ADHD, epilepsy, and related childhood psychopathology : understanding shared genetic risk, developmental trajectories, and pharmacological treatment safety

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder, affecting 5-7% of children and 2.5-5% of adults worldwide. The disorder is characterized by excessive and age-inappropriate symptoms of inattention, hyperactivity, and impulsivity, which impair everyday functioning across several settings (home, school, work). Although great advances have been made in ADHD research during the past decades, many questions remain regarding the causes and consequences of ADHD. ADHD is conceptualized as an early onset disorder, underpinned by varying degrees of neurological delay or dysfunction that may be exacerbated by environmental factors. The disorder is developmentally complex, and extensive comorbidity with other psychiatric and non-psychiatric disorders is the rule rather than the exception. In this thesis, quantitative and molecular genetic research designs were used to explore important and poorly understood questions regarding development, treatment safety, and comorbidity in ADHD, epilepsy and related childhood psychopathology. In Study 1, we addressed the question of whether perceived immaturity is related to the developmental course of ADHD from childhood to early adulthood. Using data from a longitudinal twin study, we estimated the overlap between ADHD and immaturity from ages 8-9 to 19-20 years. Results showed that immaturity plays a small but significant role in ADHD in childhood and adolescence, largely due to shared genetic factors that diminish in importance with age. We also showed evidence for ADHD-related genetic stability across ages, and genetic innovation during adolescence and early adulthood. These findings may partly explain why some children show a decrease in ADHD symptoms from childhood to early adulthood, whereas others show a more persistent, chronic, disorder expression. In Study 2, we explore whether common genetic risk variants associated with ADHD also influences a broad range of related childhood psychopathology. Results suggested that genetic risk for ADHD, summed to a polygenic risk score (PRS), is associated with higher levels of neurodevelopmental, externalizing, and to a lesser extent, internalizing problems. Importantly, these associations could largely be attributed to a general psychopathology factor, capturing covariance across symptoms dimensions. These findings provide evidence for wide-spread genetic pleiotropy across psychiatric conditions, and support the notion that many identified genetic risk variants associated with ADHD are likely to non-specifically increase liability towards broad childhood psychiatric problems. In Study 3, we broaden our focus beyond psychiatric conditions to address the overlap between ADHD and epilepsy using a family co-aggregation design. Results from this large, population based cohort suggest that ADHD and epilepsy commonly co-occur and that this risk increase extends to family members of epilepsy patients. Quantitative genetic analyses revealed only a moderate genetic overlap across the disorder. These findings suggest that, although highly comorbid, epilepsy may be less genetically related to ADHD as compared to traditional neurodevelopmental disorders. In Study 4, we address the safety of ADHD pharmacological treatment in patients with a history of epileptic seizures. Using a within-individual comparison design to adjust for time-constant confounders that vary between individuals (e.g. baseline disorder severity, shared genetic liability), we found that ADHD medications were not associated with an increased risk ofacute epileptic seizures. Despite long-standing concerns regarding the safety of stimulant ADHD medications in epilepsy patients, these findings suggest that ADHD medication treatment may be a safe and viable option even in patients with a seizure history. The main findings from this thesis suggest that ADHD is related to both later maturation and a wide range of comorbid psychiatric conditions, partly due to shared genetic risk factors. Importantly, the shared genetic liability between ADHD and related psychiatric conditions appears to be in part attributable to a general liability towards broad childhood psychopathology. In contrast, epilepsy and ADHD comorbidity seems to be less influenced by shared genetic factors and more strongly influenced by environmental factors not shared by family members. ADHD medication does however not appear to be a risk factor for acute epileptic seizures among individuals with a seizure history. Taken together, results from this thesis highlight important aspects of development and comorbidity in ADHD, and lends support to the hypothesis ADHD may be considered part of broader continuum of psychopathology that is underpinned by partly shared genetic factors. Based on evidence thus far, this genetic shared liability appears less strongly related to epilepsy

The contribution of common genetic risk variants for ADHD to a general factor of childhood psychopathology

Common genetic risk variants have been implicated in the etiology of clinical ADHD diagnoses and symptoms in the general population. However, given the extensive comorbidity across ADHD and other psychiatric conditions, the extent to which genetic variants associated with ADHD also influence broader psychopathology dimensions remains unclear. The aim of this study was to evaluate the associations between ADHD polygenic risk scores (PRS) and a broad range of childhood psychiatric problems, and to quantify the extent to which such associations can be attributed to a general factor of childhood psychopathology. We derived ADHD PRS for 13,457 children aged 9 or 12 from the Child and Adolescent Twin Study in Sweden, using results from an independent meta-analysis of genome-wide association studies of ADHD diagnosis and symptoms. We estimated associations between ADHD PRS, a general psychopathology factor, and several dimensions of neurodevelopmental, externalizing and internalizing symptoms, using structural equation modelling. Higher ADHD PRS were statistically significantly associated with elevated neurodevelopmental, externalizing and depressive symptoms (R2=0.26%-1.69%), but not with anxiety. After accounting for a general psychopathology factor, on which all symptoms loaded positively (mean loading=0.50, range=0.09-0.91), an association with specific hyperactivity/impulsivity remained significant. ADHD PRS explained ~1% (p-value<0.0001) of the variance in the general psychopathology factor and ~0.50% (p-value<0.0001) in specific hyperactivity/impulsivity. Our results suggest that common genetic risk variants associated with ADHD, and captured by PRS, also influence a general genetic liability towards broad childhood psychopathology in the general population, in addition to a specific association with hyperactivity/impulsivity symptoms

