Genetic Risk For Attention Deficit Hyperactivity Disorder Research Articles

Interaction of genetic liability for attention deficit hyperactivity disorder (ADHD) and perinatal inflammation contributes to ADHD symptoms in children

ObjectiveGenetic and environmental factors contribute to the development of Attention Deficit/Hyperactivity Disorder (ADHD). Perinatal inflammation is one of the promising environmental risk factors for ADHD, but the relationship between the genetic risk for ADHD and perinatal inflammation requires further examination. MethodsA possible gene-environmental interaction between perinatal inflammation and ADHD polygenic risk score (ADHD-PRS) on ADHD symptoms was investigated in children aged 8–9 from the Hamamatsu Birth Cohort for Mothers and Children (N = 531). Perinatal inflammation was evaluated by the level of concentration of three cytokines assayed in umbilical cord blood. The genetic risk for ADHD was assessed by calculating ADHD-PRS for each individual using a previously collected genome-wide association study of ADHD. ResultsPerinatal inflammation (β [SE], 0.263 [0.017]; P < 0.001), ADHD-PRS (β [SE], 0.116[0.042]; P = 0.006), and an interaction between the two (β [SE], 0.031[0.011]; P = 0.010) were associated with ADHD symptoms. The association between perinatal inflammation and ADHD symptoms measured by ADHD-PRS was evident only in the two higher genetic risk groups (β [SE], 0.623[0.122]; P < 0.001 for the medium-high risk group; β [SE], 0.664[0.152]; P < 0.001 for the high-risk group). ConclusionInflammation in the perinatal period both directly elevated ADHD symptoms and magnified the impact of genetic vulnerability on ADHD risk particularly among children aged 8–9 with genetically higher risk for ADHD.

ADHD and its neurocognitive substrates: A two sample Mendelian randomization study

Attention-deficit/hyperactivity disorder (ADHD) is associated with a wide array of neural and cognitive features, and other psychiatric disorders, identified mainly through cross-sectional associations studies. However, it is unclear if the disorder is causally associated with these neurocognitive features. Here, we applied a two-sample bidirectional Mendelian randomization (MR) study to summary GWAS data to explore the presence and direction of a causal effect between ADHD and a range of neurocognitive features and other psychiatric disorders. The inverse variance weighted method was used in the main analysis, and two MR methods (MR-Egger, weighted median) were used for robustness checks. We found that genetic risk for ADHD was causally associated with a decreased area of lateral orbitofrontal cortex. Conversely, we found that brain volume and some features of intrinsic functional connectivity had causal effects on ADHD risk. Bidirectional causal links were found between ADHD and adult general intelligence, as well as depression and autistic spectrum disorders. Such work highlights the important ties between ADHD and general cognitive ability, and suggest some neural features, previously merely associated with the disorder, may play a causal role in its pathogenesis.

Mother's and children's ADHD genetic risk, household chaos and children's ADHD symptoms: A gene-environment correlation study.

Chaotic home environments may contribute to children's attention-deficit hyperactivity disorder (ADHD) symptoms. However, ADHD genetic risk may also influence household chaos. This study investigated whether children in chaotic households had more ADHD symptoms, if mothers and children with higher ADHD genetic risk lived in more chaotic households, and the joint association of genetic risk and household chaos on the longitudinal course of ADHD symptoms across childhood. Participants were mothers and children from the Environmental Risk (E-Risk) Longitudinal Twin Study, a UK population-representative birth cohort of 2,232 twins. Children's ADHD symptoms were assessed at ages 5, 7, 10 and 12 years. Household chaos was rated by research workers at ages 7, 10 and 12, and by mother's and twin's self-report at age 12. Genome-wide ADHD polygenic risk scores (PRS) were calculated for mothers (n = 880) and twins (n = 1,999); of these, n = 871 mothers and n = 1,925 children had information on children's ADHD and household chaos. Children in more chaotic households had higher ADHD symptoms. Mothers and children with higher ADHD PRS lived in more chaotic households. Children's ADHD PRS was associated with household chaos over and above mother's PRS, suggesting evocative gene-environment correlation. Children in more chaotic households had higher baseline ADHD symptoms and a slower rate of decline in symptoms. However, sensitivity analyses estimated that gene-environment correlation accounted for a large proportion of the association of household chaos on ADHD symptoms. Children's ADHD genetic risk was independently associated with higher levels of household chaos, emphasising the active role of children in shaping their home environment. Our findings suggest that household chaos partly reflects children's genetic risk for ADHD, calling into question whether household chaos directly influences children's core ADHD symptoms. Our findings highlight the importance of considering parent and child genetic risk in relation to apparent environmental exposures.

Comorbidity of Attention-Deficit Hyperactivity Disorder and Autism Spectrum Disorders: Current Status and Promising Directions.

