLE data (n = 29,465) increased the strength of the association with the SNP rs12661753. In human HEK293 cells, expression of STXBP5-AS1 enhanced the expression of a reporter construct of STXBP5, a gene known to be involved in "SNAP" (Soluble NSF attachment protein) Receptor" (SNARE) complex formation. In mouse strains featuring different levels of impulsivity, transcript levels in the prefrontal cortex of the mouse ortholog Gm28905 strongly correlated negatively with motor impulsivity as measured in the five choice serial reaction time task (r2 = - 0.61; p = 0.004). Our results are consistent with an effect of the STXBP5-AS1 gene on ADHD symptom scores distribution and point to a possible biological mechanism, other than antisense RNA inhibition, involved in ADHD-related impulsivity levels.


Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Nerve Tissue Proteins/genetics , R-SNARE Proteins/genetics , RNA, Long Noncoding/genetics , Adult , Animals , Attention Deficit Disorder with Hyperactivity/metabolism , Cohort Studies , DNA, Antisense/genetics , DNA, Antisense/metabolism , Female , Genetic Predisposition to Disease/genetics , Genetics, Population/methods , Genome-Wide Association Study , Genotype , HEK293 Cells , Humans , Male , Mice , Phenotype , Polymorphism, Single Nucleotide/genetics , RNA, Long Noncoding/metabolism , Risk Factors
8.
Psychol Med ; 49(9): 1459-1469, 2019 07.
Article in English | MEDLINE | ID: mdl-30229710

ABSTRACT

BACKGROUND: Various childhood social experiences have been reported to predict adult outcomes. However, it is unclear how different social contexts may influence each other's effects in the long run. This study examined the joint contribution of adolescent family and peer experiences to young adult wellbeing and functioning. METHODS: Participants came from the TRacking Adolescents' Individual Lives Survey (TRAILS) study (n = 2230). We measured family and peer relations at ages 11 and 16 (i.e. family functioning, perceived parenting, peer status, peer relationship quality), and functioning as the combination of subjective wellbeing, physical and mental health, and socio-academic functioning at age 22. Using structural equation modelling, overall functioning was indicated by two latent variables for positive and negative functioning. Positive, negative and overall functioning at young adulthood were regressed on adolescent family experiences, peer experiences and interactions between the two. RESULTS: Family experiences during early and mid-adolescence were most predictive for later functioning; peer experiences did not independently predict functioning. Interactions between family and peer experiences showed that both protective and risk factors can have context-dependent effects, being exacerbated or overshadowed by negative experiences or buffered by positive experiences in other contexts. Overall the effect sizes were modest at best. CONCLUSIONS: Adolescent family relations as well as the interplay with peer experiences predict young adult functioning. This emphasizes the importance of considering the relative effects of one context in relation to the other.


Subject(s)
Achievement , Behavioral Symptoms/epidemiology , Family , Health Status , Interpersonal Relations , Peer Group , Personal Satisfaction , Personality Disorders/epidemiology , Adolescent , Adult , Child , Female , Follow-Up Studies , Humans , Male , Netherlands/epidemiology , Protective Factors , Risk Factors , Young Adult
9.
J Abnorm Child Psychol ; 47(3): 405-419, 2019 03.
Article in English | MEDLINE | ID: mdl-30079436

ABSTRACT

Longitudinal studies on the course of neurocognitive functioning of children with ADHD and their unaffected siblings are scarce. Also, it is unclear to what extent that course is related to ADHD outcomes. A carefully phenotyped large sample of 838 Caucasian participants (ADHD-combined type: n = 339, unaffected siblings: n = 271, controls: n = 228; mean age at baseline = 11.4 years, mean age at follow-up = 17.3 years, SD = 3.2) was used to investigate differences in the course of neurocognitive functioning of ADHD affected and unaffected siblings versus controls, and to investigate the relationship between neurocognitive change and ADHD outcomes. At baseline, an aggregated measure of overall neurocognitive functioning and eight neurocognitive measures of working memory, timing (speed/variability), motor control, and intelligence were investigated. Outcomes at follow-up were dimensional measures of ADHD symptom severity and the Kiddie-Global Assessment Scale (K-GAS) for overall functioning. At follow up, affected and unaffected siblings trended to, or fully caught up with performance levels of controls on four (44.4%) and five (55.6%) of the nine dependent variables, respectively. In contrast, performance in remaining key neurocognitive measures (i.e. verbal working memory, variability in responding) remained impaired at follow-up. Change in neurocognitive functioning was not related to ADHD outcomes. Our results question the etiological link between neurocognitive deficits and ADHD outcomes in adolescents and young adults.


