Attention-deficit/hyperactivity Disorder Polygenic Risk Research Articles

Connections Between the Middle Frontal Gyrus and the Dorsoventral Attention Network Are Associated With the Development of Attentional Symptoms

BackgroundThe right middle frontal gyrus (MFG) has been proposed as a convergence site for the dorsal attention network (DAN) and ventral attention network (VAN), regulating both networks and enabling flexible modulation of attention. However, it is unclear whether the connections between the right MFG and these networks can predict changes in attention-deficit/hyperactivity disorder (ADHD) symptoms. MethodsThis study used data from the Children School Functions and Brain Development project (N = 713, 56.2% boys). Resting-state functional magnetic resonance imaging was employed to analyze the connections of the right MFG with the DAN/VAN; connectome-based predictive modeling was applied for longitudinal prediction, and ADHD polygenic risk scores were used for genetic analysis. ResultsADHD symptoms were associated with the connections between the right MFG and DAN subregion, including the frontal eye field, as well as the VAN subregions, namely the inferior parietal lobule and inferior frontal gyrus. Furthermore, these connections of the right MFG with the frontal eye field, the inferior parietal lobule, and the inferior frontal gyrus could significantly predict changes in ADHD symptoms over 1 year and mediate the prediction of ADHD symptom changes by polygenic risk scores for ADHD. Finally, the validation samples confirmed that the functional connectivity between the right MFG and the frontal eye field/inferior parietal lobule in patients with ADHD was significantly weaker than that in typically developing control participants, and this difference disappeared after medication. ConclusionsThe connection of the right MFG with the DAN and VAN can serve as a predictive indicator for changes in ADHD symptoms over the following year, while also mediating the prediction of ADHD symptom changes by a polygenic risk score for ADHD. These findings hold promise as potential biomarkers for early identification of children who are at risk of developing ADHD.

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.

Increased Genetic Risk for ADHD Potentiates Cognitive Impairment and Brain Hypometabolism in Alzheimer’s Disease Patients

AbstractBackgroundRecent epidemiological studies showed that patients with attention‐deficit/hyperactivity disorder (ADHD) are more likely to be diagnosed with Alzheimer’s Disease (AD). Additionally, increased genetic risk for ADHD, measured with ADHD polygenic risk scores (ADHD‐PRS), was associated with amyloid‐dependent cognitive decline in older adults. However, it is unclear whether higher genetic risk for ADHD is associated with worse cognitive function in patients with AD dementia.MethodWe used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to investigate the association between cognitive function (Preclinical Alzheimer Cognitive Composite [PACC], executive function, and memory) and ADHD‐PRS in subjects with AD dementia. Additionally, we tested whether ADHD‐PRS potentiated brain hypometabolism measured with [18F]FDG‐PET. Analyses were controlled by age, sex, years of study, and number of APOE ε4 alleles.ResultWe evaluated baseline data from 264 AD patients (114 women [43.2%], mean [SD] age of 75 [7.6] years). ADHD‐PRS was associated with decreased cognitive function (p‐value = .04, η2 = .01, Figure 1a), more specifically in executive function (p‐value = .04, η2 = .01, Figure 1c). Higher ADHD‐PRS was associated with brain hypometabolism in frontal, parietal, and temporal regions (Figure 2a,b). Brain hypometabolism correlated with worse cognitive function in the following regions: postcentral gyrus (p‐value = .01, η2 = .03), superior parietal gyrus (p‐value = .001, η2 = .07), precentral gyrus (p‐value = .004, η2 = .05), and fusiform gyrus (p‐value&lt;.0001, η2 = .08, Figure 2c,d,e,f). Finally, decreased metabolism in these four regions mediated the effect of ADHD‐PRS on cognitive function (Figure 3).ConclusionFindings indicate that a higher genetic risk for ADHD is correlated with impaired cognitive function with small effect sizes. Moreover, the effects of the genetic risk of ADHD on cognitive function were mediated by hypometabolism in frontal, parietal, and temporal brain regions, which could point to a decrease resilience to AD pathology in individuals with ADHD. Clinically, our findings suggest that patients with comorbid ADHD and AD dementia have a more severe disease phenotype, with potential implications for prognosis and treatment.

