Dataset Information

The Effect of Attention Deficit/Hyperactivity Disorder on Physical Health Outcomes: A 2-Sample Mendelian Randomization Study.

ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is associated with a broad range of physical health problems. Using different research designs to test whether ADHD has a causal role in these associations is important because comorbid health problems increase the serious social and economic impacts of ADHD. We used 2-sample Mendelian randomization (MR) to infer causal relationships between ADHD and previously implicated physical health conditions. Different MR methods were used to test the robustness and plausibility of our findings. Consistent findings underwent bidirectional and multivariable MR. We found evidence of ADHD having a causal effect on childhood obesity (odds ratio = 1.29, 95% confidence interval: 1.02, 1.63) and coronary artery disease (odds ratio = 1.11, 95% confidence interval: 1.03, 1.19) with consistent results across MR approaches. There was additional MR evidence for a bidirectional relationship between ADHD and childhood obesity. The relationship with coronary artery disease attenuated when controlling for childhood obesity. There was little evidence for inferring a causal effect on other cardiometabolic, autoimmune, allergic, and neurological diseases. Our findings strengthen the argument for effective treatment of children with ADHD, and suggest that clinicians who manage ADHD need to be aware of the risk of childhood obesity to reduce future risks of coronary artery disease.

SUBMITTER: Leppert B

PROVIDER: S-EPMC8168225 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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The Effect of Attention Deficit/Hyperactivity Disorder on Physical Health Outcomes: A 2-Sample Mendelian Randomization Study.

Leppert Beate B Riglin Lucy L Wootton Robyn E RE Dardani Christina C Thapar Ajay A Staley James R JR Tilling Kate K Davey Smith George G Thapar Anita A Stergiakouli Evie E

American journal of epidemiology 20210601 6

Attention-deficit/hyperactivity disorder (ADHD) is associated with a broad range of physical health problems. Using different research designs to test whether ADHD has a causal role in these associations is important because comorbid health problems increase the serious social and economic impacts of ADHD. We used 2-sample Mendelian randomization (MR) to infer causal relationships between ADHD and previously implicated physical health conditions. Different MR methods were used to test the robust ...[more]

PMID: 33324987

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Project description:BackgroundIn some observational studies, attention-deficit/hyperactivity disorder has been linked to allergic diseases, but the findings are debatable. This study aimed to determine whether attention-deficit/hyperactivity disorder (ADHD) is causally related to allergic asthma, allergic rhinitis, pollen allergy, allergic urticaria, and allergic conjunctivitis using the two-sample Mendelian Randomization (MR) approach.MethodsWe did a two-sample Mendelian randomization (MR) study, which chose single nucleotide polymorphisms (SNPs) that are highly associated with attention-deficit/hyperactivity disorder (ADHD) levels from the Psychiatric Genomics Consortium (PGC) on 20,183 cases and 35,191 controls as our instruments. Outcomes datasets included genome-wide association study (GWAS) meta-analysis (n = 1,415,804). The summary statistics of outcome data were obtained from the FinnGen datasets including allergic asthma (10,877 cases and 180,942 controls), allergic rhinitis (8,430 cases and 298,829 controls), pollen allergy (4555cases and 301,734 controls), allergic urticaria (1792 cases and 299,491 controls) and allergic conjunctivitis (15,567 cases and 293,587 controls). Inverse variance weighted, MR-Egger, weighted median, were used to estimate the causal association between ADHD and allergic diseases. Cochran's Q test was used to quantify the heterogeneity of instrumental variables. MR-Egger intercept test, leave-one-out analysis, and the funnel plot were all used in sensitivity analyses.ResultsThe Mendelian randomization (MR) analysis indicated that ADHD in inverse variance weighted [odds ratio (OR) = 1.0612; 95% confidence interval (CI):1.0192-1.1049; p = 0.0039] lightly increased the risk of allergic asthma. In MR sensitivity analyses of the weighted median, a similar association was found. But no evidence for an effect of ADHD on allergic asthma risk was found in additional methods: MR-Egger (OR = 0.9592, 95% CI: 0.8384-1.0974, p = 0.5457), and weighted median (OR: =1.0341, 95% CI: 0.9785-1.0929, p = 0.2330). Also, no strong evidence for an effect of ADHD on other allergic diseases (allergic rhinitis, pollen allergy, allergic urticaria, and allergic conjunctivitis) incidence was found using the inverse variance weighted (IVW) method, weighted median method, and MR-Egger regression.ConclusionAlthough several studies have found a link between ADHD and allergic diseases, our findings do not support that ADHD could increase allergic diseases incidence. Randomized controlled trials or Mendelian randomization studies with larger samples are still needed to draw more precise conclusions.

