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1.
BMC Psychol ; 11(1): 245, 2023 Aug 25.
Article in English | MEDLINE | ID: mdl-37626397

ABSTRACT

BACKGROUND: Stress-related disorders such as anxiety and depression are highly prevalent and cause a tremendous burden for affected individuals and society. In order to improve prevention strategies, knowledge regarding resilience mechanisms and ways to boost them is highly needed. In the Dynamic Modelling of Resilience - interventional multicenter study (DynaM-INT), we will conduct a large-scale feasibility and preliminary efficacy test for two mobile- and wearable-based just-in-time adaptive interventions (JITAIs), designed to target putative resilience mechanisms. Deep participant phenotyping at baseline serves to identify individual predictors for intervention success in terms of target engagement and stress resilience. METHODS: DynaM-INT aims to recruit N = 250 healthy but vulnerable young adults in the transition phase between adolescence and adulthood (18-27 years) across five research sites (Berlin, Mainz, Nijmegen, Tel Aviv, and Warsaw). Participants are included if they report at least three negative burdensome past life events and show increased levels of internalizing symptoms while not being affected by any major mental disorder. Participants are characterized in a multimodal baseline phase, which includes neuropsychological tests, neuroimaging, bio-samples, sociodemographic and psychological questionnaires, a video-recorded interview, as well as ecological momentary assessments (EMA) and ecological physiological assessments (EPA). Subsequently, participants are randomly assigned to one of two ecological momentary interventions (EMIs), targeting either positive cognitive reappraisal or reward sensitivity. During the following intervention phase, participants' stress responses are tracked using EMA and EPA, and JITAIs are triggered if an individually calibrated stress threshold is crossed. In a three-month-long follow-up phase, parts of the baseline characterization phase are repeated. Throughout the entire study, stressor exposure and mental health are regularly monitored to calculate stressor reactivity as a proxy for outcome resilience. The online monitoring questionnaires and the repetition of the baseline questionnaires also serve to assess target engagement. DISCUSSION: The DynaM-INT study intends to advance the field of resilience research by feasibility-testing two new mechanistically targeted JITAIs that aim at increasing individual stress resilience and identifying predictors for successful intervention response. Determining these predictors is an important step toward future randomized controlled trials to establish the efficacy of these interventions.


Subject(s)
Resilience, Psychological , Adolescent , Humans , Young Adult , Anxiety , Anxiety Disorders , Health Status , Mental Health , Multicenter Studies as Topic , Randomized Controlled Trials as Topic
2.
Gut Microbes ; 13(1): 2006586, 2021.
Article in English | MEDLINE | ID: mdl-34856861

ABSTRACT

Research on the gut-brain axis has accelerated substantially over the course of the last years. Many reviews have outlined the important implications of understanding the relation of the gut microbiota with human brain function and behavior. One substantial drawback in integrating gut microbiome and brain data is the lack of integrative multivariate approaches that enable capturing variance in both modalities simultaneously. To address this issue, we applied a linked independent component analysis (LICA) to microbiota and brain connectivity data.We analyzed data from 58 healthy females (mean age = â€¯21.5 years). Magnetic Resonance Imaging data were acquired using resting state functional imaging data. The assessment of gut microbial composition from feces was based on sequencing of the V4 16S rRNA gene region. We used the LICA model to simultaneously factorize the subjects' large-scale brain networks and microbiome relative abundance data into 10 independent components of spatial and abundance variation.LICA decomposition resulted in four components with non-marginal contribution of the microbiota data. The default mode network featured strongly in three components, whereas the two-lateralized fronto-parietal attention networks contributed to one component. The executive-control (with the default mode) network was associated to another component. We found that the abundance of Prevotella genus was associated with the strength of expression of all networks, whereas Bifidobacterium was associated with the default mode and frontoparietal-attention networks.We provide the first exploratory evidence for multivariate associative patterns between the gut microbiota and brain network connectivity in healthy humans considering the complexity of both systems.


