Early Life Origins of ASD and ADHD

BackgroundSchizophrenia (SCZ) is a clinically and genetically heterogeneous disorder that shares genetic factors with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). A genome-wide association study (GWAS) differentiating ADHD from ASD was performed recently. Although genetic correlations of regional cortical structures with the risk of SCZ, ASD, and ADHD have been identified, no study has yet investigated the genetic correlations between the genetic factor differentiating ADHD from ASD and brain cortical structures or whether this genetic factor influences cognitive functions and brain cortical structures in patients with SCZ.Aims & ObjectivesGiven the clinical and genetic heterogeneity of SCZ and its significant overlap with ASD and ADHD, our study focuses specifically on SCZ to better understand the distinct genetic contributions to cognitive impairments and cortical abnormalities within this population. By isolating SCZ as the primary condition, we aim to elucidate the unique and shared genetic underpinnings that differentiate it from other neurodevelopmental disorders.The significance of this study lies in its potential to unravel the specific genetic influences on cognitive impairments and cortical abnormalities in SCZ. By exploring the polygenic risk scores (PRSs) differentiating ADHD from ASD, we aim to contribute to the understanding of the genetic architecture that impacts cognitive functions and brain structures in SCZ. This could lead to more precise diagnostic tools and personalized treatment strategies, ultimately improving outcomes for individuals with SCZ.MethodBased on the GWAS data (9,315 ASD and 11,964 ADHD patients), PRSs differentiating ADHD from ASD (indicating a greater risk of ADHD and a lower risk of ASD) were calculated for SCZ patients (n=168). Cognitive performance, including verbal comprehension (VC), perceptual organization (PO), working memory (WM), and processing speed (PS), was assessed using the WAIS-III (n=145). The surface areas and cortical thicknesses of 34 bilateral brain regions were extracted using FreeSurfer (n=126). We examined the associations of these PRSs with cognitive performance and cortical structures in SCZ patients.ResultsAmong the four cognitive domains, a higher PRS, indicating a greater risk of ADHD, was associated with impaired WM in SCZ patients (beta=-0.21, p=0.012). A lower PRS, indicating a greater risk of ASD, was associated with decreased surface areas of the left medial orbitofrontal (beta=0.21, p=8.29×10-4), left entorhinal (beta=0.21, p=0.025), left postcentral (beta=0.18, p=7.52×10-3), right fusiform (beta = 0.17, p = 6.64×10-3), and left fusiform cortices (beta=0.17, p=7.77×10-3) in SCZ patients. A higher PRS, indicating a greater risk of ADHD, was associated with decreased cortical thickness in the bilateral transverse temporal regions (left, beta=-0.17, p=0.039; right, beta=-0.17, p=0.045).Discussion & ConclusionsOur study revealed a relationship between genetic factors that differentiate ADHD patients from ASD patients and both cortical structure and cognitive performance in SCZ patients. These findings suggest that the heterogeneity of SCZ might be partly derived from genetic factors related to neurodevelopmental and psychiatric disorders other than SCZ.

Multiple subependymal pseudocysts in neonates play a role in later attention deficit hyperactivity and autistic spectrum disorder

Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two highly heritable neurodevelopmental disorders. Several lines of evidence point towards the presence of shared genetic factors underlying ASD and ADHD. We conducted genomic analyses of common risk variants (i.e. single nucleotide polymorphisms, SNPs) shared by ASD and ADHD, and those specific to each disorder. With the summary data from two GWAS, one on ASD (N=46,350) and another on ADHD (N=55,374) individuals, we used genomic structural equationmodelling and colocalization analysis to identify SNPs shared by ASD and ADHD and SNPs specific to each disorder. Functional genomic analyses were then conducted on shared and specific common genetic variants. Finally, we performed a bidirectional Mendelian randomization analysis to test whether the shared genetic risk between ASD and ADHD was interpretable in terms of reciprocal relationships between ASD and ADHD. We found that 37.5% of the SNPs associated with ASD (at p<1e-6) colocalized with ADHD SNPs and that 19.6% of the SNPs associated with ADHD colocalized with ASD SNPs. We identified genes mapped to SNPs that are specific to ASD or ADHD and that are shared by ASD and ADHD, including two novel genes INSM1 and PAX1. Our bidirectional Mendelian randomization analyses indicated that the risk of ASD was associated with an increased risk of ADHD and vice versa. Using multivariate genomic analyses, the present study uncovers shared and specific genetic variants associated with ASD and ADHD. Further functional investigation of genes mapped to those shared variants may help identify pathophysiological pathways and new targets for treatment.

Few studies suggest possible links between attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and Alzheimer’s disease but they have been limited by small sample sizes, diagnostic and recall bias. We used two-sample Mendelian randomization (MR) to estimate the bidirectional causal association between genetic liability to ADHD and ASD on Alzheimer’s disease. In addition, we estimated the causal effects independently of educational attainment and IQ, through multivariable Mendelian randomization (MVMR). We employed genetic variants associated with ADHD (20,183 cases/35,191 controls), ASD (18,381 cases/27,969 controls), Alzheimer’s disease (71,880 cases/383,378 controls), educational attainment (n = 766,345) and IQ (n = 269,867) using the largest GWAS of European ancestry. There was limited evidence to suggest a causal effect of genetic liability to ADHD (odds ratio [OR] = 1.00, 95% CI: 0.98–1.02, P = 0.39) or ASD (OR = 0.99, 95% CI: 0.97–1.01, P = 0.70) on Alzheimer’s disease. Similar causal effect estimates were identified as direct effects, independent of educational attainment (ADHD: OR = 1.00, 95% CI: 0.99–1.01, P = 0.76; ASD: OR = 0.99, 95% CI: 0.98–1.00, P = 0.28) and IQ (ADHD: OR = 1.00, 95% CI: 0.99–1.02. P = 0.29; ASD: OR = 0.99, 95% CI: 0.98–1.01, P = 0.99). Genetic liability to Alzheimer’s disease was not found to have a causal effect on risk of ADHD or ASD (ADHD: OR = 1.12, 95% CI: 0.86–1.44, P = 0.37; ASD: OR = 1.19, 95% CI: 0.94–1.51, P = 0.14). We found limited evidence to suggest a causal effect of genetic liability to ADHD or ASD on Alzheimer’s disease; and vice versa.