Project description:Previous research has suggested a link between gut microbiota and attention deficit hyperactivity disorder (ADHD), but their causal relationship has not been elucidated. Aiming to comprehensively investigate their causal relationship and to identify specific causal microbe taxa for ADHD, we conducted a two-sample Mendelian randomization (MR) analysis. Instrumental variables of 211 gut microbiota taxa were obtained from gene wide association study (GWAS), and Mendelian randomization study was carried out to estimate their effects on ADHD risk from PGC GWAS (20,183 ADHD cases and 35,191 controls) and FinnGen GWAS (830 ADHD cases and 215,763 controls). Wald ratio (WR), inverse variance weighted (IVW), MR-Egger, and weighted median were the main methods to analyze causality, and MR results are verified by several sensitivity analysis analyses. At locus-wide significance level (p < 1 × 10-5), IVW results confirmed that genus Eubacteriumhalliigroup (p = 0.013) and genus RuminococcaceaeUCG013 (p = 0.049) were correlated with the risk of ADHD and genus Butyricicoccus (p = 0.009), genus Roseburia (p = 0.009), genus Desulfovibrio (p = 0.015), genus LachnospiraceaeNC2004group (p = 0.026), genus Romboutsia (p = 0.028) and family Oxalobacteraceae (p = 0.048) were protective factors of ADHD. Weighted median results indicated that genus Butyricicoccus (p = 0.018) was negatively correlated with the risk of ADHD. At genome-wide statistical significance level (p < 5 × 10-8), Wald ratio results demonstrated that genus Ruminococcustorquesgroup (p = 0.003) was a risk factor for ADHD, while genus Romboutsia (p = 0.006) and family Peptostreptococcaceae (p = 0.006) had a negative correlation with the risk of ADHD. In reverse MR analysis, IVW results showed that ADHD may lead to an increase in the abundance of genus Roseburia (p = 0.020). Analysis of heterogeneity (p > 0.05) and pleiotropy (p > 0.05) confirmed the robustness of MR results. We demonstrated that there was a potential causal relationship between gut microbiota and ADHD. Our research provides a foundation for understanding the causal relationship between gut microbiota and ADHD, and the several gut bacteria found in this study that may reduce the occurrence of ADHD may have potential in the prevention and treatment of ADHD.

