Attention-deficit/hyperactivity disorder and risk for psychiatric and neurodevelopmental disorders in siblings.
ABSTRACT: BACKGROUND:Probands with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for several psychiatric and neurodevelopmental disorders. The risk of these disorders among the siblings of probands has not been thoroughly assessed in a population-based cohort. METHODS:Every child born in Finland in 1991-2005 and diagnosed with ADHD in 1995-2011 were identified from national registers. Each case was matched with four controls on sex, place, and date of birth. The full siblings of the cases and controls were born in 1981-2007 and diagnosed in 1981-2013. In total, 7369 cases with 12 565 siblings and 23 181 controls with 42 753 siblings were included in the analyses conducted using generalized estimating equations. RESULTS:44.2% of the cases and 22.2% of the controls had at least one sibling diagnosed with any psychiatric or neurodevelopmental disorder (risk ratio, RR = 2.1; 95% CI 2.0-2.2). The strongest associations were demonstrated for childhood-onset disorders including ADHD (RR = 5.7; 95% CI 5.1-6.3), conduct and oppositional disorders (RR = 4.0; 95% CI 3.5-4.5), autism spectrum disorders (RR = 3.9; 95% CI 3.3-4.6), other emotional and social interaction disorders (RR = 2.7; 95% CI 2.4-3.1), learning and coordination disorders (RR = 2.6; 95% CI 2.4-2.8), and intellectual disability (RR = 2.4; 95% CI 2.0-2.8). Also, bipolar disorder, unipolar mood disorders, schizophrenia spectrum disorders, other neurotic and personality disorders, substance abuse disorders, and anxiety disorders occurred at increased frequency among the siblings of cases. CONCLUSIONS:The results offer potential utility for early identification of neurodevelopmental and psychiatric disorders in at-risk siblings of ADHD probands and also argue for more studies on common etiologies.
Project description:<h4>Background</h4>Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder sharing genetic risk factors with other common psychiatric disorders. However, intergenerational recurrence patterns of ADHD from parents to sons and daughters are not known. We aimed to examine the risk of ADHD in offspring of parents with ADHD and parents with other psychiatric disorders by parental and offspring sex, using parents without the specific disorders as comparison.<h4>Methods</h4>In a generation study linking data from several population-based registries, all Norwegians born 1967-2011 (n = 2,486,088; Medical Birth Registry of Norway) and their parents were followed to 2015. To estimate intergenerational recurrence risk, we calculated prevalence differences (PD) and the relative risk (RR) of ADHD in offspring by parental ADHD, bipolar disorder (BD), schizophrenia spectrum disorder (SCZ), major depression (MDD), all by parental and offspring sex.<h4>Results</h4>The absolute prevalence of ADHD in offspring of parents with ADHD was very high, especially in sons of two affected parents (41.5% and 25.1% in sons and daughters, respectively), and far higher than in offspring of parents with BD, SCZ or MDD. Intergenerational recurrence risks were higher for maternal than paternal ADHD (RR<sub>maternal</sub> 8.4, 95% confidence interval (CI) 8.2-8.6 vs. RR<sub>paternal</sub> 6.2, 6.0-6.4) and this was also true on the absolute scale (PD<sub>maternal</sub> 21.1% (20.5-21.7) vs. PD<sub>paternal</sub> 14.8% (14.3-15.4)). RRs were higher in daughters, while PDs higher in sons. Parental SCZ, BD and MDD were associated with an approximately doubled risk of offspring ADHD compared to parents without the respective disorders, and estimates did not differ significantly between daughters and sons.<h4>Conclusions</h4>The intergenerational recurrence risks of ADHD were high and higher from mothers with ADHD than fathers with ADHD. Other parental psychiatric disorders also conferred increased risk of offspring ADHD, but far lower, indicating a sex- and diagnosis-specific intergenerational recurrence risk in parents with ADHD.