Predicting ADHD in alcohol dependence using polygenic risk scores for ADHD.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a high degree of comorbidity, including substance misuse. We aimed to assess whether ADHD polygenic risk scores (PRS) could predict ADHD diagnosis in alcohol dependence (AD). ADHD PRS were generated for 1223 AD subjects with ADHD diagnosis information and 1818 healthy controls. ADHD PRS distributions were compared to evaluate the differences between healthy controls and AD cases with and without ADHD. We found increased ADHD PRS means in the AD cohort with ADHD (mean 0.30, standard deviation (SD) 0.92; p = 3.9 × 10-6); and without ADHD (mean - 0.00, SD 1.00; p = 5.2 × 10-5) compared to the healthy control subjects (mean - 0.17, SD 0.99). The ADHD PRS means differed within the AD group with a higher ADHD PRS mean in those with ADHD, odds ratio (OR) 1.34, confidence interval (CI) 1.10 to 1.65; p = 0.002. This study showed a positive relationship between ADHD PRS and risk of ADHD in individuals with co-occurring AD indicating that ADHD PRS may have utility in identifying individuals that are at a higher or lower risk of ADHD. Further larger studies need to be conducted to confirm the reliability of the results before ADHD PRS can be considered as a robust biomarker for diagnosis.

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.

Polygenic risk score for attention-deficit/hyperactivity disorder and brain functional networks segregation in a community-based sample.

Neuroimaging studies suggest that brain development mechanisms might explain at least some behavioural and cognitive attention-deficit/hyperactivity disorder (ADHD) symptoms. However, the putative mechanisms by which genetic susceptibility factors influence clinical features via alterations of brain development remain largely unknown. Here, we set out to integrate genomics and connectomics tools by investigating the associations between an ADHD polygenic risk score (ADHD-PRS) and functional segregation of large-scale brain networks. With this aim, ADHD symptoms score, genetic and rs-fMRI (resting-state functional magnetic resonance image) data obtained in a longitudinal community-based cohort of 227 children and adolescents were analysed. A follow-up was conducted approximately 3 years after the baseline, with rs-fMRI scanning and ADHD likelihood assessment in both stages. We hypothesised a negative correlation between probable ADHD and the segregation of networks involved in executive functions, and a positive correlation with the default-mode network (DMN). Our findings suggest that ADHD-PRS is correlated with ADHD at baseline, but not at follow-up. Despite not surviving for multiple comparison correction, we found significant correlations between ADHD-PRS and segregation of cingulo-opercular networks and DMN at baseline. ADHD-PRS was negatively correlated with the segregation level of cingulo-opercular networks but positively correlated with the DMN segregation. These directions of associations corroborate the proposed counter-balanced role of attentional networks and DMN in attentional processes. However, the association between ADHD-PRS and brain networks functional segregation was not found at follow-up. Our results provide evidence for specific influences of genetic factors on development of attentional networks and DMN. We found significant correlations between polygenic risk score for ADHD (ADHD-PRS) and segregation of cingulo-opercular networks and default-mode network (DMN) at baseline. ADHD-PRS was negatively correlated with the segregation level of cingulo-opercular networks but positively correlated with the DMN segregation.

Genetic risk for attention-deficit/hyperactivity disorder predicts cognitive decline and development of Alzheimer's disease pathophysiology in cognitively unimpaired older adults.

Attention-deficit/hyperactivity disorder (ADHD) persists in older age and is postulated as a risk factor for cognitive impairment and Alzheimer's Disease (AD). However, these findings rely primarily on electronic health records and can present biased estimates of disease prevalence. An obstacle to investigating age-related cognitive decline in ADHD is the absence of large-scale studies following patients with ADHD into older age. Alternatively, this study aimed to determine whether genetic liability for ADHD, as measured by a well-validated ADHD polygenic risk score (ADHD-PRS), is associated with cognitive decline and the development of AD pathophysiology in cognitively unimpaired (CU) older adults. We calculated a weighted ADHD-PRS in 212 CU individuals without a clinical diagnosis of ADHD (55-90 years). These individuals had baseline amyloid-β (Aβ) positron emission tomography, longitudinal cerebrospinal fluid (CSF) phosphorylated tau at threonine 181 (p-tau181), magnetic resonance imaging, and cognitive assessments for up to 6 years. Linear mixed-effects models were used to test the association of ADHD-PRS with cognition and AD biomarkers. Higher ADHD-PRS was associated with greater cognitive decline over 6 years. The combined effect between high ADHD-PRS and brain Aβ deposition on cognitive deterioration was more significant than each individually. Additionally, higher ADHD-PRS was associated with increased CSF p-tau181 levels and frontoparietal atrophy in CU Aβ-positive individuals. Our results suggest that genetic liability for ADHD is associated with cognitive deterioration and the development of AD pathophysiology. Findings were mostly observed in Aβ-positive individuals, suggesting that the genetic liability for ADHD increases susceptibility to the harmful effects of Aβ pathology.