Project description:Attention deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder caused by a combination of genetic and environmental factors and is often thought as an entry point into a negative life trajectory, including risk for comorbid disorders, poor educational achievement or low income. In the present study, we aimed to clarify the causal relationship between ADHD and a comprehensive range of related traits. We used genome-wide association study (GWAS) summary statistics for ADHD (n = 53 293) and 124 traits related to anthropometry, cognitive function and intelligence, early life exposures, education and employment, lifestyle and environment, longevity, neurological, and psychiatric and mental health or personality and psychosocial factors available in the MR-Base database (16 067 ≤n ≤766 345). To investigate their causal relationship with ADHD, we used two-sample Mendelian randomization (MR) with a range of sensitivity analyses, and validated MR findings using causal analysis using summary effect estimates (CAUSE), aiming to avoid potential false-positive results. Our findings strengthen previous evidence of a causal effect of ADHD liability on smoking and major depression, and are consistent with a causal effect on odds of decreased average total household income [odds ratio (OR) = 0.966, 95% credible interval (CrI) = (0.954, 0.979)] and increased lifetime number of sexual partners [OR = 1.023, 95% CrI = (1.013, 1.033)]. We also found evidence for a causal effect on ADHD for liability of arm predicted mass and weight [OR = 1.452, 95% CrI = (1.307, 1.614) and OR = 1.430, 95% CrI = (1.326, 1.539), respectively] and time spent watching television [OR = 1.862, 95% CrI = (1.545, 2.246)], and evidence for a bidirectional effect for age of first sexual intercourse [beta = -0.058, 95% CrI = (-0.072, -0.044) and OR = 0.413, 95% CrI = (0.372, 0.457), respectively], odds of decreased age completed full-time education [OR = 0.972, 95% CrI = (0.962, 0.981) and OR = 0.435, 95% CrI = (0.356, 0.533), respectively] and years of schooling [beta = -0.036, 95% CrI = (-0.048, -0.024) and OR = 0.458, 95% CrI = (0.411, 0.511), respectively]. Our results may contribute to explain part of the widespread co-occurring traits and comorbid disorders across the lifespan of individuals with ADHD and may open new opportunities for developing preventive strategies for ADHD and for negative ADHD trajectories.

Project description:BackgroundObservational studies have found Attention Deficit Hyperactivity Disorder (ADHD) to be associated with an increased risk of adverse outcomes as well as with early risk factors; however it is not clear whether these associations reflect causal effects. Alternatives to traditional observational studies are needed to investigate causality: one such design is Mendelian randomization (MR), which uses genetic variants as instrumental variables for the exposure.MethodsIn this review we summarise findings from approximately 50 studies using MR to examine potentially causal associations with ADHD as either an exposure or outcome.ResultsTo-date, few MR ADHD studies have investigated causal evidence with other neurodevelopmental, mental health and neurodegenerative conditions but those that have suggest a complex relationship with autism, some evidence of a causal effect on depression and limited evidence of a causal effect on neurodegenerative conditions. For substance use, MR studies provide evidence consistent with a causal effect of ADHD on smoking initiation, but findings for other smoking behaviours and cannabis use are less consistent. Studies of physical health suggest bidirectional causal effects with higher body mass index, with stronger effects for childhood obesity, as well as some evidence of causal effects on coronary artery disease and stroke in adults and limited evidence of causal effects on other physical health problems or sleep. Studies suggest bidirectional relationships between ADHD and socio-economic markers and provide some evidence that low birthweight may be a causal risk factor for ADHD, while bidirectional evidence has been found for some environmental factors. Finally, there is emerging evidence of bidirectional causal links between ADHD genetic liability and biological markers of human metabolism and inflammation.ConclusionsWhile MR has advantages over traditional observational designs in addressing causality, we discuss limitations of current ADHD studies and future directions, including the need for larger genome-wide association studies (and using samples of different ancestries), and for triangulation with different methods.

