Risk Of Attention Deficit Hyperactivity Disorder Research Articles

Maternal asthma and asthma exacerbation during pregnancy and attention-deficit/hyperactivity disorder in offspring: a population-based cohort study.

The link between inflammatory disorders, such as asthma, and attention deficit hyperactivity disorder (ADHD) is attracting increasing attention but few studies have examined cross-generational associations. We sought to examine associations of maternal asthma and asthma exacerbation during pregnancy, as well as paternal asthma, with the risk of ADHD in children. This population-based cohort study used data from the Taiwan National Health Insurance Research Database from 2004 to 2017. Cox regression models compared the risk of ADHD in children of parents with and without asthma, adjusting for parental sociodemographic, physical, and mental health conditions, as well as the child's birth weight, and number of births. A sibling control approach was employed to compensate for unmeasured confounders of asthma exacerbation during pregnancy. In the fully adjusted models, maternal and paternal asthma were both significantly associated with an increased risk of ADHD in offspring, with hazard ratios (HRs) of 1.36 (1.31-1.40) and 1.10 (1.05-1.14), respectively. Acute asthma exacerbation during pregnancy was not associated with the risk of further offspring ADHD (adjusted HR 1.00, 95% CI: 0.75-1.34). Both maternal and paternal asthma are associated with an increased risk of ADHD in offspring. The risk was higher from maternal asthma. However, no such association was found with maternal asthma exacerbation during pregnancy of sibling comparison.

Identifying Risk Factors for Attention-Deficit/Hyperactivity Disorder (ADHD): a Public Health Concern and Opportunity.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders with significant individual and societal negative impacts of the disorder continuing into adulthood (Danielson et al. inJournal of Clinical Child and Adolescent Psychology, in press; Landes and London in Journal of Attention Disorders 25:3-13, 2021). Genetic and environmental risk (e.g., modifiable exposures such as prenatal tobacco exposure and child maltreatment) for ADHD is likely multifactorial (Faraone et al. in Neuroscience & Biobehavioral Reviews 128:789-818, 2021). However, the evidence for potentially modifiable contextual risks is spread across studies with different methodologies and ADHD criteria limiting understanding of the relationship between early risk factors and later childhood ADHD. Using common methodology across six meta-analyses (Bitsko et al. in Prevention Science, 2022; Claussen et al. in Prevention Science 1-23,2022; Dimitrov et al. in Prevention Science, 2023; Maher et al. in Prevention Science, 2023; Robinson, Bitskoet al. in Prevention Science, 2022; So et al. in Prevention Science, 2022) examining 59 risk factors for childhood ADHD, the papers in this special issue use a public health approach to address prior gaps in the literature. This introductory paper provides examples of comprehensive public health approaches focusing on policy, systems, and environmental changes across socio-ecological contexts to improve health and wellbeing through prevention, early intervention, and support across development using findings from these meta-analyses. Together, the findings from these studies and a commentary by an author independent from the risk studies have the potential to minimize risk conditions, prioritize prevention efforts, and improve the long-term health and wellbeing of children and adults with ADHD.

Acetaminophen Use During Pregnancy and Children’s Risk of Autism, ADHD, and Intellectual Disability

Several studies suggest that acetaminophen (paracetamol) use during pregnancy may increase risk of neurodevelopmental disorders in children. If true, this would have substantial implications for management of pain and fever during pregnancy. To examine the associations of acetaminophen use during pregnancy with children's risk of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability. This nationwide cohort study with sibling control analysis included a population-based sample of 2 480 797 children born in 1995 to 2019 in Sweden, with follow-up through December 31, 2021. Use of acetaminophen during pregnancy prospectively recorded from antenatal and prescription records. Autism, ADHD, and intellectual disability based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes in health registers. In total, 185 909 children (7.49%) were exposed to acetaminophen during pregnancy. Crude absolute risks at 10 years of age for those not exposed vs those exposed to acetaminophen were 1.33% vs 1.53% for autism, 2.46% vs 2.87% for ADHD, and 0.70% vs 0.82% for intellectual disability. In models without sibling control, ever-use vs no use of acetaminophen during pregnancy was associated with marginally increased risk of autism (hazard ratio [HR], 1.05 [95% CI, 1.02-1.08]; risk difference [RD] at 10 years of age, 0.09% [95% CI, -0.01% to 0.20%]), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; RD, 0.21% [95% CI, 0.08%-0.34%]), and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; RD, 0.04% [95% CI, -0.04% to 0.12%]). To address unobserved confounding, matched full sibling pairs were also analyzed. Sibling control analyses found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, -0.14% to 0.18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, -0.02% [95% CI, -0.21% to 0.15%]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, -0.10% to 0.13%]). Similarly, there was no evidence of a dose-response pattern in sibling control analyses. For example, for autism, compared with no use of acetaminophen, persons with low (<25th percentile), medium (25th-75th percentile), and high (>75th percentile) mean daily acetaminophen use had HRs of 0.85, 0.96, and 0.88, respectively. Acetaminophen use during pregnancy was not associated with children's risk of autism, ADHD, or intellectual disability in sibling control analysis. This suggests that associations observed in other models may have been attributable to familial confounding.