Association of genetic risk factors for psychiatric disorders and traits of these disorders in a Swedish population twin sample

Importance Psychiatric traits associated with categorically defined psychiatric disorders are heritable and present to varying degrees in the general population. It is commonly assumed that diagnoses represent the extreme end of continuously distributed traits in the population, but this assumption has yet to be robustly tested for many psychiatric phenotypes. Objective To assess whether genetic risk factors associated with psychiatric disorders are also associated with continuous variation in milder population traits. Design, Setting, and Participants This study combined a novel twin analytic approach with polygenic risk score (PRS) analyses in a large population-based twin sample.Phenotypic and genetic data were available from the Child and Adolescent Twin Study in Sweden. Inpatient data were available for January 1, 1987, to December 31, 2014, and outpatient data for January 1, 2001, to December 31, 2013. The last day of follow-up was December 31, 2014. Data analysis was performed from January 1, 2017, to September 30, 2017. Main Outcomes and Measures Questionnaires that assessed traits of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), learning difficulties, tic disorders (TDs), obsessive-compulsive disorder (OCD), anxiety, major depressive disorder (MDD), mania, and psychotic experiences were administered to a large Swedish twin sample. Individuals with clinical psychiatric diagnoses were identified using the Swedish National Patient Register. Joint categorical/continuous twin modeling was used to estimate genetic correlations between psychiatric diagnoses and continuous traits. The PRSs for psychiatric disorders were calculated based on independent discovery genetic data. The association between PRSs for each disorder and associated continuous traits was tested. Results Phenotype data were available for 13 923 twin pairs (35.1% opposite sex and 31.7% same-sex females) at 9 years of age, 5165 pairs (36.9% opposite sex and 34.0% same-sex females) at 15 years of age, and 4273 pairs (36.5% opposite sex and 34.4% same-sex females) at 18 years of age. Genetic data were available for 13 412 individuals (50.2% females). Twin genetic correlations between numerous psychiatric diagnoses and corresponding traits ranged from 0.31 to 0.69. Disorder PRSs were associated with related population traits for ASD (β [SE] = 0.04 [0.01] at 9 years of age), ADHD (β [SE] = 0.27 [0.03] at 9 years of age), TDs (β [SE] = 0.02 [0.004] at 9 years of age), OCD (β [SE] = 0.13 [0.05] at 18 years of age), anxiety (β [SE] = 0.18 [0.08] at 9 years of age; β [SE] = 0.07 [0.02] at 15 years of age; and β [SE] = 0.40 [0.17] at 18 years of age), MDD (β [SE] = 0.10 [0.03] at 9 years of age; β [SE] = 0.11 [0.02] at 15 years of age; and β [SE] = 0.41 [0.10] at 18 years of age), and schizophrenia (β [SE] = 0.02 [0.01] at 18 years of age). Polygenic risk scores for depressive symptoms were associated with MDD diagnoses (odds ratio, 1.16; 95% CI, 1.02-1.32). Conclusions and Relevance These results suggest that genetic factors associated with psychiatric disorders are also associated with milder variation in characteristic traits throughout the general population for many psychiatric phenotypes. This study suggests that many psychiatric disorders are likely to be continuous phenotypes rather than the categorical entities currently defined in diagnostic manuals, which has strong implications for genetic research in particular