Subject(s)
Attention Deficit Disorder with Hyperactivity/physiopathology , Cognitive Dysfunction/physiopathology , Outcome Assessment, Health Care , Siblings , Adolescent , Attention Deficit Disorder with Hyperactivity/complications , Attention Deficit Disorder with Hyperactivity/therapy , Child , Child, Preschool , Cognitive Dysfunction/etiology , Cognitive Dysfunction/therapy , Female , Follow-Up Studies , Humans , Male , Young Adult
10.
Psychol Med ; 48(11): 1787-1794, 2018 08.
Article in English | MEDLINE | ID: mdl-29521611

ABSTRACT

BACKGROUND: We modeled both psychopathology and executive function (EF) as bi-factor models to study if EF impairments are transdiagnostic or relate to individual syndromes, and concurrently, if such associations are with general EF or specific EF impairments. METHODS: Data were obtained from the Tracking Adolescents' Individual Lives Survey (TRAILS; N = 2230). Psychopathology was assessed with parent-report questionnaires at ages 11, 14, 16, and 19, and EF with tasks from the Amsterdam Neuropsychological Tasks program at ages 11 and 19. Bi-factor models were fitted to the data using confirmatory factor analysis. Correlations were estimated to study the associations between general or specific components of both psychopathology and EF. RESULTS: A bi-factor model with a general psychopathology factor, alongside internalizing (INT), externalizing, attention deficit/hyperactivity (ADHD), and autism spectrum (ASD) problem domains, and a bi-factor model with a general EF factor, alongside specific EFs were adequately fitting measurement models. The best-fitting model between EF and psychopathology showed substantial associations of specific EFs with the general psychopathology factor, in addition to distinct patterns of association with ASD, ADHD, and INT problems. CONCLUSIONS: By studying very diverse psychopathology domains simultaneously, we show how EF impairments cross diagnostic boundaries. In addition to this generic relation, ADHD, ASD, and INT symptomatology show separable profiles of EF impairments. Thus, inconsistent findings in the literature may be explained by substantial transdiagnostic EF impairments. Whether general EF or specific EFs are related to psychopathology needs to be further studied, as differences in fit between these models were small.


Subject(s)
Adolescent Behavior/physiology , Attention Deficit Disorder with Hyperactivity/physiopathology , Autism Spectrum Disorder/physiopathology , Behavioral Symptoms/physiopathology , Cognitive Dysfunction/physiopathology , Executive Function/physiology , Mental Disorders/physiopathology , Models, Statistical , Adolescent , Adult , Attention Deficit Disorder with Hyperactivity/epidemiology , Autism Spectrum Disorder/epidemiology , Behavioral Symptoms/epidemiology , Child , Cognitive Dysfunction/epidemiology , Female , Humans , Male , Mental Disorders/epidemiology , Netherlands/epidemiology , Prospective Studies , Young Adult
11.
Eur Child Adolesc Psychiatry ; 27(10): 1347-1359, 2018 Oct.
Article in English | MEDLINE | ID: mdl-29478191