Maternal age at birth and child attention-deficit hyperactivity disorder: causal association or familial confounding?

Causal explanations for the association of young motherhood with increased risk for child attention-deficit hyperactivity disorder (ADHD) remain unclear. The ABCD Study recruited 11,878 youth from 22 sites across the United States between June 1, 2016 and October 15, 2018. This cross-sectional analysis of 8,514 children aged 8-11 years excluded 2,260 twins/triplets, 265 adopted children, and 839 younger siblings. We examined associations of maternal age with ADHD clinical range diagnoses based on the Child Behavior Checklist and NIH Toolbox Flanker Attention Scores using mixed logistic and linear regression models, respectively. We conducted confounding and causal mediation analyses using genotype array, demographic, socioeconomic, and prenatal environment data to investigate which genetic and environmental variables may explain the association between young maternal age and child ADHD. In crude models, each 10-year increase in maternal age was associated with 32% decreased odds of ADHD clinical range diagnosis (OR=0.68; 95% CI [0.59, 0.78]) and 1.09-points increased NIH Flanker Attention Scores (β= 1.09; 95% CI [0.76, 1.41]), indicating better child visual selective attention. However, adjustment for confounders weakened these associations. The strongest confounders were family income, caregiver education, and ADHD polygenic risk score for ADHD clinical range diagnoses, and family income, caregiver education, and race/ethnicity for NIH Flanker Attention Scores. Breastfeeding duration, prenatal alcohol exposure, and prenatal tobacco exposure were responsible for up to 18%, 6%, and 4% mediation, respectively. Socioeconomic disadvantages were likely the primary explanation for the association of young maternal age with child ADHD, although genetics and modifiable environmental factors also played a role. Public policies aimed at reducing the burden of ADHD associated with young motherhood should target socioeconomic inequalities and support young pregnant women by advocating for reduced prenatal tobacco exposure and healthy breastfeeding practices after childbirth.

Direct and Indirect Effects in Trio Studies: You Don’t Know What You’re Missing

In the current issue of Biological Psychiatry, Martin et al. (1) analyzed genome-wide single nucleotide polymorphism array data of probands with attention-deficit/hyperactivity disorder (ADHD) and their parents to evaluate the potential contributions of direct (transmitted) and indirect (nontransmitted) genetic effects of polygenic liability for several neurodevelopmental and psychiatric disorders, as well as cognitive ability, in ADHD probands. The authors observed overtransmission of ADHD polygenic risk scores (PRSs) from parents to ADHD probands, as well as undertransmission of PRSs for cognitive ability and obsessive-compulsive disorder (OCD).

Interplay of ADHD Polygenic Liability With Birth-Related, Somatic, and Psychosocial Factors in ADHD: A Nationwide Study.

