Non-mental diseases associated with ADHD across the lifespan: Fidgety Philipp and Pippi Longstocking at risk of multimorbidity?

Kittel‐Schneider, Sarah; Arteaga-Henríquez, Gara; Vásquez, Alejandro Arias; Asherson, Philip; Banaschewski, Tobias; Brikell, Isabell; Buitelaar, Jan K.; Cormand, Bru; Faraone, Stephen V.; Freitag, Christine M.; Ginsberg, Ylva; Haavik, Jan; Hartman, Catharina A.; Kuntsi, Jonna; Larsson, Henrik; Matura, Silke; McNeill, Rhiannon V.; Ramos‐Quiroga, Josep Antoni; Ribasés, Marta; Romanos, Marcel; Vainieri, Isabella; Franke, Barbara; Reif, Andreas

doi:10.1016/j.neubiorev.2021.10.035

Cited by 32 publications

(24 citation statements)

References 326 publications

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“…However, ADHD in adults is often underdiagnosed and/or untreated, which may lead to negative psychosocial and health consequences (4). Evidence from previous studies have shown substantial comorbidity between ADHD and both psychiatric and somatic medical conditions, such as hypertension, migraine, obesity and type 2 diabetes, in adulthood (5)(6)(7). Yet, the comorbidities in undiagnosed or subclinical ADHD populations are far less clear.…”

Section: Introductionmentioning

confidence: 99%

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

Haan

Krebs

Võsa

et al. 2022

Preprint

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Background: 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. Methods: We used data from the Estonian Biobank cohort (N=111,261) and generated polygenic risk scores (PRS) for ADHD (PRSADHD) based on the latest ADHD genome-wide association study. We performed a phenome-wide association study (PheWAS) to test for associations between standardized PRS<ADHD> and 1,515 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. Results: After Bonferroni correction (p=3.3x10-5) 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. Conclusions: 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.

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Section: Introductionmentioning

confidence: 99%

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

Haan

Krebs

Võsa

et al. 2022

Preprint

Self Cite

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“…previously in patients with familiar schizophrenia (Bespalova et al, 2010) hinting at a role in mental disorders. The risk of obesity and diabetes mellitus is increased in ADHD patients over the life span which might be due to underlying shared risk genes and shared biological factors like the increased C1QTNF3 expression in the ADHD PARK2 duplication carrier as well as the decreased expression in the deletion carrier after nutrient deprivation stress we found here (Kittel-Schneider et al, 2021).…”

Section: Discussionmentioning

confidence: 56%

“…Up to 50–60% of the adults with a history of childhood ADHD still fulfill diagnostic criteria for the ADHD diagnosis or show persisting impairing symptoms (Franke et al, 2018; Hesson & Fowler, 2015). Core symptoms are attention deficit, hyperactivity and impulsivity and co‐occurring mental and non‐mental disorders are more the rule than the exception (Gross‐Lesch et al, 2013; Instanes, Klungsoyr, Halmoy, Fasmer, & Haavik, 2018; Jacob et al, 2007; Kittel‐Schneider et al, 2021). The etiopathogenesis of ADHD is not fully understood, but genetic factors play an important role.…”

Section: Introductionmentioning

confidence: 99%

ADHD‐associated PARK2 copy number variants: A pilot study on gene expression and effects of supplementary deprivation in patient‐derived cell lines