Association of cerebral palsy with autism spectrum disorder and attention-deficit/hyperactivity disorder in children: a large-scale nationwide population-based study

ObjectiveTo examine the association of cerebral palsy with autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), providing evidence for interdisciplinary medical service for children with cerebral palsy.DesignA large-scale nationwide population-based...

Maternal diabetes and risk of attention-deficit/hyperactivity disorder in offspring in a multinational cohort of 3.6 million mother-child pairs.

Previous studies report an association between maternal diabetes mellitus (MDM) and attention-deficit/hyperactivity disorder (ADHD), often overlooking unmeasured confounders such as shared genetics and environmental factors. We therefore conducted a multinational cohort study with linked mother-child pairs data in Hong Kong, New Zealand, Taiwan, Finland, Iceland, Norway and Sweden to evaluate associations between different MDM (any MDM, gestational diabetes mellitus (GDM) and pregestational diabetes mellitus (PGDM)) and ADHD using Cox proportional hazards regression. We included over 3.6 million mother-child pairs between 2001 and 2014 with follow-up until 2020. Children who were born to mothers with any type of diabetes during pregnancy had a higher risk of ADHD than unexposed children (pooled hazard ratio (HR) = 1.16, 95% confidence interval (CI) = 1.08-1.24). Higher risks of ADHD were also observed for both GDM (pooled HR = 1.10, 95% CI = 1.04-1.17) and PGDM (pooled HR = 1.39, 95% CI = 1.25-1.55). However, siblings with discordant exposure to GDM in pregnancy had similar risks of ADHD (pooled HR = 1.05, 95% CI = 0.94-1.17), suggesting potential confounding by unmeasured, shared familial factors. Our findings indicate that there is a small-to-moderate association between MDM and ADHD, whereas the association between GDM and ADHD is unlikely to be causal. This finding contrast with previous studies, which reported substantially higher risk estimates, and underscores the need to reevaluate the precise roles of hyperglycemia and genetic factors in the relationship between MDM and ADHD.

Associations between breakfast skipping and outcomes in neuropsychiatric disorders, cognitive performance, and frailty: a Mendelian randomization study

BackgroundPrior studies have identified a correlation between breakfast skipping and a heightened risk of mental health issues. This investigation aimed to employ a Two-Sample Mendelian Randomization (MR) approach to explore the potential causal links between breakfast skipping and various psychiatric, neurological disorders, cognitive performance, and frailty.MethodsUtilizing data from genome-wide association studies within European demographics, this research scrutinized the association between breakfast habits and several neuropsychiatric conditions and physical health outcomes, including Alzheimer’s disease (AD), Attention Deficit Hyperactivity Disorder (ADHD), Bipolar Disorder (BD), Major Depressive Disorder (MDD), Narcolepsy, Insomnia, cognitive performance, and frailty. In this MR analysis, the Inverse Variance Weighted (IVW) method was primarily utilized for evaluation. Outcomes were reported as Odds Ratios (OR) and regression coefficients (β), and underwent validation through False Discovery Rate (FDR) corrections, thereby offering a rigorous evaluation of the effects of breakfast habits on both mental and physical health dimensions.ResultsFindings demonstrate a significant causal link between skipping breakfast and an increased risk of ADHD (OR = 2.74, 95%CI: 1.54–4.88, PFDR = 0.003) and MDD (OR = 1.7, 95%CI: 1.22–2.37, PFDR = 0.005). Conversely, no substantial causal associations were identified between breakfast skipping and AD, BD, narcolepsy, or insomnia (PFDR > 0.05). Moreover, a notable causal relationship was established between skipping breakfast and a reduction in cognitive performance (β = -0.16, 95%CI: -0.29–0.04, PFDR = 0.024) and an increase in frailty (β = 0.29, 95%CI: 0.12–0.45, PFDR = 0.003).ConclusionThe MR analysis reveals that skipping breakfast is associated with an increased risk of ADHD, MDD, decreased cognitive performance, and greater frailty, while showing no associations were found with AD, BD, narcolepsy, or insomnia. These findings warrant further investigation into the underlying mechanisms and emphasize the importance of regular breakfast consumption for mental and physical well-being.