Project description:BACKGROUND:Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) share common genetic factors but seem to have specific patterns of psychiatric comorbidities. There are few systematic studies on adults; therefore, we compared psychiatric comorbidities in adults with these two neurodevelopmental disorders using population-based data and analyzed their genetic correlations to evaluate underlying factors. METHODS:Using data from Norwegian registries, we assessed patterns of psychiatric disorders in adults with ADHD (n = 38,636; 2.3%), ASD (n = 7528; 0.4%), and both diagnoses (n = 1467; 0.1%) compared with the remaining adult population (n = 1,653,575). We calculated their prevalence ratios (PRs) and differences using Poisson regression, also examining sex-specific relations. Genetic correlations (rg) among ADHD, ASD, and the examined psychiatric disorders were calculated by linkage disequilibrium score regression, exploiting summary statistics from relevant genome-wide association studies. RESULTS:For all psychiatric comorbidities, PRs differed between ADHD and ASD. Associations were strongest in individuals with ADHD and ADHD+ASD for most comorbidities, in both men and women. The relative prevalence increase of substance use disorder was three times larger in ADHD than in ASD (PRADHD, 6.2; 95% confidence interval [CI], 6.1-6.4; PRASD, 1.9; 95% CI, 1.7-2.2; p < .001); however, the opposite was true for schizophrenia (PRASD, 13.9; 95% CI, 12.7-15.2; PRADHD, 4.4; 95% CI, 4.1-4.7; p < .001). Genetic correlations supported these patterns but were significantly different between ADHD and ASD only for the substance use disorder proxies and personality traits (p < .006 for all). CONCLUSIONS:Adults with ADHD, ASD, or both ADHD and ASD have specific patterns of psychiatric comorbidities. This may partly be explained by differences in underlying genetic factors.
Project description:Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent and heritable psychiatric disorders. While previous studies have focussed on mapping focal or connectivity differences at the group level, the present study employed pattern recognition to quantify group separation between unaffected siblings, participants with ADHD, and healthy controls on the basis of spatially distributed brain activations. This was achieved using an fMRI-adapted version of the Stop-Signal Task in a sample of 103 unaffected siblings, 184 participants with ADHD, and 128 healthy controls. We used activation maps derived from three task regressors as features in our analyses employing a Gaussian process classifier. We showed that unaffected siblings could be distinguished from participants with ADHD (area under the receiver operating characteristic curve (AUC) = 0.65, p = 0.002, 95% Modified Wald CI: 0.59-0.71 AUC) and healthy controls (AUC = 0.59, p = 0.030, 95% Modified Wald CI: 0.52-0.66 AUC), although the latter did not survive correction for multiple comparisons. Further, participants with ADHD could be distinguished from healthy controls (AUC = 0.64, p = 0.001, 95% Modified Wald CI: 0.58-0.70 AUC). Altogether the present results characterise a pattern of frontolateral, superior temporal and inferior parietal expansion that is associated with risk for ADHD. Unaffected siblings show differences primarily in frontolateral regions. This provides evidence for a neural profile shared between participants with ADHD and their healthy siblings.
Project description:BACKGROUND:Epilepsy and attention-deficit/hyperactivity disorder (ADHD) are strongly associated; however, the underlying factors contributing to their co-occurrence remain unclear. A shared genetic liability has been proposed as one possible mechanism. Therefore, our goal in this study was to investigate the familial coaggregation of epilepsy and ADHD and to estimate the contribution of genetic and environmental risk factors to their co-occurrence. METHODS:We identified 1,899,654 individuals born between 1987 and 2006 via national Swedish registers and linked each individual to his or her biological relatives. We used logistic regression to estimate the association between epilepsy and ADHD within individual and across relatives. Quantitative genetic modeling was used to decompose the cross-disorder covariance into genetic and environmental factors. RESULTS:Individuals with epilepsy had a statistically significant increased risk of ADHD (odds ratio [OR] = 3.47, 95% confidence interval [CI] = 3.33-3.62). This risk increase extended to children whose mothers had epilepsy (OR = 1.85, 95% CI = 1.75-1.96), children whose fathers had epilepsy (OR = 1.64, 95% CI = 1.54-1.74), full siblings (OR = 1.56, 95% CI = 1.46-1.67), maternal half siblings (OR = 1.28, 95% CI = 1.14-1.43), paternal half siblings (OR = 1.10, 95% CI = 0.96-1.25), and cousins (OR = 1.15, 95% CI = 1.10-1.20). The genetic correlation was 0.21 (95% CI = 0.02-0.40) and explained 40% of the phenotypic correlation between epilepsy and ADHD, with the remaining variance largely explained by nonshared environmental factors (49%, nonshared environmental correlation = 0.36, 95% CI = 0.23-0.49). The contribution of shared environmental factors to the cross-disorder overlap was not statistically significant (11%, shared environmental correlation = 0.32, 95% CI = -0.16-0.79). CONCLUSIONS:This study demonstrates a strong and etiologically complex association between epilepsy and ADHD, with shared familial factors and risk factors unique to the individual contributing to co-occurrence of the disorders. Our findings suggest that epilepsy and ADHD may share less genetic risk as compared with other neurodevelopmental disorders.