ABSTRACT

Knowledge on the validity of the Strengths and Difficulties Questionnaire (SDQ) among adolescents is limited but essential for the interpretation of SDQ scores preceding the diagnostic process. This study assessed the predictive and discriminative value of adolescent- and parent-rated SDQ scores for psychiatric disorders, diagnosed by professionals in outpatient community clinics, in a sample of 2753 Dutch adolescents aged 12-17. Per disorder, the predictive accuracy of the SDQ scale that is contentwise related to that particular disorder and the SDQ impact scale was assessed. That is, 24 logistic regression analyses were performed, for each combination of DSM-IV diagnosis [4: Attention-Deficit/Hyperactivity Disorder (ADHD), Conduct/Oppositional Defiant Disorder (CD/ODD), Anxiety/Mood disorder, Autism Spectrum Disorder (ASD)], informant (3: adolescent, parent, both), and SDQ scale(s) (2; related scale only, related scale and impact scale). Additional logistic regression analyses were performed to assess the discriminative strength of the SDQ scales. The results show both fair predictive strength and fair discriminative strength for the adolescent- and parent-reported hyperactivity scales, the parent-reported conduct scale, and the parent-reported social and prosocial scales, indicating that these scales provide useful information about the presence of ADHD, CD/ODD, and ASD, respectively. The SDQ emotional scale showed to be insufficiently predictive. The findings suggest that parent-rated SDQ scores can be used to provide clinicians with a preliminary impression of the type of problems for ADHD, CD/ODD, and ASD, and adolescent for ADHD.


Subject(s)
Diagnostic and Statistical Manual of Mental Disorders , Mental Disorders/diagnosis , Surveys and Questionnaires/statistics & numerical data , Adolescent , Female , Humans , Male , Mental Disorders/pathology , Sweden
12.
Transl Psychiatry ; 7(6): e1145, 2017 06 06.
Article in English | MEDLINE | ID: mdl-28585928

ABSTRACT

Identifying genetic variants contributing to attention-deficit/hyperactivity disorder (ADHD) is complicated by the involvement of numerous common genetic variants with small effects, interacting with each other as well as with environmental factors, such as stress exposure. Random forest regression is well suited to explore this complexity, as it allows for the analysis of many predictors simultaneously, taking into account any higher-order interactions among them. Using random forest regression, we predicted ADHD severity, measured by Conners' Parent Rating Scales, from 686 adolescents and young adults (of which 281 were diagnosed with ADHD). The analysis included 17 374 single-nucleotide polymorphisms (SNPs) across 29 genes previously linked to hypothalamic-pituitary-adrenal (HPA) axis activity, together with information on exposure to 24 individual long-term difficulties or stressful life events. The model explained 12.5% of variance in ADHD severity. The most important SNP, which also showed the strongest interaction with stress exposure, was located in a region regulating the expression of telomerase reverse transcriptase (TERT). Other high-ranking SNPs were found in or near NPSR1, ESR1, GABRA6, PER3, NR3C2 and DRD4. Chronic stressors were more influential than single, severe, life events. Top hits were partly shared with conduct problems. We conclude that random forest regression may be used to investigate how multiple genetic and environmental factors jointly contribute to ADHD. It is able to implicate novel SNPs of interest, interacting with stress exposure, and may explain inconsistent findings in ADHD genetics. This exploratory approach may be best combined with more hypothesis-driven research; top predictors and their interactions with one another should be replicated in independent samples.


Subject(s)
Attention Deficit Disorder with Hyperactivity/diagnosis , Stress, Psychological/genetics , Telomerase/genetics , Adolescent , Arabidopsis Proteins , Attention Deficit Disorder with Hyperactivity/genetics , Attention Deficit Disorder with Hyperactivity/psychology , Female , Humans , Hypothalamo-Hypophyseal System/physiopathology , Intramolecular Lyases , Male , Pituitary-Adrenal System/physiopathology , Polymorphism, Single Nucleotide , Severity of Illness Index , Stress, Psychological/physiopathology , Stress, Psychological/psychology , Young Adult
13.
Psychol Med ; 47(7): 1271-1282, 2017 May.
Article in English | MEDLINE | ID: mdl-28065168