Associations between attention-deficit hyperactivity disorder genetic liability and ICD-10 medical conditions in adults: utilizing electronic health records in a Phenome-Wide Association Study.

Attention-deficit hyperactivity disorder (ADHD) is often comorbid with other medical conditions in adult patients. However, ADHD is extremely underdiagnosed in adults and little is known about the medical comorbidities in undiagnosed adult individuals with high ADHD liability. In this study we investigated associations between ADHD genetic liability and electronic health record (EHR)-based ICD-10 diagnoses across all diagnostic categories, in individuals without ADHD diagnosis history. We used data from the Estonian Biobank cohort (N = 111 261) and generated polygenic risk scores (PRS) for ADHD (PRSADHD) based on the ADHD genome-wide association study. We performed a phenome-wide association study (PheWAS) to test for associations between standardized PRSADHD and 1515 EHR-based ICD-10 diagnoses in the full and sex-stratified sample. We compared the observed significant ICD-10 associations to associations with (1) ADHD diagnosis and (2) questionnaire-based high ADHD risk analyses. After Bonferroni correction (p = 3.3 × 10-5) we identified 80 medical conditions associated with PRSADHD. The strongest evidence was seen with chronic obstructive pulmonary disease (OR 1.15, CI 1.11-1.18), obesity (OR 1.13, CI 1.11-1.15), and type 2 diabetes (OR 1.11, CI 1.09-1.14). Sex-stratified analysis generally showed similar associations in males and females. Out of all identified associations, 40% and 78% were also observed using ADHD diagnosis or questionnaire-based ADHD, respectively, as the predictor. Overall our findings indicate that ADHD genetic liability is associated with an increased risk of a substantial number of medical conditions in undiagnosed individuals. These results highlight the need for timely detection and improved management of ADHD symptoms in adults.

No evidence for a causal contribution of bioavailable testosterone to ADHD in sex-combined and sex-specific two-sample Mendelian randomization studies.

The higher prevalence of attention-deficit/hyperactivity disorder (ADHD) in males raises the question of whether testosterone is implicated in ADHD risk. However, cross-sectional studies did not identify an association between ADHD and testosterone levels. Mendelian randomization (MR) studies can overcome limitations inherent to association studies, especially of reverse causation and residual confounding. In the current study, sex-combined and sex-specific two-sample MR analyses were conducted to address whether testosterone has a causal influence on ADHD risk. Sex-combined as well as sex-specific target-genetic variants for bioavailable testosterone were derived from a large genome-wide association study (GWAS) on up to 382,988 adult white European UK Biobank study participants. In our sex-specific analyses for ADHD, including data from 14,154 males and 4,945 females with ADHD (17,948 and 16,246 controls respectively), no association between bioavailable testosterone and ADHD risk was found, neither in males (inverse-variance weighted (IVW): beta = 0.09, 95%-CI [-0.10, 0.27]) nor in females (IVW: beta=-0.01, 95%-CI [-0.20, 0.19]). However, in the sex-combined analysis, including 38,691 cases and 186,843 controls, genetically predicted bioavailable testosterone was associated with ADHD risk (IVW: beta = 0.24, 95%-CI [0.09, 0.39]). The inclusion of birth weight and/or SHBG as additional variables in multivariable MR analyses did not alter this result. However, when correcting for potential BMI-driven pleiotropy by a multivariable MR study, all effect estimates for testosterone showed non-significant results. Taken together, no robust evidence for a causal effect of bioavailable testosterone on the risk for ADHD was found.