High rates of co-occurring Attention-Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorders (ASD) suggest common causal pathways, which await elucidation. What is well-established, however, is the negative impact of comorbid ADHD and ASD on outcomes for everyday living, particularly in social interaction and communication and on broader psychopathology. Neurocognitive approaches suggest correlates of comorbidity are rooted in functional connectivity networks associated with executive control. There is support for familial origins, with molecular-genetic studies suggesting a causal role of pleiotropic genes. Further investigation is needed to elucidate fully how genetic risk for ADHD and ASD affects neurodevelopment and to identify structural and functional neural correlates and their behavioral sequelae. Identification of intermediate phenotypes is necessary to advance understanding, which requires studies that include the full spectrum of ASD and ADHD symptom severity, use longitudinal designs and multivariate methods to probe broad constructs, such as executive and social function, and consider other sources of heterogeneity, such as age, sex, and other psychopathology. Randomized efficacy trials targeting comorbid symptomatology are needed to mitigate negative developmental outcomes.

Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study

Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = −0.14; 95% confidence interval [CI]: −0.24 to −0.03; p value = 0.010) and MDD (β = −0.16; 95% CI: −0.27 to −0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34–1.93; p value = 2e−7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.

Elevated risk of attention deficit hyperactivity disorder (ADHD) in Japanese children with higher genetic susceptibility to ADHD with a birth weight under 2000 g

BackgroundBoth genetic and pre- and perinatal factors, including birth weight, have been implicated in the onset of attention deficit hyperactivity disorder (ADHD) traits among children. This study aimed to elucidate to what extent the genetic risk of ADHD moderates the association between birth weight and ADHD traits among Japanese children.MethodsWe conducted a longitudinal birth cohort study (Hamamatsu Birth Cohort for Mother and Children Study) to investigate the association of genetic risk for ADHD and low birth weight with ADHD traits among Japanese children. Out of 1258 children, we included 796 who completed follow-ups at 8 to 9 years of age. Birth weight was categorized as <2000 g, 2000–2499 g, and ≥2500 g. Polygenic risk score for ADHD was generated using the summary data of a large-scale genome-wide association study. The Rating Scale IV (ADHD-RS) assessed ADHD traits (inattention and hyperactivity/impulsivity) based on parental reports. Following previous studies, sex, birth order of the child, gestational age at birth, mother’s age at delivery, educational attainment, pre-pregnancy body mass index, pre-pregnancy or during pregnancy smoking status, alcohol consumption during pregnancy, father’s age, education, and annual family income were considered as covariates. Multivariable negative binomial regression was applied to evaluate the association between birth weight and ADHD traits, while adjusting for potential covariates. The interaction term between birth weight categories and binary polygenic risk was added to the model.ResultsBirth weight of 2000–2499 g was not associated with ADHD traits. Birth weight under 2000 g was significantly associated with both inattention and hyperactivity. When accounting for higher and lower genetic risk for ADHD, only those with higher genetic risk and birth weight < 2000 g were associated with inattention (rate ratio [RR] 1.56, 95% CI 1.07–2.27) and hyperactivity (RR 1.87, 95% CI 1.14–3.06).ConclusionsBirth weight under 2000 g, together with the genetic risk of ADHD, contributes to higher levels of ADHD traits among Japanese children aged 8 to 9 years. The suggested association between low birth weight and ADHD is confined to children with a genetic susceptibility to ADHD, indicating the relevance of genetic-environmental interactions in the etiology.

Resilience Factors That Modify Genetic Risk for ADHD Matter for Later Life Emotional and Cognitive Health Outcomes

Having features of Attention Deficit Hyperactivity Disorder (ADHD) is associated with challenges with emotional regulation and cognitive function. Heritability for ADHD in adults is estimated to be 30%. The degree to which genetic risk for ADHD can be modified by protective factors, such as strong personal relationships and pursuing more education, to result in better emotional and cognitive outcomes at later ages is not well understood. We evaluated these relationships in a population-representative sample of older adults in the U.S. Health and Retirement Study, with 9,003 European Americans (EA; 57% women, age M=68.6, SD=10.4), and 1,622 African Americans (AA; 63% women, age M=64.4, SD=9.5). Outcomes included validated scales for psychological resilience, life satisfaction, depressive symptoms (DepSx), cognitive functioning, and impairment, assessed between 2008-2012. A genetic risk score for ADHD (GRS-ADHD) was calculated from a genomewide-scan, using a mixed ancestry sample. We used multivariable linear and logistic regression models, adjusted for age, gender, and genetic ancestry. We found a protective effect such that stronger personal relationships in adulthood reduced the inverse relationship between the GRS-ADHD and resilience and life satisfaction in later age (interaction p’s<.004 in EAs), but not with DepSx. In contrast, strong parental relationships in childhood attenuated the association between the GRS-ADHD and later life DepSx (interaction p’s<.007 in EAs and AAs) only. Education did not modify, but mediated the main effect of the GRS-ADHD on cognitive abilities and impairment in EAs and AAs. Findings have implications for later age health for those at greater genetic risk for ADHD.