ABSTRACT

BACKGROUND: Various sources indicate that mental disorders are the leading contributor to the burden of disease among youth. An important determinant of functioning is current mental health status. This study investigated whether psychiatric history has additional predictive power when predicting individual differences in functional outcomes. METHOD: We used data from the Dutch TRAILS study in which 1778 youths were followed from pre-adolescence into young adulthood (retention 80%). Of those, 1584 youths were successfully interviewed, at age 19, using the World Health Organization Composite International Diagnostic Interview (CIDI 3.0) to assess current and past CIDI-DSM-IV mental disorders. Four outcome domains were assessed at the same time: economic (e.g. academic achievement, social benefits, financial difficulties), social (early motherhood, interpersonal conflicts, antisocial behavior), psychological (e.g. suicidality, subjective well-being, loneliness), and health behavior (e.g. smoking, problematic alcohol, cannabis use). RESULTS: Out of the 19 outcomes, 14 were predicted by both current and past disorders, three only by past disorders (receiving social benefits, psychiatric hospitalization, adolescent motherhood), and two only by current disorder (absenteeism, obesity). Which type of disorders was most important depended on the outcome. Adjusted for current disorder, past internalizing disorders predicted in particular psychological outcomes while externalizing disorders predicted in particular health behavior outcomes. Economic and social outcomes were predicted by a history of co-morbidity of internalizing and externalizing disorder. The risk of problematic cannabis use and alcohol consumption dropped with a history of internalizing disorder. CONCLUSION: To understand current functioning, it is necessary to examine both current and past psychiatric status.


Subject(s)
Health Behavior , Mental Disorders/epidemiology , Adolescent , Adult , Child , Comorbidity , Female , Follow-Up Studies , Humans , Male , Netherlands/epidemiology , Young Adult
14.
Psychol Med ; 46(16): 3371-3382, 2016 12.
Article in English | MEDLINE | ID: mdl-27624913

ABSTRACT

BACKGROUND: In search of empirical classifications of depression and anxiety, most subtyping studies focus solely on symptoms and do so within a single disorder. This study aimed to identify and validate cross-diagnostic subtypes by simultaneously considering symptoms of depression and anxiety, and disability measures. METHOD: A large cohort of adults (Lifelines, n = 73 403) had a full assessment of 16 symptoms of mood and anxiety disorders, and measurement of physical, social and occupational disability. The best-fitting subtyping model was identified by comparing different hybrid mixture models with and without disability covariates on fit criteria in an independent test sample. The best model's classes were compared across a range of external variables. RESULTS: The best-fitting Mixed Measurement Item Response Theory model with disability covariates identified five classes. Accounting for disability improved differentiation between people reporting isolated non-specific symptoms ['Somatic' (13.0%), and 'Worried' (14.0%)] and psychopathological symptoms ['Subclinical' (8.8%), and 'Clinical' (3.3%)]. Classes showed distinct associations with clinically relevant external variables [e.g. somatization: odds ratio (OR) 8.1-12.3, and chronic stress: OR 3.7-4.4]. The Subclinical class reported symptomatology at subthreshold levels while experiencing disability. No pure depression or anxiety, but only mixed classes were found. CONCLUSIONS: An empirical classification model, incorporating both symptoms and disability identified clearly distinct cross-diagnostic subtypes, indicating that diagnostic nets should be cast wider than current phenomenology-based categorical systems.


Subject(s)
Activities of Daily Living , Anxiety Disorders/psychology , Anxiety/psychology , Depression/psychology , Depressive Disorder, Major/psychology , Social Behavior , Adolescent , Adult , Aged , Agoraphobia/physiopathology , Agoraphobia/psychology , Anxiety/physiopathology , Anxiety Disorders/physiopathology , Cohort Studies , Depression/physiopathology , Depressive Disorder, Major/physiopathology , Disability Evaluation , Female , Humans , Male , Middle Aged , Netherlands , Panic Disorder/physiopathology , Panic Disorder/psychology , Phobia, Social/physiopathology , Phobia, Social/psychology , Young Adult
15.
Genes Brain Behav ; 15(7): 627-36, 2016 09.
Article in English | MEDLINE | ID: mdl-27391809