Estimating the causal effect of air pollution on mental disorders: A two-sample Mendelian randomization study

BackgroundObservational studies have reported a link between particulate matter 2.5 (PM2.5) and the risk of mental disorders; however, the causality is unclear. MethodsUsing publicly available genome-wide association studies, we conducted a two-sample Mendelian randomization (MR) study to assess the causal relationship between PM2.5 and six mental disorders: attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), schizophrenia (SCZ), and anxiety disorder (ANX). The inverse-variance weighting method was used as the main method for estimating causal effects. MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO were applied as supplementary analyses. ResultsUsing the inverse-variance weighting method, genetically predicted PM2.5 exposure increased the risk of ADHD (odds ratio [OR] = 1.52, 95% confidence interval [CI] = 1.16 to 1.99, p = 0.002), ANX (OR = 2.96, 95% CI = 1.29 to 6.81, p = 0.01), and SCZ (OR = 2.21, 95% CI = 1.40 to 3.47, p = 0.001). However, there was no evidence to suggest that genetically predicted exposure to PM2.5 increased the risk of the other three mental disorders (p > 0.05). ConclusionsThe present findings enhance our understanding of the role of PM2.5 exposure on ADHD, ANX, and SCZ risk. It may be necessary to search for novel components with neuroprotective effects to provide new preventive and therapeutic strategies for PM2.5-induced brain damage.

Childhood attention-deficit hyperactivity disorder: socioeconomic inequalities in symptoms, impact, diagnosis and medication.

Children from disadvantaged backgrounds are at greater risk of attention-deficit hyperactivity disorder (ADHD)-related symptoms, being diagnosed with ADHD, and being prescribed ADHD medications. We aimed to examine how inequalities manifest across the 'patient journey', from perceptions of impacts of ADHD symptoms on daily life, to the propensity to seek and receive a diagnosis and treatment. We investigated four 'stages': (1) symptoms, (2) caregiver perception of impact, (3) diagnosis and (4) medication, in two data sets: UK Millennium Cohort Study (MCS, analyticn ~ 9,000), with relevant (parent-reported) information on all four stages (until 14 years); and a population-wide 'administrative cohort', which includes symptoms (child health checks) and prescriptions (dispensing records), born in Scotland, 2010-2012 (analytic n ~ 100,000), until ~6 years. We described inequalities according to maternal occupational status, with percentages and relative indices of inequality (RII). The prevalence of ADHD symptoms and medication receipt was considerably higher in the least compared to the most advantaged children in the administrative cohort (RIIs of 5.9 [5.5-6.4] and 8.1 [4.2-15.6]) and the MCS (3.08 [2.68-3.55], 3.75 [2.21-6.36]). MCS analyses highlighted complexities between these two stages, however, those from least advantaged backgrounds, with ADHD symptoms, were the least likely to perceive impacts on daily life (15.7% vs. average 19.5%) and to progress from diagnosis to medication (44.1% vs. average 72.5%). Despite large inequalities in ADHD symptoms and medication, parents from the least advantaged backgrounds were less likely to report impacts of ADHD symptoms on daily life, and their children were less likely to have received medication postdiagnosis, highlighting how patient journeys differed according to socioeconomic circumstances.

Combined and sequential exposure to prenatal second hand smoke and postnatal maternal distress is associated with cingulo-opercular global efficiency and attention problems in school-age children