Project description:BACKGROUND:Many psychiatric disorders show gender differences in prevalence. Recent studies suggest that female patients diagnosed with anxiety and depression carry more genetic risks related to attention-deficit hyperactivity disorder (ADHD) compared with affected males. AIMS:In this register-based study, we aimed to test whether female patients who received clinical diagnoses of anxiety, depressive, bipolar and eating disorders are at higher familial risk for ADHD and other neurodevelopmental disorders, compared with diagnosed male patients. METHOD:We analysed data from a record-linkage of several Swedish national registers, including 151 025 sibling pairs from 103 941 unique index individuals diagnosed with anxiety, depressive, bipolar or eating disorders, as well as data from 646 948 cousin pairs. We compared the likelihood of having a relative diagnosed with ADHD/neurodevelopmental disorders in index males and females. RESULTS:Female patients with anxiety disorders were more likely than affected males to have a brother with ADHD (odd ratio (OR) = 1.13, 95% CI 1.05-1.22). Results for broader neurodevelopmental disorders were similar and were driven by ADHD diagnoses. Follow-up analyses revealed similar point estimates for several categories of anxiety disorders, with the strongest effect observed for agoraphobia (OR = 1.64, 95% CI 1.12-2.39). No significant associations were found in individuals with depressive, bipolar or eating disorders, or in cousins. CONCLUSIONS:These results provide modest support for the possibility that familial/genetic risks for ADHD may show gender-specific phenotypic expression. Alternatively, there could be gender-specific biases in diagnoses of anxiety and ADHD. These factors could play a small role in the observed gender differences in prevalence of ADHD and anxiety.
Project description:OBJECTIVE:Irritability, which is strongly associated with impairment and negative outcomes, is a common reason for referral to mental health services but is a nosological and treatment challenge. A major issue is how irritability should be conceptualized. The authors used a developmental approach to test the hypothesis that there are several forms of irritability, including a "neurodevelopmental/ADHD-like" type, with onset in childhood, and a "depression/mood" type, with onset in adolescence. METHODS:Data were analyzed from the Avon Longitudinal Study of Parents and Children, a prospective U.K. population-based cohort. Irritability trajectory classes were estimated for 7,924 individuals with data at multiple time points across childhood and adolescence (four possible time points from approximately ages 7 to 15). Psychiatric diagnoses were assessed at approximately ages 7 and 15. Psychiatric genetic risk was indexed by polygenic risk scores (PRSs) for attention deficit hyperactivity disorder (ADHD) and depression, derived using large genome-wide association study results. RESULTS:Five irritability trajectory classes were identified: low (81.2%), decreasing (5.6%), increasing (5.5%), late-childhood limited (5.2%), and high-persistent (2.4%). The early-onset high-persistent trajectory was associated with male preponderance, childhood ADHD (odds ratio=108.64, 95% CI=57.45-204.41), and ADHD PRS (odds ratio=1.31, 95% CI=1.09-1.58). The adolescent-onset increasing trajectory was associated with female preponderance, adolescent depression (odds ratio=5.14, 95% CI=2.47-10.73), and depression PRS (odds ratio=1.20, 95% CI=1.05-1.38). Both the early-onset high-persistent and adolescent-onset increasing trajectory classes were associated with adolescent depression diagnosis and ADHD PRS. CONCLUSIONS:The developmental context of irritability may be important in its conceptualization: early-onset persistent irritability may be more neurodevelopmental/ADHD-like and later-onset irritability more depression/mood-like. These findings have implications for treatment as well as nosology.