Neural Correlates of the Dual-Pathway Model for ADHD in Adolescents.

The dual-pathway model has been proposed to explain the heterogeneity in symptoms of attention deficit hyperactivity disorder (ADHD) by two independent psychological pathways based on distinct brain circuits. The authors sought to test whether the hypothesized cognitive and motivational pathways have separable neural correlates. In a longitudinal community-based cohort of 1,963 adolescents, the neuroanatomical correlates of ADHD were identified by a voxel-wise association analysis and then validated using an independent clinical sample (99 never-medicated patients with ADHD, 56 medicated patients with ADHD, and 267 healthy control subjects). The cognitive and motivational pathways were assessed by neuropsychological tests of working memory, intrasubject variability, stop-signal reaction time, and delay discounting. The associations were tested between the identified neuroanatomical correlates and both ADHD symptoms 2 years later and the polygenic risk score for ADHD. Gray matter volumes of both a prefrontal cluster and a posterior occipital cluster were negatively associated with inattention. Compared with healthy control subjects, never-medicated patients, but not medicated patients, had significantly lower gray matter volumes in these two clusters. Working memory and intrasubject variability were associated with the posterior occipital cluster, and delay discounting was independently associated with both clusters. The baseline gray matter volume of the posterior occipital cluster predicted the inattention symptoms in a 2-year follow-up and was associated with the genetic risk for ADHD. The dual-pathway model has both shared and separable neuroanatomical correlates, and the shared correlate in the occipital cortex has the potential to serve as an imaging trait marker of ADHD, especially the inattention symptom domain.

Common Polygenic Variations for Psychiatric Disorders and Cognition in Relation to Brain Morphology in the General Pediatric Population.

This study examined the relation between polygenic scores (PGSs) for 5 major psychiatric disorders and 2 cognitive traits with brain magnetic resonance imaging morphologic measurements in a large population-based sample of children. In addition, this study tested for differences in brain morphology-mediated associations between PGSs for psychiatric disorders and PGSs for related behavioral phenotypes. Participants included 1,139 children from the Generation R Study assessed at 10 years of age with genotype and neuroimaging data available. PGSs were calculated for schizophrenia, bipolar disorder, major depression disorder, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, intelligence, and educational attainment using results from the most recent genome-wide association studies. Image processing was performed using FreeSurfer to extract cortical and subcortical brain volumes. Greater genetic susceptibility for ADHD was associated with smaller caudate volume (strongest prior= 0.01: β=-0.07, p= .006). In boys, mediation analysis estimates showed that 11% of the association between the PGS for ADHD and the PGS attention problems was mediated by differences in caudate volume (n= 535), whereas mediation was not significant in girls or the entire sample. PGSs for educational attainment and intelligence showed positive associations with total brain volume (strongest prior= 0.5: β= 0.14, p= 7.12× 10-8; and β= 0.12, p= 6.87× 10-7, respectively). The present findings indicate that the neurobiological manifestation of polygenic susceptibility for ADHD, educational attainment, and intelligence involve early morphologic differences in caudate and total brain volumes in childhood. Furthermore, the genetic risk for ADHD might influence attention problems through the caudate nucleus in boys.

A case\u2013control genome-wide association study of ADHD discovers a novel association with the tenascin R (TNR) gene

It is well-established that there is a strong genetic contribution to the aetiology of attention deficit hyperactivity disorder (ADHD). Here, we employed a hypothesis-free genome-wide association study (GWAS) design in a sample of 480 clinical childhood ADHD cases and 1208 controls to search for novel genetic risk loci for ADHD. DNA was genotyped using Illumina’s Human Infinium PsychArray-24v1.2., and the data were subsequently imputed to the 1000 Genomes reference panel. Rigorous quality control and pruning of genotypes at both individual subject and single nucleotide polymorphism (SNP) levels was performed. Polygenic risk score (PGRS) analysis revealed that ADHD case–control status was explained by genetic risk for ADHD, but no other major psychiatric disorders. Logistic regression analysis was performed genome-wide to test the association between SNPs and ADHD case–control status. We observed a genome-wide significant association (p = 3.15E−08) between ADHD and rs6686722, mapped to the Tenascin R (TNR) gene. Members of this gene family are extracellular matrix glycoproteins that play a role in neural cell adhesion and neurite outgrowth. Suggestive evidence of associations with ADHD was observed for an additional 111 SNPs (⩽9.91E−05). Although intriguing, the association between DNA variation in the TNR gene and ADHD should be viewed as preliminary given the small sample size of this discovery dataset.

Heterotypic trajectories of dimensional psychopathology across the lifespan: the case of youth-onset attention deficit/hyperactivity disorder.