BackgroundPrenatal exposure to secondhand (environmental) tobacco smoke (SHS) is associated with adverse neurodevelopmental outcomes, including altered functional activation of cognitive control brain circuitry and increased attention problems in children. Exposure to SHS is more common among Black youth who are also disproportionately exposed to socioeconomic disadvantage and concomitant maternal distress. We examine the combined effects of exposure to prenatal SHS and postnatal maternal distress on the global efficiency (GE) of the brain's cingulo-opercular (CO) and fronto-parietal control (FP) networks in childhood, as well as associated attention problems. MethodsThirty-two children of non-smoking mothers followed in a prospective longitudinal birth cohort at the Columbia Center for Children's Environmental Health (CCCEH) completed magnetic resonance imaging (MRI) at ages 7–9 years old. GE scores were extracted from general connectivity data collected while children completed the Simon Spatial Incompatibility functional magnetic resonance imaging (fMRI) task. Prenatal SHS was measured using maternal urinary cotinine from the third trimester; postnatal maternal distress was assessed at child age 5 using the Psychiatric Epidemiology Research Interview (PERI-D). The Child Behavior Checklist (CBCL) measured Attention and Attention Deficit Hyperactivity Disorder (ADHD) problems at ages 7–9. Linear regressions examined the interaction between prenatal SHS and postnatal maternal distress on the GE of the CO or FP networks, as well as associations between exposure-related network alterations and attention problems. All models controlled for age, sex, maternal education at prenatal visit, race/ethnicity, global brain correlation, and mean head motion. ResultsThe prenatal SHS by postnatal maternal distress interaction term associated with the GE of the CO network (β = 0.673, Bu = 0.042, t(22) = 2.427, p = .024, D = 1.42, 95% CI [0.006, 0.079], but not the FP network (β = 0.138, Bu = 0.006, t(22) = 0.434, p = .668, 95% CI [−0.022, 0.033]). Higher GE of the CO network was associated with more attention problems (β = 0.472, Bu = 43.076, t(23) = 2.780, p = .011, D = 1.74, n = 31, 95% CI [11.024, 75.128], n = 31) and ADHD risk (β = 0.436, Bu = 21.961, t(29) = 2.567, p = .018, D = 1.81, 95% CI [4.219, 39.703], n = 30). ConclusionsThese preliminary findings suggest that sequential prenatal SHS exposure and postnatal maternal distress could alter the efficiency of the CO network and increase risk for downstream attention problems and ADHD. These findings are consistent with prior studies showing that prenatal SHS exposure is associated with altered function of brain regions that support cognitive control and with ADHD problems. Our model also identifies postnatal maternal distress as a significant moderator of this association. These data highlight the combined neurotoxic effects of exposure to prenatal SHS and postnatal maternal distress. Critically, such exposures are disproportionately distributed among youth from minoritized groups, pointing to potential pathways to known mental health disparities.

Insomnia Polygenic Component on Attention Deficit-Hyperactivity Disorder: Exploring this Association Using Genomic Data from Brazilian Families

Abstract Introduction Insomnia is highly prevalent among individuals with Attention-Deficit/Hyperactivity Disorder (ADHD). However, the biological mechanisms shared between both conditions is still elusive. We aimed to investigate whether insomnia's genomic component is able to predict ADHD in childhood and adolescence. Methods A Brazilian sample of 259 ADHD probands and their biological parents were included in the study. Their genomic DNA genotypes were used to construct the polygenic risk score for insomnia (Insomnia PRS), using the largest GWAS summary statistics as a discovery sample. The association was tested using logistic regression, under a case-pseudocontrol design. Results Insomnia PRS was nominally associated with ADHD (OR = 1.228, p = 0.022), showing that the alleles that increase the risk for insomnia also increase the risk for ADHD. Discussion Our results suggest that genetic factors associated with insomnia may play a role in the ADHD genetic etiology, with both phenotypes likely to have a shared genetic mechanism.

ADHD medications use and risk of mortality and unintentional injuries: a population-based cohort study

We assessed the association between the use of medications for attention-deficit/hyperactivity disorder (ADHD) and the risk of all-cause mortality and unintentional injuries leading to emergency department (ED) or hospital admission in individuals aged ≤24 years with ADHD. We conducted a population-based retrospective cohort study between 2000 and 2021 using Quebec health administrative data. Individuals were followed from the first ADHD diagnosis or ADHD medication claim until turning 25, death, or study end. Exposure was defined as mutually exclusive episodes of ADHD medication use and/or coverage under the public provincial drug plan (PDP): 1) covered and not treated with ADHD medication; 2) covered and treated with ADHD medication; and 3) not covered under the PDP. The risk of all-cause mortality and unintentional injuries associated with exposure episodes was estimated using multivariable survival analyses. The cohort included n = 217 192 individuals aged 1–24 years with a male to female ratio of close to 2:1. Compared to non-medication use, episodes of ADHD medication use, overall, were associated with reduced all-cause mortality (adjusted hazard ratio, aHR 0.61, 95% CI 0.48–0.76) and unintentional injury leading to ED (0.75, 0.74–0.77) or hospitalisation (0.71, 0.68–0.75). Episodes of stimulants were associated with a lower risk of all-cause mortality and reduced risk of unintentional injuries, while episodes with non-stimulants and with both stimulants and non-stimulants concomitantly were associated with reduced risk of unintentional injuries, but not of all-cause mortality. Although residual confounding cannot be excluded, stimulants may have a protective effect in terms of risk of all-cause mortality and both stimulants and non-stimulants for ADHD may reduce the risk of unintentional injuries. The findings of the current study should inform clinical decision making on the choice of starting a pharmacological treatment for ADHD, when a balance needs to be struck between expected benefits and possible risks.