The role of ADHD genetic risk in mid-to-late life somatic health conditions

Growing evidence suggests that ADHD, an early onset neurodevelopmental disorder, is associated with poor somatic health in adulthood. However, the mechanisms underlying these associations are poorly understood. Here, we tested whether ADHD polygenic risk scores (PRS) are associated with mid-to-late life somatic health in a general population sample. Furthermore, we explored whether potential associations were moderated and mediated by life-course risk factors. We derived ADHD-PRS in 10,645 Swedish twins born between 1911 and 1958. Sixteen cardiometabolic, autoimmune/inflammatory, and neurological health conditions were evaluated using self-report (age range at measure 42–88 years) and clinical diagnoses defined by International Classification of Diseases codes in national registers. We estimated associations of ADHD-PRS with somatic outcomes using generalized estimating equations, and tested moderation and mediation of these associations by four life-course risk factors (education level, body mass index [BMI], tobacco use, alcohol misuse). Results showed that higher ADHD-PRS were associated with increased risk of seven somatic outcomes (heart failure, cerebro- and peripheral vascular disease, obesity, type 1 diabetes, rheumatoid arthritis, and migraine) with odds ratios ranging 1.07 to 1.20. We observed significant mediation effects by education, BMI, tobacco use, and alcohol misuse, primarily for associations of ADHD-PRS with cardiometabolic outcomes. No moderation effects survived multiple testing correction. Our findings suggests that higher ADHD genetic liability confers a modest risk increase for several somatic health problems in mid-to-late life, particularly in the cardiometabolic domain. These associations were observable in the general population, even in the absence of medical treatment for ADHD, and appear to be in part mediated by life-course risk factors

Genetic association study of childhood aggression across raters, instruments, and age

Genòmica; Comportament humàGenómica; Comportamiento humanoGenomics; Human behaviourChildhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E–06), PCDH7 (P = 2.0E–06), and IPO13 (P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range |rg|: 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |rg|: 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.We very warmly thank all participants, their parents, and teachers for making this study possible. The project was supported by the “Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies” project (ACTION). ACTION received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no 602768. Cohort-specific acknowledgements and funding information may be found in the Supplementary text

Genetic liability to ADHD and substance use disorders in individuals with ADHD

Aims 1) To investigate whether genetic liability to attention‐deficit/hyperactivity disorder (ADHD), indexed by polygenic risk scores for ADHD (PRS‐ADHD), is associated with substance use disorders (SUD) in individuals with ADHD. 2) To investigate whether other individual‐ or family‐related risk factors for SUD could mediate or confound this association. Design Population‐based cohort study Setting and participants ADHD cases in the iPSYCH sample (a Danish case‐cohort sample of genotyped cases with specific mental disorders), born in Denmark between 1981 and 2003 (N = 13 116). Register‐based information on hospital diagnoses of SUD was available until December 31, 2016. Measurements We estimated odds ratios (ORs) with 95% confidence intervals (CIs) for any SUD as well as for different SUD types (alcohol, cannabis, and other illicit drugs) and severities (use, abuse, and addiction), with effect sizes corresponding to a comparison of the highest PRS‐ADHD decile to the lowest. Findings PRS‐ADHD were associated with any SUD (OR = 1.30, 95% CI: 1.11–1.51). Estimates were similar across different types and severity levels of SUD. Other risk factors for SUD (male sex, age at ADHD diagnosis, comorbid conduct problems, and parental factors including SUD, mental disorders, and socio‐economic status) were independently associated with increased risk of SUD. PRS‐ADHD explained a minor proportion of the variance in SUD (0.2% on the liability scale) compared to the other risk factors. The association between PRS‐ADHD and any SUD was slightly attenuated (OR = 1.21, 95% CI: 1.03–1.41) after adjusting for the other risk factors for SUD. Furthermore, associations were nominally higher in females than in males (ORfemales = 1.59, 95% CI: 1.19–2.12, ORmales = 1.18, 95% CI: 0.98–1.42). Conclusions A higher genetic liability to attention‐deficit/hyperactivity disorder appears to be associated with higher risks of substance use disorders in individuals with attention‐deficit/hyperactivity disorder

Genetic association study of childhood aggression across raters, instruments, and age

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association metaanalysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis AGGoverall was 3.31% (SE= 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P= 1.6E-06), PCDH7 (P= 2.0E-06), and IPO13 (P= 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations rg among rater-specific assessment of AGG ranged from rg= 0.46 between self- and teacher-assessment to rg= 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range |rg|: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg=∼-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |rg| : 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.</p

Insights into attention-deficit/hyperactivity disorder from recent genetic studies

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder (NDD). In this narrative review, we summarize recent advances in quantitative and molecular genetic research from the last 5-10 years. Combined with large-scale international collaboration, these advances have resulted in fast-paced progress in understanding the etiology of ADHD and how genetic risk factors map on to clinical heterogeneity. Studies are converging on a number of key insights. First, ADHD is a highly polygenic NDD with a complex genetic architecture encompassing risk variants across the spectrum of allelic frequencies, which are implicated in neurobiological processes. Second, genetic studies strongly suggest that ADHD diagnosis shares a large proportion of genetic risks with continuously distributed traits of ADHD in the population, with shared genetic risks also seen across development and sex. Third, ADHD genetic risks are shared with those implicated in many other neurodevelopmental, psychiatric and somatic phenotypes. As sample sizes and the diversity of genetic studies continue to increase through international collaborative efforts, we anticipate further success with gene discovery, characterization of how the ADHD phenotype relates to other human traits and growing potential to use genomic risk factors for understanding clinical trajectories and for precision medicine approaches