Subject(s)
Brain/physiology , Gastrointestinal Microbiome/physiology , Nerve Net/physiology , Bifidobacterium/isolation & purification , Bifidobacterium/physiology , Brain/diagnostic imaging , Brain-Gut Axis/physiology , Female , Gastrointestinal Microbiome/genetics , Healthy Volunteers , Humans , Magnetic Resonance Imaging , Nerve Net/diagnostic imaging , Prevotella/isolation & purification , Prevotella/physiology , Rest/physiology , Young Adult
3.
Eur Neuropsychopharmacol ; 30: 102-113, 2020 01.
Article in English | MEDLINE | ID: mdl-30292416

ABSTRACT

Known comorbidities for Attention-Deficit Hyperactivity Disorder (ADHD) include conduct problems, substance use disorder and gaming. Comorbidity with conduct problems may increase the risk for substance use disorder and gaming in individuals with ADHD. The aim of the study was to build a causal model of the relationships between ADHD and comorbid conduct problems, and alcohol, nicotine, and other substance use, and gaming habits, while accounting for age and sex. We used a state-of-the-art causal discovery algorithm to analyze a case-only sample of 362 ADHD-diagnosed individuals in the ages 12-24 years. We found that conduct problem severity mediates between ADHD severity and nicotine use, but not with more severe alcohol or substance use. More severe ADHD-inattentive symptoms lead to more severe gaming habits. Furthermore, our model suggests that ADHD severity has no influence on severity of alcohol or other drug use. Our findings suggest that ADHD severity is a risk factor for nicotine use, and that this effect is fully mediated by conduct problem severity. Finally, ADHD-inattentive severity was a risk factor for gaming, suggesting that gaming dependence has a different causal pathway than substance dependence and should be treated differently. By identifying these intervention points, our model can aid both researchers and clinicians.


Subject(s)
Attention Deficit Disorder with Hyperactivity/psychology , Conduct Disorder/psychology , Internet Addiction Disorder/psychology , Substance-Related Disorders/psychology , Video Games/psychology , Adolescent , Attention Deficit Disorder with Hyperactivity/diagnosis , Attention Deficit Disorder with Hyperactivity/epidemiology , Bayes Theorem , Case-Control Studies , Child , Child, Preschool , Conduct Disorder/diagnosis , Conduct Disorder/epidemiology , Female , Humans , Internet Addiction Disorder/diagnosis , Internet Addiction Disorder/epidemiology , Male , Risk Factors , Substance-Related Disorders/diagnosis , Substance-Related Disorders/epidemiology , Surveys and Questionnaires
4.
Neurobiol Stress ; 10: 100141, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30937347

ABSTRACT

Probiotics are microorganisms that provide health benefits when consumed. In animals, probiotics reverse gut microbiome-related alterations in depression-like symptoms, in cognition, and in hormonal stress response. However, in humans, a causal understanding of the gut-brain link in emotion and cognition is lacking. Additionally, whether the effects of probiotics on neurocognition are visible only in presence of stress, remains unclear. We investigated the effects of a multispecies probiotic (Ecologic®Barrier) on specific neurocognitive measures of emotion reactivity, emotion regulation, and cognitive control using fMRI. Critically, we also tested whether probiotics can buffer against the detrimental effects of acute stress on working memory. In a double blind, randomized, placebo-controlled, between-subjects intervention study, 58 healthy participants were tested once before and once after a 28-day intervention. Without stress induction, probiotics did not affect brain, behavioral, or related self-report measures. However, relative to placebo, the probiotics group did show a significant stress-related increase in working memory performance after supplementation. This change was associated with intervention-related neural changes in frontal cortex during cognitive control exclusively in the probiotics group. Overall, our results show neurocognitive effects of a multispecies probiotic in healthy women only under challenging situations, buffering against the detrimental effects of stress on cognition.

5.
Eur Neuropsychopharmacol ; 29(4): 509-518, 2019 04.
Article in English | MEDLINE | ID: mdl-30851996

ABSTRACT

Dysregulation of executive function (EF) involves alterations in cognitive flexibility / control and is underscored by learning impairments in neurodevelopmental disorders. Here, we examine cognitive inflexibility in BALB/cJ mice (a mouse model showing diminished sociability, increased anxiety and inattentive behaviour) and closely related "reference" BALB/cByJ mice. We used an appetitive extinction paradigm to investigate if cognitive flexibility measures are different between learning acquisition and extinction. The two BALB/c sub-strains learned to respond to a stimulus in a touchscreen operant chamber, after which the reward was removed and responses should be inhibited. Both mice sub-strains showed a different rate of learning while acquiring the task, in which the BALB/cJ mice were faster learners compared to the BALB/cByJ mice. This was not observed during the extinction phase, in which the BALB/cJ mice were able to extinguish responding to unrewarded stimuli equally. Within the BALB/cJ sub-strain, variation in the ability to inhibit a learnt response was observed when comparing them to similar grouped BALB/cByJ mice: BALB/cJ animals that reached the criterion were more reward driven, while BALB/cJ mice failing to reach the set criterion during extinction processing make more mistakes. Additionally, the changes observed during acquisition, were driven by animals not reaching the extinction criterion. Our results suggest that the BALB/c mice sub-strains may use different strategies to learn during appetitive extinction. This may be useful in the phenotypic dissection of cognitive flexibility in BALB/c sub-strains and their mapping on genetic variance revealed by next-generation sequencing in future studies.