Attention deficit hyperactivity disorder (ADHD) is a multifactorial neurodevelopmental disorder, yet the interplay between ADHD polygenic risk scores (PRSs) and other risk factors remains relatively unexplored. The authors investigated associations, confounding, and interactions of ADHD PRS with birth-related, somatic, and psychosocial factors previously associated with ADHD. Participants included a random general population sample (N=21,578) and individuals diagnosed with ADHD (N=13,697) from the genotyped Danish iPSYCH2012 case cohort, born between 1981 and 2005. The authors derived ADHD PRSs and identified 24 factors previously associated with ADHD using national registers. Logistic regression was used to estimate associations of ADHD PRS with each risk factor in the general population. Cox models were used to evaluate confounding of risk factor associations with ADHD diagnosis by ADHD PRS and parental psychiatric history, and interactions between ADHD PRS and each risk factor. ADHD PRS was associated with 12 of 24 risk factors (odds ratio range, 1.03-1.30), namely, small gestational age, infections, traumatic brain injury, and most psychosocial risk factors. Nineteen risk factors were associated with ADHD diagnosis (odds ratio range, 1.20-3.68), and adjusting for ADHD PRS and parental psychiatric history led to only minor attenuations. Only the interaction between ADHD PRS and maternal autoimmune disease survived correction for multiple testing. Higher ADHD PRS in the general population is associated with small increases in risk for certain birth-related and somatic ADHD risk factors, and broadly to psychosocial adversity. Evidence of gene-environment interaction was limited, as was confounding by ADHD PRS and family psychiatric history on ADHD risk factor associations. This suggests that the majority of the investigated ADHD risk factors act largely independently of current ADHD PRS to increase risk of ADHD.

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.

Clinical and Genetic Correlates of Bipolar Disorder With Childhood-Onset Attention Deficit Disorder.

Background:Bipolar disorder (BD) with co-occurring attention deficit-hyperactivity disorder (ADHD) is associated with an unfavorable course of illness. We aimed to identify potential clinical and genetic correlates of BD with and without ADHD.MethodsAmong patients with BD (N = 2,198) enrolled in the Mayo Clinic Bipolar Biobank we identified those with ADHD diagnosed in childhood (BD+cADHD; N = 350), those with adult-onset attention deficit symptoms (BD+aAD; N = 254), and those without ADHD (N = 1,594). We compared the groups using linear or logistic regression adjusting for age, sex, and recruitment site. For genotyped patients (N = 1,443), logistic regression was used to compare ADHD and BD polygenic risk scores (PRSs) between the BD groups, as well as to non-BD controls (N = 777).ResultsCompared to the non-ADHD BD group, BD+cADHD patients were younger, more often men and had a greater number of co-occurring anxiety and substance use disorders (all p < 0.001). Additionally, BD+cADHD patients had poorer responses to lithium and lamotrigine (p = 0.005 and p = 0.007, respectively). In PRS analyses, all BD patient subsets had greater genetic risk for BD and ADHD when compared to non-BD controls (p < 0.001 in all comparisons). BD+cADHD patients had a higher ADHD-PRS than non-ADHD BD patients (p = 0.012). However, BD+aAD patients showed no evidence of higher ADHD-PRS than non-ADHD BD patients (p = 0.38).ConclusionsBD+cADHD was associated with a greater number of comorbidities and reduced response to mood stabilizing treatments. The higher ADHD PRS for the BD+cADHD group may reflect a greater influence of genetic factors on early presentation of ADHD symptoms.

Neurobiological, familial and genetic risk factors for dimensional psychopathology in the Adolescent Brain Cognitive Development study.

Adolescence is a key period for brain development and the emergence of psychopathology. The Adolescent Brain Cognitive Development (ABCD) study was created to study the biopsychosocial factors underlying healthy and pathological brain development during this period, and comprises the world's largest youth cohort with neuroimaging, family history and genetic data. We examined 9856 unrelated 9-to-10-year-old participants in the ABCD study drawn from 21 sites across the United States, of which 7662 had multimodalmagnetic resonance imaging scans passing quality control, and 4447 were non-Hispanic white and used for polygenic risk score analyses. Using data available at baseline, we associated eight 'syndrome scale scores' from the Child Behavior Checklist-summarizing anxious/depressed symptoms, withdrawn/depressed symptoms, somatic complaints, social problems, thought problems, attention problems, rule-breaking behavior, and aggressive behavior-with resting-state functional and structural brain magnetic resonance imaging measures; eight indicators of family history of psychopathology; and polygenic risk scores for major depression, bipolar disorder, schizophrenia, attention deficit hyperactivity disorder (ADHD) and anorexia nervosa. As a sensitivity analysis, we excluded participants with clinically significant (>97th percentile) or borderline (93rd-97th percentile) scores for each dimension. Most Child Behavior Checklist dimensions were associated with reduced functional connectivity within one or more of four large-scale brain networks-default mode, cingulo-parietal, dorsal attention, and retrosplenial-temporal. Several dimensions were also associated with increased functional connectivity between the default mode, dorsal attention, ventral attention and cingulo-opercular networks. Conversely, almost no global or regional brain structural measures were associated with any of the dimensions. Every family history indicator was associated with every dimension. Major depression polygenic risk was associated with six of the eight dimensions, whereas ADHD polygenic risk was exclusively associated with attention problems and externalizing behavior (rule-breaking and aggressive behavior). Bipolar disorder, schizophrenia and anorexia nervosa polygenic risk were not associated with any of the dimensions. Many associations remained statistically significant even after excluding participants with clinically significant or borderline psychopathology, suggesting that the same risk factors that contribute to clinically significant psychopathology also contribute to continuous variation within the clinically normal range. This study codifies neurobiological, familial and genetic risk factors for dimensional psychopathology across a population-scale cohort of community-dwelling preadolescents. Future efforts are needed to understand how these multiple modalities of risk intersect to influence trajectories of psychopathology into late adolescence and adulthood.