Project description:<h4>Background & aims</h4>During the last 15 years, several single-gene mendelian disorders have been discovered that might account for some of the familial aggregation detected in large population studies of colorectal cancer (CRC). Mutations in DNA mismatch repair (MMR) genes cause hereditary nonpolyposis colorectal cancer-Lynch syndrome, the most common of the recognized CRC-predisposition syndromes, in which one major feature is a young age for cancer onset. However, for young-onset microsatellite stable (MSS) CRC, the familial risk for CRC is unknown.<h4>Methods</h4>Patients with CRC who were <50 years old were identified through Minnesota Cancer Surveillance System (MCSS) and Mayo Clinic, Rochester, MN. CRCs in which the DNA MMR function was deficient as evidenced by high level microsatellite instability and/or loss of expression of MMR gene product by immunostaining were excluded. A total of 278 probands (131 from MCSS; 147 from Mayo Clinic) were included. Data on 1862 relatives were collected, of whom 68 were found to have had CRC, and an additional 165 had primary cancers of other types.<h4>Results</h4>Compared with Surveillance Epidemiology and End Results program data, relatives of young-onset CRC probands had increased risks for CRC. This relative risk (RR) was increased among first-degree relatives (RR, 1.65; 95% confidence interval [CI], 1.29-2.07) and was greater for siblings (RR, 2.67; 95% CI, 1.50-4.41) than parents (RR, 1.5; 95% CI, 1.14-1.94).<h4>Conclusions</h4>We studied 278 probands with young-onset MSS CRC. We determined that the RR for CRC was greatest in siblings, which is consistent with an autosomal recessive inheritance pattern.
Project description:Preconception and prenatal nutrition is critical for fetal brain development. However, its associations with offspring neurodevelopmental disorders are not well understood. This study aims to systematically review the associations of preconception and prenatal nutrition with offspring risk of neurodevelopmental disorders. We searched the PubMed and Embase for articles published through March 2019. Nutritional exposures included nutrient intake or status, food intake, or dietary patterns. Neurodevelopmental outcomes included autism spectrum disorders (ASD), attention deficit disorder-hyperactivity (ADHD) and intellectual disabilities. A total of 2169 articles were screened, and 20 articles on ASD and 17 on ADHD were eventually reviewed. We found an overall inverse association between maternal folic acid or multivitamin supplementation and children's risk of ASD; a meta-analysis including six prospective cohort studies estimated an RR of ASD of 0.64 (95% CI: 0.46, 0.90). Data on associations of other dietary factors and ASD, ADHD and related outcomes were inconclusive and warrant future investigation. Future studies should integrate comprehensive and more objective methods to quantify the nutritional exposures and explore alternative study design such as Mendelian randomization to evaluate potential causal effects.