Subject(s)
Extinction, Psychological , Inhibition, Psychological , Learning , Mice, Inbred BALB C/psychology , Species Specificity , Animals , Male , Mice , Reward
6.
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
7.
Mol Psychiatry ; 23(5): 1205-1212, 2018 05.
Article in English | MEDLINE | ID: mdl-28507316

ABSTRACT

Autism spectrum disorders (ASDs) and autistic traits in the general population may share genetic susceptibility factors. In this study, we investigated such potential overlap based on common genetic variants. We developed and validated a self-report questionnaire of autistic traits in adults. We then conducted genome-wide association studies (GWASs) of six trait scores derived from the questionnaire through exploratory factor analysis in 1981 adults from the general population. Using the results from the Psychiatric Genomics Consortium GWAS of ASDs, we observed genetic sharing between ASDs and the autistic traits 'childhood behavior', 'rigidity' and 'attention to detail'. Gene-set analysis subsequently identified 'rigidity' to be significantly associated with a network of ASD gene-encoded proteins that regulates neurite outgrowth. Gene-wide association with the well-established ASD gene MET reached significance. Taken together, our findings provide evidence for an overlapping genetic and biological etiology underlying ASDs and autistic population traits, which suggests that genetic studies in the general population may yield novel ASD genes.


Subject(s)
Autism Spectrum Disorder/genetics , Autistic Disorder/genetics , Adult , Autism Spectrum Disorder/etiology , Autism Spectrum Disorder/physiopathology , Autistic Disorder/etiology , Autistic Disorder/physiopathology , Female , Genetic Predisposition to Disease/genetics , Genetic Variation/genetics , Genome-Wide Association Study , Genotype , Humans , Male , Phenotype , Proto-Oncogene Proteins c-met/genetics , Self Report , Surveys and Questionnaires
9.
Mol Psychiatry ; 22(10): 1431-1439, 2017 10.
Article in English | MEDLINE | ID: mdl-28167838

ABSTRACT

The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P=3.3 × 10-8; rs191260602, P=3.9 × 10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3845) and a case-control sample with the categorical phenotype PD/AG (Ncombined =1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P=3.8 × 10-4) and rs7688285 (P=7.6 × 10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.


Subject(s)
Agoraphobia/genetics , Agoraphobia/metabolism , Receptors, Glycine/genetics , Adult , Alleles , Anxiety/complications , Anxiety Disorders/genetics , Brain/metabolism , Brain/physiology , Case-Control Studies , Cognition/physiology , Fear/physiology , Fear/psychology , Female , Gene Frequency/genetics , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Genotype , Germany , Humans , Male , Mutation/genetics , Panic Disorder/genetics , Receptors, Glycine/metabolism , Reflex, Startle/genetics
10.
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
11.
Mol Psychiatry ; 21(9): 1202-7, 2016 09.
Article in English | MEDLINE | ID: mdl-26573769

ABSTRACT

A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 × 10(-4)) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders.


Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Biological Psychiatry/methods , Adolescent , Autistic Disorder/genetics , Canada , Child , Child, Preschool , DNA Copy Number Variations/genetics , Databases, Nucleic Acid , Europe , Female , Genetic Association Studies/methods , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Humans , Ireland , Male , Neurodevelopmental Disorders/genetics , Polymorphism, Single Nucleotide/genetics , Schizophrenia/genetics , United Kingdom
12.
Genes Brain Behav ; 13(7): 675-85, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25130324