Polygenic risk for mental disorder reveals distinct association profiles across social behaviour in the general population

Many mental health conditions present a spectrum of social difficulties that overlaps with social behaviour in the general population including shared but little characterised genetic links. Here, we systematically investigate heterogeneity in shared genetic liabilities with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder (BP), major depression (MD) and schizophrenia across a spectrum of different social symptoms. Longitudinally assessed low-prosociality and peer-problem scores in two UK population-based cohorts (4–17 years; parent- and teacher-reports; Avon Longitudinal Study of Parents and Children(ALSPAC): N ≤ 6,174; Twins Early Development Study(TEDS): N ≤ 7,112) were regressed on polygenic risk scores for disorder, as informed by genome-wide summary statistics from large consortia, using negative binomial regression models. Across ALSPAC and TEDS, we replicated univariate polygenic associations between social behaviour and risk for ADHD, MD and schizophrenia. Modelling variation in univariate genetic effects jointly using random-effect meta-regression revealed evidence for polygenic links between social behaviour and ADHD, ASD, MD, and schizophrenia risk, but not BP. Differences in age, reporter and social trait captured 45–88% in univariate effect variation. Cross-disorder adjusted analyses demonstrated that age-related heterogeneity in univariate effects is shared across mental health conditions, while reporter- and social trait-specific heterogeneity captures disorder-specific profiles. In particular, ADHD, MD, and ASD polygenic risk were more strongly linked to peer problems than low prosociality, while schizophrenia was associated with low prosociality only. The identified association profiles suggest differences in the social genetic architecture across mental disorders when investigating polygenic overlap with population-based social symptoms spanning 13 years of child and adolescent development.

Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression.

Anxiety and depression are common mental health disorders and have a higher prevalence in females. They are modestly heritable, share genetic liability with other psychiatric disorders, and are highly heterogeneous. There is evidence that genetic liability to neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) is associated with anxiety and depression, particularly in females. We investigated sex differences in family history for neurodevelopmental and psychiatric disorders and neurodevelopmental genetic risk burden (indexed by ADHD polygenic risk scores (PRS) and rare copy number variants; CNVs) in individuals with anxiety and depression, also taking into account age at onset. We used two complementary datasets: 1) participants with a self-reported diagnosis of anxiety or depression (N = 4,178, 65.5% female; mean age = 41.5 years; N = 1,315 with genetic data) from the National Centre for Mental Health (NCMH) cohort and 2) a clinical sample of 13,273 (67.6% female; mean age = 45.2 years) patients with major depressive disorder (MDD) from the Psychiatric Genomics Consortium (PGC). We tested for sex differences in family history of psychiatric problems and presence of rare CNVs (neurodevelopmental and >500kb loci) in NCMH only and for sex differences in ADHD PRS in both datasets. In the NCMH cohort, females were more likely to report family history of neurodevelopmental and psychiatric disorders, but there were no robust sex differences in ADHD PRS or presence of rare CNVs. There was weak evidence of higher ADHD PRS in females compared to males in the PGC MDD sample, particularly in those with an early onset of MDD. These results do not provide strong evidence of sex differences in neurodevelopmental genetic risk burden in adults with anxiety and depression. This indicates that sex may not be a major index of neurodevelopmental genetic heterogeneity, that is captured by ADHD PRS and rare CNV burden, in adults with anxiety and depression.