Polygenic risk for major depression, attention deficit hyperactivity disorder, neuroticism, and schizophrenia are correlated with experience of intimate partner violence

Research has suggested that mental illness may be a risk factor for, as well as a sequela of, experiencing intimate partner violence (IPV). The association between IPV and mental illness may also be due in part to gene-environment correlations. Using polygenic risk scores for six psychiatric disorders - attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BPD), major depressive disorder (MDD), neuroticism, and schizophrenia—and a combined measure of overall genetic risk for mental illness, we tested whether women’s genetic risk for mental illness was associated with the experience of three types of intimate partner violence. In this cohort of women of European ancestry (N = 11,095), participants in the highest quintile of genetic risk for ADHD (OR range: 1.38–1.49), MDD (OR range: 1.28–1.43), neuroticism (OR range: (1.18–1.25), schizophrenia (OR range: 1.30–1.34), and overall genetic risk (OR range: 1.30–1.41) were at higher risk for experiencing more severe emotional and physical abuse, and, except schizophrenia, more severe sexual abuse, as well as more types of abuse and chronic abuse. In addition, participants in the highest quintile of genetic risk for neuroticism (OR = 1.43 95% CI: 1.18, 1.72), schizophrenia (OR = 1.33 95% CI: 1.10, 1.62), and the overall genetic risk (OR = 1.40 95% CI: 1.15, 1.71) were at higher risk for experiencing intimate partner intimidation and control. Participants in the highest quintile of genetic risk for ADHD, ASD, MDD, schizophrenia, and overall genetic risk, compared to the lowest quintile, were at increased risk for experiencing harassment from a partner (OR range: 1.22–1.92). No associations were found between genetic risk for BPD with IPV. A better understanding of the salience of the multiple possible pathways linking genetic risk for mental illness with risk for IPV may aid in preventing IPV victimization or re-victimization.

Association of Chronic Obstructive Pulmonary Disease with Risk of Psychiatric Disorders: A Two-Sample Mendelian Randomization Study.

Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disorder often accompanied by comorbidities. Although the past few years have witnessed significant scientific progress, the potential relationship between COPD and mental illness remains a subject of debate. We retrieved COPD data from the genome-wide association studies (GWAS) directory and data on mental illnesses, including Alzheimer's disease, schizophrenia, panic disorder, attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, multiple disabilities, obsessive-compulsive disorder, post-traumatic stress disorder, and schizophrenia, from the Psychiatric Genomics Consortium. A two-sample Mendelian randomization (MR) approach was applied to explore the association between COPD and mental illnesses, with subgroup analyses based on smoking history. Our two-sample MR analysis revealed no causal link between overall COPD and the development of common psychiatric disorders. Subgroup analyses based on smoking history showed no causal association between never-smokers with COPD and the occurrence of psychiatric disorders. However, ever-smokers with COPD were associated with a significantly increased risk of ADHD (OR: 2.303, 95% CI: 1.558-3.403, P = 0.001) and a modestly reduced risk of Alzheimer's disease (OR: 0.994, 95% CI: 0.988-0.999, P = 0.034). COPD patients with a history of smoking face a higher risk of developing ADHD but may experience a slight reduction in the risk of Alzheimer's disease. Conversely, there was no observed causal association between COPD and psychiatric disorders among patients who never smoked.

Cumulative Effects of Resting-State Connectivity Across All Brain Networks Significantly Correlate with Attention-Deficit Hyperactivity Disorder Symptoms.