ABSTRACT

Heschl's gyrus (HG) is a core region of the auditory cortex whose morphology is highly variable across individuals. This variability has been linked to sound perception ability in both speech and music domains. Previous studies show that variations in morphological features of HG, such as cortical surface area and thickness, are heritable. To identify genetic variants that affect HG morphology, we conducted a genome-wide association scan (GWAS) meta-analysis in 3054 healthy individuals using HG surface area and thickness as quantitative traits. None of the single nucleotide polymorphisms (SNPs) showed association P values that would survive correction for multiple testing over the genome. The most significant association was found between right HG area and SNP rs72932726 close to gene DCBLD2 (3q12.1; P=2.77 × 10(-7) ). This SNP was also associated with other regions involved in speech processing. The SNP rs333332 within gene KALRN (3q21.2; P=2.27 × 10(-6) ) and rs143000161 near gene COBLL1 (2q24.3; P=2.40 × 10(-6) ) were associated with the area and thickness of left HG, respectively. Both genes are involved in the development of the nervous system. The SNP rs7062395 close to the X-linked deafness gene POU3F4 was associated with right HG thickness (Xq21.1; P=2.38 × 10(-6) ). This is the first molecular genetic analysis of variability in HG morphology.


Subject(s)
Auditory Cortex/anatomy & histology , Genome, Human , Quantitative Trait Loci , Adolescent , Adult , Aged , Female , Guanine Nucleotide Exchange Factors/genetics , Humans , Male , Membrane Proteins/genetics , Middle Aged , POU Domain Factors/genetics , Polymorphism, Single Nucleotide , Protein Serine-Threonine Kinases/genetics , Ubiquitin-Protein Ligases/genetics
13.
Genes Brain Behav ; 13(5): 508-16, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24589356

ABSTRACT

The brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT) genes are relevant candidates for depression. Variation in these genes is associated with stress sensitivity and depressotypic cognitive biases. The interaction between genes and stressful events is considered as an important mechanism in the development of depression. This study examined the effects of the BDNF and COMT genes on biased processing and the interaction with childhood stress in vulnerable individuals. A total of 198 remitted depressed individuals performed an n-back task with emotional facial stimuli (happy and sad). Childhood events were measured with a questionnaire. Genotype by childhood events interactions were analyzed for happy and sad expressions for BDNF (Val66Met; rs6265) and COMT (Val158Met; rs4680), individually and combined. BDNF and COMT both interacted significantly (P = 0.006 and P = 0.014, respectively) with childhood trauma on reaction time for happy faces. For both genes, Met-carriers with childhood trauma showed less positive bias for happy faces than those without childhood trauma. Val-carriers did not show a differential bias. Individuals with childhood trauma and 3 or 4 risk alleles (BDNF and COMT combined) showed less positive bias than those without childhood trauma (P = 0.011). The BDNF × COMT × childhood trauma interaction yielded a P = 0.055, but had limited power. A potential weakness is the measurement method of the childhood events, as negative bias might have affected participants' recall. Our findings endorse the association of BDNF and COMT with stress and depression and provide a possible intermediate, i.e. biased processing of positive information. Tailoring treatment to specific risk profiles based on genetic susceptibility and childhood stress could be promising.


Subject(s)
Brain-Derived Neurotrophic Factor/genetics , Catechol O-Methyltransferase/genetics , Depression/genetics , Stress, Psychological/genetics , Adult , Child , Child Abuse/psychology , Depression/etiology , Depression/psychology , Emotions , Female , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Stress, Psychological/complications , Visual Perception
14.
Mol Psychiatry ; 19(4): 452-61, 2014 Apr.
Article in English | MEDLINE | ID: mdl-23568192

ABSTRACT

Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64,888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 × 10(-5), odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10(-6)). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.


Subject(s)
Bipolar Disorder/ethnology , Bipolar Disorder/genetics , Cyclic AMP Response Element-Binding Protein/genetics , Gene Expression Regulation/genetics , Genetic Predisposition to Disease , Hippocampus/pathology , Polymorphism, Single Nucleotide/genetics , Adult , Age Factors , Aged , Aged, 80 and over , Asian People/genetics , Case-Control Studies , Computational Biology , Female , Gene Frequency/genetics , Genetic Association Studies , Humans , Male , Middle Aged , Neuroimaging , Neuropsychological Tests , Phenotype , RNA, Messenger/metabolism , White People/genetics
15.
Eur Neuropsychopharmacol ; 23(6): 448-57, 2013 Jun.
Article in English | MEDLINE | ID: mdl-22841130