Discrepancies of polygenic effects on symptom dimensions between adolescents and adults with ADHD

A significant proportion of individuals with attention-deficit/hyperactivity disorder (ADHD) show persistence into adulthood. The genetic and neural correlates of ADHD in adolescents versus adults remain poorly characterized. We investigated ADHD polygenic risk score (PRS) in relation to previously identified gray matter (GM) patterns, neurocognitive, and symptom findings in the same ADHD sample (462 adolescents & 422 adults from the NeuroIMAGE and IMpACT cohorts). Significant effects of ADHD PRS were found on hyperactivity and impulsivity symptoms in adolescents, hyperactivity symptom in adults, but not GM volume components. A distinct PRS effect between adolescents and adults on individual ADHD symptoms is suggested.

Identification of genetic loci associated with nocturnal enuresis: a genome-wide association study

Nocturnal enuresis (bedwetting) is a common disorder affecting 10-16% of 7-year-old children globally. Nocturnal enuresis is highly heritable, but its genetic determinants remain unknown. We aimed to identify genetic variants associated with nocturnal enuresis and explore its genetic architecture and underlying biology. We did a genome-wide association study (GWAS) of nocturnal enuresis. Nocturnal enuresis cases were identified in iPSYCH2012, a large Danish population-based case cohort established to investigate mental disorders, on the basis of 10th revision of the International Statistical Classification of Diseases (ICD-10) diagnoses and redeemed desmopressin prescriptions in Danish registers. The GWAS was done in a genetically homogeneous sample of unrelated individuals using logistic regression with relevant covariates. All genome-wide significant variants were analysed for their association with nocturnal enuresis in an independent Icelandic sample from deCODE genetics. Standardised polygenic risk scores for attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder were constructed from summary statistics of large GWASs and analysed for association with nocturnal enuresis. The GWAS included 3882 nocturnal enuresis cases and 31 073 controls. We found two loci at chromosome 6 and chromosome 13 significantly associated with nocturnal enuresis. Six genetic variants at the two loci (five variants at chromosome 6q16.2 and one variant at chromosome 13q22.3) surpassed the threshold for genome-wide significance (p<5 × 10-8). There were two lead variants: rs9376454 (chromosome 6q16.2), with an odds ratio (OR) of 1·199 (95% CI 1·135-1·267; p=9·91 × 10-11), and rs60721117 (chromosome 13q22.3), with an OR of 1·149 (1·095-1·205; p=1·21 × 10-8). All associated variants in the chromosome 6 locus were replicated (p<8 × 10-3) in the independent Icelandic cohort of 5475 nocturnal enuresis cases and 303 996 controls, whereas the associated variant in the chromosome 13 locus showed nominal significant association (p=0·031). The percentage of nocturnal enuresis phenotypic variance explained by the common genetic variants was 23·9-30·4%. Polygenic risk for ADHD was associated with nocturnal enuresis (OR 1·06, 95% CI, 1·01-1·10; p=0·011). Among the potential nocturnal enuresis risk genes mapped, PRDM13 and EDNRB have biological functions associated with known pathophysiological mechanisms in nocturnal enuresis, and SIM1 regulates the formation of the hypothalamic neuroendocrine lineage that produces arginine vasopressin, a well known nocturnal enuresis drug target. This study shows that common genetic variants contribute considerably to nocturnal enuresis, and it identifies potential nocturnal enuresis risk genes with roles in sleep, urine production, and bladder function. Given that available treatments target these mechanisms, any of the identified genes and their functional gene networks are potential drug targets. The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Stanley Foundation.

Mapping relationships between ADHD genetic liability, stressful life events, and ADHD symptoms in healthy adults.