ABSTRACT

The glucocorticoid receptor plays a pivotal role in the brain's response to stress; a haplotype of functional polymorphisms in the NR3C1 gene encoding this receptor has been associated with attention-deficit hyperactivity disorder (ADHD). The serotonin transporter (5-HTT) gene polymorphism 5-HTTLPR is known to influence the relation between stress exposure and ADHD severity, which may be partly because of its reported effects on glucocorticoid levels. We therefore investigated if NR3C1 moderates the relation of stress exposure with ADHD severity and brain structure, and the potential role of 5-HTTLPR. Neuroimaging, genetic and stress exposure questionnaire data were available for 539 adolescents and young adults participating in the multicenter ADHD cohort study NeuroIMAGE (average age: 17.2 years). We estimated the effects of genetic variation in NR3C1 and 5-HTT, stress exposure and their interactions on ADHD symptom count and gray matter volume. We found that individuals carrying the ADHD risk haplotype of NR3C1 showed significantly more positive relation between stress exposure and ADHD severity than non-carriers. This gene-environment interaction was significantly stronger for 5-HTTLPR L-allele homozygotes than for S-allele carriers. These two- and three-way interactions were reflected in the gray matter volume of the cerebellum, parahippocampal gyrus, intracalcarine cortex and angular gyrus. Our findings illustrate how genetic variation in the stress response pathway may influence the effects of stress exposure on ADHD severity and brain structure. The reported interplay between NR3C1 and 5-HTT may further explain some of the heterogeneity between studies regarding the role of these genes and hypothalamic-pituitary-adrenal axis activity in ADHD.


Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Brain/anatomy & histology , Brain/physiopathology , Receptors, Glucocorticoid/genetics , Stress, Psychological/genetics , Adolescent , Attention Deficit Disorder with Hyperactivity/pathology , Cohort Studies , Female , Gene Frequency , Gene-Environment Interaction , Genetic Variation , Haplotypes , Humans , Hypothalamo-Hypophyseal System/physiopathology , Male , Pituitary-Adrenal System/physiopathology , Polymorphism, Single Nucleotide , Receptors, Glucocorticoid/metabolism , Serotonin Plasma Membrane Transport Proteins/genetics , Serotonin Plasma Membrane Transport Proteins/metabolism , Stress, Psychological/metabolism , Young Adult
16.
Transl Psychiatry ; 6: e771, 2016 Apr 05.
Article in English | MEDLINE | ID: mdl-27045841

ABSTRACT

Little is known about the causes of individual differences in reward sensitivity. We investigated gene-environment interactions (GxE) on behavioral and neural measures of reward sensitivity, in light of the differential susceptibility theory. This theory states that individuals carrying plasticity gene variants will be more disadvantaged in negative, but more advantaged in positive environments. Reward responses were assessed during a monetary incentive delay task in 178 participants with and 265 without attention-deficit/hyperactivity disorder (ADHD), from N=261 families. We examined interactions between variants in candidate plasticity genes (DAT1, 5-HTT and DRD4) and social environments (maternal expressed emotion and peer affiliation). HTTLPR short allele carriers showed the least reward speeding when exposed to high positive peer affiliation, but the most when faced with low positive peer affiliation or low maternal warmth. DAT1 10-repeat homozygotes displayed similar GxE patterns toward maternal warmth on general task performance. At the neural level, DRD4 7-repeat carriers showed the least striatal activation during reward anticipation when exposed to high maternal warmth, but the most when exposed to low warmth. Findings were independent of ADHD severity. Our results partially confirm the differential susceptibility theory and indicate the importance of positive social environments in reward sensitivity and general task performance for persons with specific genotypes.


Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Dopamine Plasma Membrane Transport Proteins/genetics , Maternal Behavior , Peer Group , Receptors, Dopamine D4/genetics , Reward , Serotonin Plasma Membrane Transport Proteins/genetics , Adolescent , Adolescent Behavior , Attention Deficit Disorder with Hyperactivity/diagnostic imaging , Attention Deficit Disorder with Hyperactivity/physiopathology , Attention Deficit Disorder with Hyperactivity/psychology , Case-Control Studies , DNA Copy Number Variations , Female , Functional Neuroimaging , Gene Frequency , Gene-Environment Interaction , Genetic Predisposition to Disease , Homozygote , Humans , Magnetic Resonance Imaging , Male , Neostriatum/diagnostic imaging , Neostriatum/physiopathology , Neuronal Plasticity/genetics , Young Adult
17.
Transl Psychiatry ; 6: e769, 2016 Mar 29.
Article in English | MEDLINE | ID: mdl-27023175

ABSTRACT

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10(-8)) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.