Radtke

Palladino

McNeill

et al. 2022

American J of Med Genetics Pt B

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Recent studies show an association of Parkin RBR E3 ubiquitin protein ligase (PARK2) copy number variations (CNVs) with attention deficit hyperactivity disorder (ADHD). The aim of our pilot study to investigate gene expression associated with PARK2 CNVs in human‐derived cellular models. We investigated gene expression in fibroblasts, hiPSC and dopaminergic neurons (DNs) of ADHD PARK2 deletion and duplication carriers by qRT PCR compared with healthy and ADHD cell lines without PARK2 CNVs. The selected 10 genes of interest were associated with oxidative stress response (TP53, NQO1, and NFE2L2), ubiquitin pathway (UBE3A, UBB, UBC, and ATXN3) and with a function in mitochondrial quality control (PINK1, MFN2, and ATG5). Additionally, an exploratory RNA bulk sequencing analysis in DNs was conducted. Nutrient deprivation as a supplementary deprivation stress paradigm was used to enhance potential genotype effects. At baseline, in fibroblasts, hiPSC, and DNs, there was no significant difference in gene expression after correction for multiple testing. After nutrient deprivation in fibroblasts NAD(P)H‐quinone‐dehydrogenase 1 (NQO1) expression was significantly increased in PARK2 CNV carriers. In a multivariate analysis, ubiquitin C (UBC) was significantly upregulated in fibroblasts of PARK2 CNV carriers. RNA sequencing analysis of DNs showed the strongest significant differential regulation in Neurontin (NNAT) at baseline and after nutrient deprivation. Our preliminary results suggest differential gene expression in pathways associated with oxidative stress, ubiquitine‐proteasome, immunity, inflammation, cell growth, and differentiation, excitation/inhibition modulation, and energy metabolism in PARK2 CNV carriers compared to wildtype healthy controls and ADHD patients.

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“…Second, alongside increasing sample sizes and validation efforts, future research will be needed to increase the diversity of samples with regard to age, sex, comorbidities, ethnicity, race, and geographical region. As highlighted throughout our review, most evidence to date is based on samples of children (mainly boys) from White majority backgrounds and high-income countries, typically with few psychiatric and medical co-occurring conditions, even though comorbidities are the norm in patients with ADHD [ 6 , 129 ]. Several reviewed studies conducted in Western countries do not even provide information on race/ethnicity (Tables 1 – 5 ), likely suggesting the use of all-White or predominantly-White samples that are not representative of the wider population of individuals with ADHD [ 130 ].…”

Section: Discussionmentioning

confidence: 99%

Treatment biomarkers for ADHD: Taking stock and moving forward

et al. 2022

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The development of treatment biomarkers for psychiatric disorders has been challenging, particularly for heterogeneous neurodevelopmental conditions such as attention-deficit/hyperactivity disorder (ADHD). Promising findings are also rarely translated into clinical practice, especially with regard to treatment decisions and development of novel treatments. Despite this slow progress, the available neuroimaging, electrophysiological (EEG) and genetic literature provides a solid foundation for biomarker discovery. This article gives an updated review of promising treatment biomarkers for ADHD which may enhance personalized medicine and novel treatment development. The available literature points to promising pre-treatment profiles predicting efficacy of various pharmacological and non-pharmacological treatments for ADHD. These candidate predictive biomarkers, particularly those based on low-cost and non-invasive EEG assessments, show promise for the future stratification of patients to specific treatments. Studies with repeated biomarker assessments further show that different treatments produce distinct changes in brain profiles, which track treatment-related clinical improvements. These candidate monitoring/response biomarkers may aid future monitoring of treatment effects and point to mechanistic targets for novel treatments, such as neurotherapies. Nevertheless, existing research does not support any immediate clinical applications of treatment biomarkers for ADHD. Key barriers are the paucity of replications and external validations, the use of small and homogeneous samples of predominantly White children, and practical limitations, including the cost and technical requirements of biomarker assessments and their unknown feasibility and acceptability for people with ADHD. We conclude with a discussion of future directions and methodological changes to promote clinical translation and enhance personalized treatment decisions for diverse groups of individuals with ADHD.

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Non-mental diseases associated with ADHD across the lifespan: Fidgety Philipp and Pippi Longstocking at risk of multimorbidity?

Cited by 32 publications

References 326 publications

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

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

ADHD‐associated PARK2 copy number variants: A pilot study on gene expression and effects of supplementary deprivation in patient‐derived cell lines

Treatment biomarkers for ADHD: Taking stock and moving forward

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