Identification of replicable neuroimaging correlates of attention-deficit hyperactivity disorder (ADHD) has been hindered by small sample sizes, small effects, and heterogeneity of methods. Given evidence that ADHD is associated with alterations in widely distributed brain networks and the small effects of individual brain features, a whole-brain perspective focusing on cumulative effects is warranted. The use of large, multisite samples is crucial for improving reproducibility and clinical utility of brain-wide MRI association studies. To address this, a polyneuro risk score (PNRS) representing cumulative, brain-wide, ADHD-associated resting-state functional connectivity was constructed and validated using data from the Adolescent Brain Cognitive Development (ABCD, N = 5,543, 51.5% female) study, and was further tested in the independent Oregon-ADHD-1000 case-control cohort (N = 553, 37.4% female). The ADHD PNRS was significantly associated with ADHD symptoms in both cohorts after accounting for relevant covariates (p < 0.001). The most predictive PNRS involved all brain networks, though the strongest effects were concentrated among the default mode and cingulo-opercular networks. In the longitudinal Oregon-ADHD-1000, non-ADHD youth had significantly lower PNRS (Cohen's d = -0.318, robust p = 5.5 × 10-4) than those with persistent ADHD (age 7-19). The PNRS, however, did not mediate polygenic risk for ADHD. Brain-wide connectivity was robustly associated with ADHD symptoms in two independent cohorts, providing further evidence of widespread dysconnectivity in ADHD. Evaluation in enriched samples demonstrates the promise of the PNRS approach for improving reproducibility in neuroimaging studies and unraveling the complex relationships between brain connectivity and behavioral disorders.

Prescription Stimulant Use During Pregnancy and Risk of Neurodevelopmental Disorders in Children

Use of medications for attention-deficit/hyperactivity disorder (ADHD) during pregnancy is increasing in the US. Whether exposure to these medications in utero impacts the risk of neurodevelopmental disorders in children is uncertain. To evaluate the association of childhood neurodevelopmental disorders with in utero exposure to stimulant medications for ADHD. This cohort study included health care utilization data from publicly insured (Medicaid data from 2000 to 2018) and commercially insured (MarketScan Commercial Claims Database data from 2003 to 2020) pregnant individuals aged 12 to 55 years in the US with enrollment from 3 months prior to pregnancy through 1 month after delivery, linked to children. Children were monitored from birth until outcome diagnosis, disenrollment, death, or end of the study (December 2018 for Medicaid and December 2020 for MarketScan). Dispensing of amphetamine/dextroamphetamine or methylphenidate in the second half of pregnancy. Autism spectrum disorder, ADHD, and a composite of any neurodevelopmental disorder were defined using validated algorithms. Hazard ratios were estimated comparing amphetamine/dextroamphetamine and methylphenidate to no exposure. The publicly insured cohort included 2 496 771 stimulant-unexposed, 4693 amphetamine/dextroamphetamine-exposed, and 786 methylphenidate-exposed pregnancies with a mean (SD) age of 25.2 (6.0) years. The commercially insured cohort included 1 773 501 stimulant-unexposed, 2372 amphetamine/dextroamphetamine-exposed, and 337 methylphenidate-exposed pregnancies with a mean (SD) age of 31.6 (4.6) years. In unadjusted analyses, amphetamine/dextroamphetamine and methylphenidate exposure were associated with a 2- to 3-fold increased risk of the neurodevelopmental outcomes considered. After adjustment for measured confounders, amphetamine/dextroamphetamine exposure was not associated with any outcome (autism spectrum disorder: hazard ratio [HR], 0.80; 95% CI, 0.56-1.14]; ADHD: HR, 1.07; 95% CI, 0.89-1.28; any neurodevelopmental disorder: HR, 0.91; 95% CI, 0.81-1.28). Methylphenidate exposure was associated with an increased risk of ADHD (HR, 1.43; 95% CI, 1.12-1.82]) but not other outcomes after adjustment (autism spectrum disorder: HR, 1.06; 95% CI, 0.62-1.81; any neurodevelopmental disorder: HR, 1.15; 95% CI, 0.97-1.36). The association between methylphenidate and ADHD did not persist in sensitivity analyses with stricter control for confounding by maternal ADHD. The findings in this study suggest that amphetamine/dextroamphetamine and methylphenidate exposure in utero are not likely to meaningfully increase the risk of childhood neurodevelopmental disorders.