ABSTRACT

The shared genetic basis of attention deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) was explored by investigating the association of candidate risk factors in neurotransmitter genes with both disorders. One hundred seven methadone maintenance treatment patients, 36 having an ADHD diagnosis, 176 adult patients with ADHD without SUDs, and 500 healthy controls were genotyped for variants in the DRD4 (exon 3 VNTR), DRD5 (upstream VNTR), HTR1B (rs6296), DBH (rs2519152), COMT (rs4680; Val158Met), and OPRM1 (rs1799971; 118A>G) genes. Association with disease was tested using logistic regression models. This pilot study was adequately powered to detect larger genetic effects (OR≥2) of risk alleles with a low frequency. Compared to controls, ADHD patients (with and without SUDs) showed significantly increased frequency of the DBH (rs2519152: OR 1.73; CI 1.15-2.59; P=0.008) and the OPRM1 risk genotypes (rs1799971: OR 1.71; CI 1.17-2.50; P=0.006). The DBH risk genotype was associated with ADHD diagnosis, with the association strongest in the pure ADHD group. The OPRM1 risk genotype increased the risk for the combined ADHD and SUD phenotype. The present study strengthens the evidence for a shared genetic basis for ADHD and addiction. The association of OPRM1 with the ADHD and SUD combination could help to explain the contradictory results of previous studies. The power limitations of the study restrict the significance of these findings: replication in larger samples is warranted.


Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Dopamine beta-Hydroxylase/genetics , Polymorphism, Single Nucleotide , Receptors, Opioid, mu/genetics , Substance-Related Disorders/genetics , Adolescent , Adult , Aged , Attention Deficit Disorder with Hyperactivity/complications , Attention Deficit Disorder with Hyperactivity/metabolism , Catechol O-Methyltransferase/genetics , Catechol O-Methyltransferase/metabolism , Diagnostic and Statistical Manual of Mental Disorders , Dopamine beta-Hydroxylase/metabolism , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Netherlands , Pilot Projects , Receptors, Biogenic Amine , Receptors, Opioid, mu/metabolism , Substance-Related Disorders/complications , Substance-Related Disorders/metabolism , Young Adult
17.
Genes Brain Behav ; 10(8): 844-51, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21815997

ABSTRACT

Different analytic strategies, including linkage, association and meta-analysis support a role of CDH13 in the susceptibility to attention deficit/hyperactivity disorder (ADHD). CDH13 codes for cadherin 13 (or H-cadherin), which is a member of a family of calcium-dependent cell-cell adhesion proteins and a regulator of neural cell growth. We tested the association between CDH13 on three executive functioning tasks that are promising endophenotypes of ADHD. An adjusted linear regression analysis was performed in 190 ADHD-affected Dutch probands of the IMAGE project. Three executive functions were examined: inhibition, verbal and visuo-spatial working memory (WM). We tested 2632 single nucleotide polymorphisms (SNPs) within CDH13 and 20 kb up- and downstream of the gene (capturing regulatory sequences). To adjust for multiple testing within the gene, we applied stringent permutation steps. Intronic SNP rs11150556 is associated with performance on the Verbal WM task. No other SNP showed gene-wide significance with any of the analyzed traits, but a 72-kb SNP block located 446 kb upstream of SNP rs111500556 showed suggestive evidence for association (P-value range 1.20E-03 to 1.73E-04) with performance in the same Verbal WM task. This study is the first to examine CDH13 and neurocognitive functioning. The mechanisms underlying the associations between CDH13 and the clinical phenotype of ADHD and verbal WM are still unknown. As such, our study may be viewed as exploratory, with the results presented providing interesting hypotheses for further testing.


Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Attention Deficit Disorder with Hyperactivity/psychology , Cadherins/genetics , Memory, Short-Term/physiology , Psychomotor Performance/physiology , Adolescent , Child , Child, Preschool , DNA/genetics , DNA/isolation & purification , Female , Genetic Association Studies , Genotype , Humans , Inhibition, Psychological , Male , Netherlands , Neuropsychological Tests , Phenotype , Polymorphism, Single Nucleotide , Regression Analysis , Space Perception/physiology , Visual Perception/physiology , Wechsler Scales
18.
Psychol Med ; 41(4): 861-71, 2011 Apr.
Article in English | MEDLINE | ID: mdl-20522277

ABSTRACT

BACKGROUND: Twin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ. METHOD: Multivariate familial models were run on data from 1265 individuals aged 6-18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice-delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI). RESULTS: Significant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41-0.71) and IQ (rF=-0.25 to -0.49). The association between ADHD and cognitive performance was largely independent (80-87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ. CONCLUSIONS: The aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADHD.


Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Attention Deficit Disorder with Hyperactivity/psychology , Cognition Disorders/genetics , Cognition Disorders/psychology , Intelligence/genetics , Neuropsychological Tests/statistics & numerical data , Phenotype , Adolescent , Attention Deficit Disorder with Hyperactivity/diagnosis , Child , Choice Behavior , Cognition Disorders/diagnosis , Europe , Female , Humans , Inhibition, Psychological , Internal-External Control , Male , Multivariate Analysis , Personality Assessment/statistics & numerical data , Psychometrics , Reaction Time/genetics , Reward
19.
Mol Psychiatry ; 15(3): 260-71, 2010 Mar.
Article in English | MEDLINE | ID: mdl-18852698

ABSTRACT

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animals and may be implicated in the etiology of mood-related phenotypes. However, genetic association studies of the BDNF Val66Met polymorphism (single nucleotide polymorphism rs6265) in major depressive disorder (MDD) have produced inconsistent results. We conducted a meta-analysis of studies comparing the frequency of the BDNF Val66Met-coding variant in depressed cases (MDD) and nondepressed controls. A total of 14 studies involving 2812 cases with DSM-III or -IV defined MDD and 10 843 nondepressed controls met the inclusion criteria. Analyses were stratified either by gender or ethnicity (Asian and Caucasian) because MDD is more prevalent in women and in Caucasians and because BDNF allele frequencies differ by ethnicity. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were provided for allelic analyses (Met versus Val), as well as for genotypic analyses (Met/Met and Val/Met versus Val/Val). In the total sample, the BDNF Val66Met polymorphism was not significantly associated with depression. However, the gender stratified analyses revealed significant effects in both the allelic and genotypic analyses in men (OR(MET), 95% CI; 1.27 (1.10-1.47); OR(MET/MET), 95% CI; 1.67 (1.19-2.36)). Stratification according to ethnicity did not show significant effects of the Val66Met polymorphism on MDD. Our results suggest that the BDNF Val66Met polymorphism is of greater importance in the development of MDD in men than in women. Future research into gender issues will be of interest.


Subject(s)
Asian People/genetics , Brain-Derived Neurotrophic Factor/genetics , Depressive Disorder, Major/genetics , Polymorphism, Single Nucleotide , White People/genetics , Alleles , Female , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Sex Characteristics
20.
Am J Med Genet B Neuropsychiatr Genet ; 147B(8): 1576-9, 2008 Dec 05.
Article in English | MEDLINE | ID: mdl-18802924

ABSTRACT

ADHD is a neuropsychiatric disorder characterized by chronic hyperactivity, inattention and impulsivity, which affects about 5% of school-age children. ADHD persists into adulthood in at least 15% of cases. It is highly heritable and familial influences seem strongest for ADHD persisting into adulthood. However, most of the genetic research in ADHD has been carried out in children with the disorder. The gene that has received most attention in ADHD genetics is SLC6A3/DAT1 encoding the dopamine transporter. In the current study we attempted to replicate in adults with ADHD the reported association of a 10-6 SLC6A3-haplotype, formed by the 10-repeat allele of the variable number of tandem repeat (VNTR) polymorphism in the 3' untranslated region of the gene and the 6-repeat allele of the VNTR in intron 8 of the gene, with childhood ADHD. In addition, we wished to explore the role of a recently described VNTR in intron 3 of the gene. Two hundred sixteen patients and 528 controls were included in the study. We found a 9-6 SLC6A3-haplotype, rather than the 10-6 haplotype, to be associated with ADHD in adults. The intron 3 VNTR showed no association with adult ADHD. Our findings converge with earlier reports and suggest that age is an important factor to be taken into account when assessing the association of SLC6A3 with ADHD. If confirmed in other studies, the differential association of the gene with ADHD in children and in adults might imply that SLC6A3 plays a role in modulating the ADHD phenotype, rather than causing it.


Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Dopamine Plasma Membrane Transport Proteins/genetics , Genetic Predisposition to Disease , Haplotypes , 3' Untranslated Regions , Adult , Attention Deficit Disorder with Hyperactivity/diagnosis , Case-Control Studies , Chi-Square Distribution , Female , Genotype , Humans , Introns , Male , Microsatellite Repeats , Polymorphism, Genetic
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