Project description:Importance:Depression often first manifests in adolescence. Thereafter, individual trajectories vary substantially, but it is not known what shapes depression trajectories in youth. Adult studies suggest that genetic risk for schizophrenia, a psychiatric disorder with a neurodevelopmental component, may contribute to an earlier onset of depression. Objective:To test the hypothesis that there are distinct trajectories of depressive symptoms and that genetic liability for neurodevelopmental psychiatric disorders (eg, schizophrenia, attention deficit/hyperactivity disorder [ADHD]), as well as for major depressive disorder (MDD), contribute to early-onset depression. Design, Setting, and Participants:The Avon Longitudinal Study of Parents and Children is an ongoing, prospective, longitudinal, population-based cohort that has been collecting data since September 6, 1990, including data on 7543 adolescents with depressive symptoms at multiple time points. The present study was conducted between November 10, 2017, and August 14, 2018. Main Outcomes and Measures:Trajectories based on self-reported depressive symptoms dichotomized by the clinical cutpoint; MDD, schizophrenia, and ADHD polygenic risk score (PRS) were predictors. Results:In 7543 adolescents with depression data on more than 1 assessment point between a mean (SD) age of 10.64 (0.25) years and 18.65 (0.49) years (3568 [47.3%] male; 3975 [52.7%] female), 3 trajectory classes were identified: persistently low (73.7%), later-adolescence onset (17.3%), and early-adolescence onset (9.0%). The later-adolescence-onset class was associated with MDD genetic risk only (MDD PRS: odds ratio [OR], 1.27; 95% CI, 1.09-1.48; P = .003). The early-adolescence-onset class was also associated with MDD genetic risk (MDD PRS: OR, 1.24; 95% CI, 1.06-1.46; P = .007) but additionally with genetic risk for neurodevelopmental disorders (schizophrenia PRS: OR, 1.22; 95% CI, 1.04-1.43; P = .01; ADHD PRS: OR, 1.32; 95% CI, 1.13-1.54; P < .001) and childhood ADHD (χ21 = 6.837; P = .009) and neurodevelopmental traits (pragmatic language difficulties: OR, 1.31; P = .004; social communication difficulties: OR, 0.68; P < .001). Conclusions and Relevance:The findings of this study appear to demonstrate evidence of distinct depressive trajectories, primarily distinguished by age at onset. The more typical depression trajectory with onset of clinically significant symptoms at age 16 years was associated with MDD genetic risk. The less-common depression trajectory, with a very early onset, was particularly associated with ADHD and schizophrenia genetic risk and, phenotypically, with childhood ADHD and neurodevelopmental traits. Findings are consistent with emerging evidence for a neurodevelopmental component in some cases of depression and suggest that the presence of this component may be more likely when the onset of depression is very early.
Project description:<h4>Background</h4>Attention-deficit/hyperactivity disorder (ADHD) is associated with substance use disorders (SUD; alcohol and/or drug dependence) and nicotine dependence. This study aims to advance our knowledge about the association between SUD, nicotine dependence, and the course of ADHD (persistent versus remittent ADHD and late-onset ADHD).<h4>Methods</h4>ADHD, SUD, and nicotine dependence were longitudinally assessed (mean age at study entry 11.3?years, mean age at follow-up 21.1?years) using structured psychiatric interviews and multi-informant questionnaires in a subsample of the Dutch part of the International Multicenter ADHD Genetics study. Individuals with persistent ADHD (n?=?62), remittent ADHD (n?=?12), late-onset ADHD (n?=?18; age of onset after 12?years), unaffected siblings (n?=?50), and healthy controls (n?=?47) were assessed. Hazard ratios (HR) with 95% confidence intervals (CIs) were estimated by Cox regression and adjusted for clustered family data, gender, follow-up length, and current age.<h4>Results</h4>Individuals with persistent ADHD were at significantly higher risk of development of SUD relative to healthy controls (HR?=?4.56, CI 1.17-17.81). In contrast, levels of SUD in those with remittent ADHD were not different from healthy controls (HR?=?1.00, CI .07-13.02). ADHD persisters had also higher prevalence rates of nicotine dependence (24.2%) than ADHD remitters (16.7%) and healthy controls (4.3%). A similar pattern was found in initially unaffected siblings who met ADHD criteria at follow-up ("late-onset" ADHD); they had also a higher prevalence of SUD (33%) compared to stable unaffected siblings (20%) and were at significantly increased risk of development of nicotine dependence compared to healthy controls (HR?=?13.04, CI 2.08-81.83).<h4>Conclusions</h4>SUD and nicotine dependence are associated with a negative ADHD outcome. Results further emphasize the need for clinicians to comprehensively assess substance use when diagnosing ADHD in adolescents and adults.