Attention‐deficit/hyperactivity disorder (ADHD) symptoms are continuously distributed in the general population, where both genetic and environmental factors play roles. Stressful life events (SLEs) have been associated with ADHD diagnosis, but the relationship between ADHD genetic liability, SLEs, and ADHD symptoms in healthy individuals is less clear. Using a sample of 1,531 healthy adults (average age 26.9 years; 55.8% female), we investigated relationships between ADHD polygenic risk scores (ADHD‐PRSs), SLEs, and ADHD symptoms in a general population sample. Confirming earlier findings in an overlapping sample, all SLE‐measures assessed (lifetime SLEs, recent SLEs, and childhood trauma (CT)) were significantly correlated with total ADHD, inattention (IA), and hyperactivity‐impulsivity (HI) scores (r 2 range = .08–.15; all p < .005). ADHD‐PRSs was associated with HI (R2 best‐fit = .37%), lifetime SLEs (R2 best‐fit = .56%), and CT (R2 best‐fit = .40%). Mediation analyses showed that lifetime SLEs partially mediated the association between ADHD‐PRSs and HI (indirect effect: β = 68.6, bias corrected accelerated 95% confident interval (BCa95%CI) [11.9, 131.0], p = .016, proportion mediated (PM) =19.5%), with strongest effects contributed by CT (β = 34.4, BCa95%CI [0.4, 76.5], p = .040, PM = 9.8%). On the other hand, HI partially mediated the association between the ADHD‐PRSs and lifetime SLEs (β = 42.9, BCa95%CI [7.3, 83.9], p = .014, PM = 18.8%). Our study observed a complex relationship of genetic and environmental risk factors contributing to ADHD symptoms in the healthy adult population.

Impulsivity and Venturesomeness in an Adult ADHD Sample: Relation to Personality, Comorbidity, and Polygenic Risk.

While impulsivity is a basic feature of attention-deficit/hyperactivity disorder (ADHD), no study explored the effect of different components of the Impulsiveness (Imp) and Venturesomeness (Vent) scale (IV7) on psychiatric comorbidities and an ADHD polygenic risk score (PRS). We used the IV7 self-report scale in an adult ADHD sample of 903 patients, 70% suffering from additional comorbid disorders, and in a subsample of 435 genotyped patients. Venturesomeness, unlike immediate Impulsivity, is not specific to ADHD. We consequently analyzed the influence of Imp and Vent also in the context of a PRS on psychiatric comorbidities of ADHD. Vent shows a distinctly different distribution of comorbidities, e.g., less anxiety and depression. PRS showed no effect on different ADHD comorbidities, but correlated with childhood hyperactivity. In a complementary analysis using principal component analysis with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ADHD criteria, revised NEO Personality Inventory, Imp, Vent, and PRS, we identified three ADHD subtypes. These are an impulsive–neurotic type, an adventurous–hyperactive type with a stronger genetic component, and an anxious–inattentive type. Our study thus suggests the importance of adventurousness and the differential consideration of impulsivity in ADHD. The genetic risk is distributed differently between these subtypes, which underlines the importance of clinically motivated subtyping. Impulsivity subtyping might give insights into the organization of comorbid disorders in ADHD and different genetic background.

Predicting the course of ADHD symptoms through the integration of childhood genomic, neural, and cognitive features.

Childhood attention deficit hyperactivity disorder (ADHD) shows a highly variable course with age: some individuals show improving, others stable or worsening symptoms. The ability to predict symptom course could help individualize treatment and guide interventions. By studying a cohort of 362 youth, we ask if polygenic risk for ADHD, combined with baseline neural and cognitive features could aid in the prediction of the course of symptoms over an average period of 4.8 years. Compared to a never-affected comparison group, we find that participants with worsening symptoms carried the highest polygenic risk for ADHD, followed by those with stable symptoms, then those whose symptoms improved. Participants with worsening symptoms also showed atypical baseline cognition. Atypical microstructure of the cingulum bundle and anterior thalamic radiation was associated with improving symptoms while reduction of thalamic volume was found in those with stable symptoms. Machine-learning algorithms, trained and tested on independent groups, performed well in classifying those never affected against groups with worsening, stable, and improving symptoms (area under the curve >0.79). We conclude that some measures of polygenic risk, cognition, and neuroimaging show significant associations with the future course of ADHD symptoms and may have modest predictive power. These features warrant further exploration as prognostic tools.