Prenatal cannabis use and the risk of attention deficit hyperactivity disorder and autism spectrum disorder in offspring: A systematic review and meta-analysis

BackgroundIt is plausible that exposure to cannabis in-utero could be associated with an increased risk of neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) during childhood and adolescence; however, mixed results have been reported. This study investigated whether there is an association between prenatal cannabis use and ADHD symptoms and ASD in offspring using a systematic review and meta-analysis methodology. MethodsA systematic literature search was conducted in PubMed/Medline, Scopus, EMBASE, Web of Science, Psych-Info, and Google Scholar to identify relevant studies. The study protocol has been preregistered in the Prospective Register of Systematic Reviews (PROSPERO) (CRD42022345001), and the Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess the methodological quality of included studies. An inverse variance weighted random effect meta-analysis was conducted to pool the overall effect estimates from the included studies. ResultsFourteen primary studies, consisting of ten on ADHD and four on ASD, with a total of 203,783 participants, were included in this study. Our meta-analysis underscores an increased risk of ADHD symptoms and/or disorder [β = 0.39: 95 % CI (0.20–0.58), I2 = 66.85 %, P = 0.001)] and ASD [RR = 1.30: 95 % CI (1.03–1.64), I2 = 45.5 %, P = 0.14] associated with in-utero cannabis exposure in offspring compared to their non-exposed counterparts. Additionally, our stratified analysis highlighted an elevated risk of ADHD symptoms [β = 0.54: 95 % CI (0.26–0.82)] and a marginally significant increase in the risk of diagnostic ADHD among exposed offspring compared to non-exposed counterparts [RR = 1.13, 95 % CI (1.01, 1.26)]. ConclusionThis study indicated that maternal prenatal cannabis exposure is associated with a higher risk of ADHD symptoms and ASD in offspring.

Causal association of attention-deficit/hyperactivity disorder and autism spectrum disorder with post-traumatic stress disorder.

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two neurodevelopmental disorders that often result in individuals experiencing traumatic events. However, little is known about the connection between ADHD/ASD and post-traumatic stress disorder (PTSD). This study aimed to investigate the genetic associations between these disorders. Genetic correlation analysis was used to examine the genetic components shared between ADHD (38 691 cases and 275 986 controls), ASD (18 381 cases and 27 969 controls) and PTSD (23 212 cases and 151 447 controls). Two-sample Mendelian randomization analyses were employed to explore the bidirectional causal relationships between ADHD/ASD and PTSD. The results of the genetic correlation analysis revealed significant positive correlations of PTSD with ADHD(r g  = 0.70) and ASD (r g  = 0.34). Furthermore, the Mendelian randomization analysis revealed that genetic liabilities to ADHD [odds ratio (OR) = 1.14; 95% confidence interval (CI), 1.06-1.24; P  = 7.88 × 10 -4 ] and ASD (OR = 1.04; CI, 1.01-1.08; P  = 0.014) were associated with an increased risk of developing PTSD later in life. However, no evidence supported that genetic liability to PTSD could elevate the risk of ADHD or ASD. The findings of this study supported that ADHD and ASD may increase the risk of PTSD, but not vice versa.

Genetic Association of Lipids and Lipid-Lowering Drug Target Genes With Attention Deficit Hyperactivity Disorder.

Lipid metabolism plays an essential role in nervous system development. Cholesterol deficiency leads to a variety of neurodevelopmental disorders, such as autism spectrum disorder and fragile X syndrome. There have been a lot of efforts to search for biological markers associated with and causal to ADHD, among which lipid is one possible etiological factor that is quite widely studied. We aimed to evaluate the causal relationship between lipids traits, lipid-lowering drugs, and attention deficit hyperactivity disorder (ADHD) outcomes using Mendelian randomization (MR) studies. We used summary data from genome-wide association studies to explore the causal relationships between circulating lipid-related traits and ADHD. Then, quantitative trait loci for the expression of lipid-lowering drug target genes and genetic variants associated with lipid traits were extracted. Summary-data-based MR and inverse-variance-weighted MR (IVW-MR) were used to investigate the correlation between the expression of these drug-target genes and ADHD. After rigorous screening, 939 instrumental variables were finally included for univariable mendelian randomization analysis. However, there is no correlation between lipid profile and ADHD risk. Drug target analysis by IVW-MR method observed that APOB-mediated low-density lipoprotein cholesterol was associated with lower ADHD risk (odds ratio [OR] = 0.90, 95% confidence interval [CI] [0.84, 0.97]; p = .007), whereas LPL-mediated triglycerides levels were associated with a higher risk of ADHD (OR = 1.13, 95% CI [1.06, 1.21]; p < .001). Our results suggest that APOB gene and LPL gene may be candidate drug target genes for the treatment of ADHD.