Project description:BackgroundImmune system modulation has been shown to have a significant impact on attention deficit hyperactivity disorder (ADHD). Mendelian randomization (MR) analysis was used in this study to investigate the potential role of different immune cells in the development of ADHD to provide therapy and preventative alternatives.MethodsIn this study, 731 immune cells and the risk of ADHD were examined using publicly accessible genetic data and a two-sample MR analysis. Included were four different types of immunological profiles: determinate cells (DC), proportional cells (PC), median brightness level (MBL), and morphological characteristics (MA). It was discovered that single-nucleotide polymorphisms (SNPs) are linked to ADHD. To evaluate the dependability of the results, we conducted sensitivity analysis (heterogeneity and pleiotropy) and employed supplementary MR techniques, such as the inverse variance weighted (IVW) and MR-Egger. Graphs are used to display the final findings of the pertinent analyses.ResultsFollowing MR analysis, immune cells associated with a few low p value phenotypes may influence ADHD, and these immune cells may serve as an inspiration for clinical treatment practices that aim to prevent and cure ADHD. Immune cell phenotypes that may both increase and worsen the likelihood of having ADHD were identified by IVW results. These included CD27 on memory B cells (OR = 1.066, 95% CI = 1.024-1.109, p = 2E-3) and CD27 on IgD-CD38- (OR = 1.059, 95% CI = 1.018-1.103, p = 5E-3), among others. Immune cell phenotypes that may act as a safeguard against ADHD included CD3 on resting Treg (OR = 0.925, 95% CI = 0.888-0.963, p = 1.5E-4) and SSC-A on monocytes (OR = 0.951, 95% CI = 0.924-0.980, p = 8.5E-4), among others. The primary findings and the outcomes of the sensitivity analysis matched.ConclusionsThis study provides a broad theoretical foundation for the development of immune-oriented therapeutic strategies in future clinical practice by demonstrating a potential genetic relationship between immune cells and ADHD. This study also advances our understanding of how to use the immune pathway to prevent and treat ADHD.

Project description:ContextCortisol, a hormone regulated by the hypothalamic-pituitary-adrenal (HPA) axis, has been linked to attention deficit hyperactivity disorder (ADHD). The nature of the relationship between cortisol and ADHD, and whether it is causal or explained by reverse causality, remains a matter of debate.ObjectiveThis study aims to evaluate the bidirectional causal relationship between morning plasma cortisol levels and ADHD.MethodsThis study used a bidirectional 2-sample Mendelian randomization (MR) design to analyze the association between morning plasma cortisol levels and ADHD using genetic information from the authoritative Psychiatric Genomics Collaboration (PGC) database (n = 55,347) and the ADHD Working Group of the CORtisol NETwork (CORNET) Consortium (n = 12,597). MR analyses were employed: inverse variance weighting (IVW), MR-Egger regression, and weighted medians. OR values and 95% CI were used to evaluate whether there was a causal association between morning plasma cortisol levels on ADHD and ADHD on morning plasma cortisol levels. The Egger-intercept method was employed to test for level pleiotropy. Sensitivity analysis was performed using the "leave-one-out" method, MR pleiotropy residual sum, and MR pleiotropy residual sum and outlier (MR-PRESSO).ResultsFindings from bidirectional MR demonstrated that lower morning plasma cortisol levels were associated with ADHD (ADHD-cortisol OR = 0.857; 95% CI, 0.755-0.974; P = 0.018), suggesting there is a reverse causal relationship between cortisol and ADHD. However, morning plasma cortisol levels were not found to have a causal effect on the risk of ADHD (OR = 1.006; 95% CI, 0.909-1.113; P = 0.907), despite the lack of genetic evidence. The MR-Egger method revealed intercepts close to zero, indicating that the selected instrumental variables had no horizontal multiplicity. The "leave-one-out" sensitivity analysis revealed stable results, with no instrumental variables significantly affecting the results. Heterogeneity tests were insignificant, and MR-PRESSO did not detect any significant outliers. The selected single-nucleotide polymorphisms (SNPs) F were all >10, indicating no weak instrumental variables. Thus, the overall MR analysis results were reliable.ConclusionThe study findings suggest a reverse causal relationship between morning plasma cortisol levels and ADHD, with low cortisol levels associated with ADHD. No genetic evidence was found to support a causal relationship between morning plasma cortisol levels and the risk of ADHD. These results suggest that ADHD may lead to a significant reduction in morning plasma cortisol secretion.

Dataset Information

The Effect of Attention Deficit/Hyperactivity Disorder on Physical Health Outcomes: A 2-Sample Mendelian Randomization Study.

Publications

The Effect of Attention Deficit/Hyperactivity Disorder on Physical Health Outcomes: A 2-Sample Mendelian Randomization Study.

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