Subject(s)
Marijuana Abuse/genetics , Marijuana Smoking/genetics , Adolescent , Adult , Aged , Aged, 80 and over , CD56 Antigen/genetics , Carrier Proteins/genetics , Cell Adhesion Molecules/genetics , Female , Genome-Wide Association Study , Humans , Male , Membrane Proteins/genetics , Middle Aged , Potassium Channels/genetics , Potassium Channels, Sodium-Activated , Young Adult
19.
Eur Neuropsychopharmacol ; 26(4): 674-83, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26899587

ABSTRACT

Diffusion tensor imaging (DTI) has revealed white matter abnormalities in individuals with attention-deficit/hyperactivity disorder (ADHD). Stimulant treatment may affect such abnormalities. The current study investigated associations between long-term stimulant treatment and white matter integrity within the frontal-striatal and mesolimbic pathways, in a large sample of children, adolescents and young adults with ADHD. Participants with ADHD (N=172; mean age 17, range 9-26) underwent diffusion-weighted MRI scanning, along with an age- and gendermatched group of 96 control participants. Five study-specific white matter tract masks (orbitofrontal-striatal, orbitofrontal-amygdalar, amygdalar-striatal, dorsolateral-prefrontal-striatal and medialprefrontal-striatal) were created. First we analyzed case-control differences in fractional anisotropy (FA) and mean diffusivity (MD) within each tract. Second, FA and MD in each tract was predicted from cumulative stimulant intake within the ADHD group. After correction for multiple testing, participants with ADHD showed reduced FA in the orbitofrontal-striatal pathway (p=0.010, effect size=0.269). Within the ADHD group, higher cumulative stimulant intake was associated with lower MD in the same pathway (p=0.011, effect size=-0.164), but not with FA. The association between stimulant treatment and orbitofrontal-striatal MD was of modest effect size. It fell short of significance after adding ADHD severity or ADHD type to the model (p=0.036 and p=0.094, respectively), while the effect size changed little. Our findings are compatible with stimulant treatment enhancing orbitofrontal-striatal white matter connectivity, and emphasize the importance of the orbitofrontal cortex and its connections in ADHD. Longitudinal studies including a drug-naïve baseline assessment are needed to distinguish between-subject variability in ADHD severity from treatment effects.


Subject(s)
Attention Deficit Disorder with Hyperactivity/drug therapy , Central Nervous System Stimulants/therapeutic use , Corpus Striatum/drug effects , Neural Pathways/drug effects , Prefrontal Cortex/drug effects , Adolescent , Adult , Anisotropy , Attention Deficit Disorder with Hyperactivity/pathology , Attention Deficit Disorder with Hyperactivity/physiopathology , Case-Control Studies , Child , Corpus Striatum/pathology , Corpus Striatum/physiology , Diffusion Magnetic Resonance Imaging , Female , Humans , Male , Neural Pathways/pathology , Neural Pathways/physiology , Neuroimaging , Prefrontal Cortex/pathology , Prefrontal Cortex/physiology , White Matter/drug effects , White Matter/pathology , White Matter/physiology , Young Adult
20.
Mol Psychiatry ; 21(10): 1391-9, 2016 10.
Article in English | MEDLINE | ID: mdl-26754954

ABSTRACT

Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10(-9)). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.


Subject(s)
Anxiety Disorders/genetics , Case-Control Studies , Genetic Association Studies/methods , Genetic Predisposition to Disease , Genetic Variation , Genome-Wide Association Study/methods , Genotype , Humans , Polymorphism, Single Nucleotide , Risk Factors , White People/genetics
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