Recent studies have demonstrated the existence of a distinct late-onset attention deficit/hyperactivity disorder (ADHD) trajectory. Our objective is to test if there are distinct ADHD trajectories regarding age of onset from childhood to adolescence and to compare clinical manifestations, cognitive functions and genetic risk for ADHD among distinct longitudinal groups. Nine hundred and twenty four children and adolescents from the community participated in the study. We compared clinical, cognitive features and genetic risk among four groups of participants: (a) childhood-limited, (b) youth-onset, (c) childhood-onset with youth persistence, and (d) community comparisons without ADHD. Symptomatic and diagnostic assessments were performed using the Development and Well-Being Behavior Assessment, the Strengths and Difficulties Questionnaire, and the Child Behavior Checklist. Cognitive functions were measured using a battery of standardized tests. Genetic risk for ADHD was calculating using summary statistics from the Psychiatric Genomics Consortium. Half of the adolescents (52%) with ADHD had their symptom onset in adolescence. The impairment level of this group in adolescence is similar to the persistent group. Despite not having ADHD, the youth-onset group already presented in childhood more symptoms from other domains of psychopathology, higher shared variance in psychiatric symptomatology (p-factor), school impairment, and executive dysfunctions than community comparisons. Furthermore, the youth-onset group presented lower levels of genetic risk for ADHD compared to other cases. A significant proportion of adolescents with ADHD were youth-onset cases and presented similar impairment levels as those cases with early-onset ADHD. The presence of cognitive impairments and higher levels of clinical symptoms in the youth-onset group already at childhood speaks in favor of a heterotypic trajectory of psychopathology suggesting that youth-onset ADHD might be an artificial consequence of categorizing dimensional psychopathology into discrete diagnostic groups.

Investigating the genetic underpinnings of early-life irritability

Severe irritability is one of the commonest reasons prompting referral to mental health services. It is frequently seen in neurodevelopmental disorders that manifest early in development, especially attention-deficit/hyperactivity disorder (ADHD). However, irritability can also be conceptualized as a mood problem because of its links with anxiety/depressive disorders; notably DSM-5 currently classifies severe, childhood-onset irritability as a mood disorder. Investigations into the genetic nature of irritability are lacking although twin studies suggest it shares genetic risks with both ADHD and depression. We investigated the genetic underpinnings of irritability using a molecular genetic approach, testing the hypothesis that early irritability (in childhood/adolescence) is associated with genetic risk for ADHD, as indexed by polygenic risk scores (PRS). As a secondary aim we investigated associations between irritability and PRS for major depressive disorder (MDD). Three UK samples were utilized: two longitudinal population-based cohorts with irritability data from childhood (7 years) to adolescence (15–16 years), and one ADHD patient sample (6–18 years). Irritability was defined using parent reports. PRS were derived from large genome-wide association meta-analyses. We observed associations between ADHD PRS and early irritability in our clinical ADHD sample and one of the population samples. This suggests that early irritability traits share genetic risk with ADHD in the general population and are a marker of higher genetic loading in individuals with an ADHD diagnosis. Associations with MDD PRS were not observed. This suggests that early-onset irritability could be conceptualized as a neurodevelopmental difficulty, behaving more like disorders such as ADHD than mood disorders.

Spatial Attentional Bias as a Marker of Genetic Risk, Symptom Severity, and Stimulant Response in ADHD

Attention-deficit hyperactivity disorder (ADHD) is a heritable childhood onset disorder that is marked by variability at multiple levels including clinical presentation, cognitive profile, and response to stimulant medications. It has been suggested that this variability may reflect etiological differences, particularly, at the level of underlying genetics. This study examined whether an attentional phenotype-spatial attentional bias could serve as a marker of symptom severity, genetic risk, and stimulant response in ADHD. A total of 96 children and adolescents with ADHD were assessed on the Landmark Task, which is a sensitive measure of spatial attentional bias. All children were genotyped for polymorphisms (3' untranslated (UTR) and intron 8 variable number of tandem repeats (VNTRs)) of the dopamine transporter gene (DAT1). Spatial attentional bias correlated with ADHD symptom levels and varied according to DAT1 genotype. Children who were homozygous for the 10-repeat allele of the DAT1 3'-UTR VNTR displayed a rightward attentional bias and had higher symptom levels compared to those with the low-risk genotype. A total of 26 of these children who were medication naive performed the Landmark Task at baseline and then again after 6 weeks of stimulant medication. Left-sided inattention (rightward bias) at baseline was associated with an enhanced response to stimulants at 6 weeks. Moreover, changes in spatial bias with stimulant medications, varied as a function of DAT1 genotype. This study suggests an attentional phenotype that relates to symptom severity and genetic risk for ADHD, and may have utility in predicting stimulant response in ADHD.