BackgroundAntidepressant exposure during pregnancy has been associated with an increased risk of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) in several observational studies. We performed a systematic review of these studies to highlight the effect that important methodological limitations have on such analyses and to consider approaches to the conduct, reporting and interpretation of future studies.MethodsA review of MEDLINE and EMBASE identified case–control, cohort and sibling studies assessing the risk of ASD and ADHD with antidepressant use during pregnancy. Approaches to confounding adjustment were described. Crude and adjusted effect estimates for comparisons between antidepressant exposure during pregnancy vs. all unexposed women were first meta-analysed using a generic inverse variance method of analysis, followed by effect estimates for alternative pre-selected comparison groups.ResultsA total of 15 studies measuring ASD as an outcome (involving 3,585,686 children and 40,585 cases) and seven studies measuring ADHD as an outcome (involving 2,765,723 patients and 52,313 cases) were identified. Variation in confounding adjustment existed between studies. Updated effect estimates for the association between maternal antidepressant exposure during pregnancy vs. all unexposed women remained statistically significant for ASD (adjusted random-effects risk ratio [RaRR] 1.53, 95% confidence interval [CI] 1.31–1.78). Similar significant associations were observed using pre-pregnancy maternal antidepressant exposure (RaRR 1.48, 95% CI 1.29–1.71) and paternal antidepressant exposure during pregnancy (1.29, 95% CI 1.08–1.53), but analyses restricted to using women with a history of affective disorder (1.18, 95% CI 0.91–1.52) and sibling studies (0.96, 95% CI 0.65–1.42) were not statistically significant. Corresponding associations for risk of ADHD with exposure were: RaRR 1.38, 95% CI 1.13–1.69 (during pregnancy), RaRR 1.38, 95% CI 1.14–1.69 (during pre-pregnancy), RaRR 1.71, 95% CI 1.31–2.23 (paternal exposure), RaRR 0.98, 95% CI 0.77–1.24 (women with a history of affective disorder) and RaRR 0.88, 95% CI 0.70–1.11 (sibling studies).ConclusionsExisting observational studies measuring the risk of ASD and ADHD with antidepressant exposure are heterogeneous in their design. Classical comparisons between exposed and unexposed women during pregnancy are at high risk of residual confounding. Alternative comparisons and sibling designs may aid the interpretation of causality and their utility requires further evaluation, including understanding potential limitations of undertaking meta-analyses with such data.

SU16 - THE IMPACT OF CNVs ON ASD/ADHD RISK IN MULTIPLEX FAMILIES

BackgroundIt is plausible that exposure to cannabis in-utero could be associated with an increased risk of neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) during childhood and adolescence; however, mixed results have been reported. This study investigated whether there is an association between prenatal cannabis use and ADHD symptoms and ASD in offspring using a systematic review and meta-analysis methodology. MethodsA systematic literature search was conducted in PubMed/Medline, Scopus, EMBASE, Web of Science, Psych-Info, and Google Scholar to identify relevant studies. The study protocol has been preregistered in the Prospective Register of Systematic Reviews (PROSPERO) (CRD42022345001), and the Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess the methodological quality of included studies. An inverse variance weighted random effect meta-analysis was conducted to pool the overall effect estimates from the included studies. ResultsFourteen primary studies, consisting of ten on ADHD and four on ASD, with a total of 203,783 participants, were included in this study. Our meta-analysis underscores an increased risk of ADHD symptoms and/or disorder [β = 0.39: 95 % CI (0.20–0.58), I2 = 66.85 %, P = 0.001)] and ASD [RR = 1.30: 95 % CI (1.03–1.64), I2 = 45.5 %, P = 0.14] associated with in-utero cannabis exposure in offspring compared to their non-exposed counterparts. Additionally, our stratified analysis highlighted an elevated risk of ADHD symptoms [β = 0.54: 95 % CI (0.26–0.82)] and a marginally significant increase in the risk of diagnostic ADHD among exposed offspring compared to non-exposed counterparts [RR = 1.13, 95 % CI (1.01, 1.26)]. ConclusionThis study indicated that maternal prenatal cannabis exposure is associated with a higher risk of ADHD symptoms and ASD in offspring.

Thyroid hormones are critical for neural development, and during the first trimester of pregnancy, the fetus relies fully on maternal thyroid hormone production. To investigate the associations between maternal thyroid hormone levels in the first trimester with the child's school performance, risk of attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). Information from the Copenhagen Primary Care Laboratory Pregnancy Database on first trimester TSH and free thyroxine measurements in mothers of children born in 2000 through 2014 were linked with information on the child's standardized test scores in school, ADHD (patient record diagnoses and medication), and ASD (patient record diagnoses) until the end of 2018. Associations of TSH and free thyroxine with the outcomes were individually assessed by linear mixed models and Cox regression models. The analyses were stratified by preexisting maternal thyroid disorders. TSH measurements were available for 17 909 mother-child dyads. Among those with children born in 2000 through 2009, 6126 had a standardized school test score and were analyzed for the association between maternal thyroid hormone levels and child's school performance, and no support for an association was found. The association between thyroid hormone levels and child's risk of ADHD and ASD were analyzed for the 17 909 dyads and with no support for an association between thyroid hormone levels and these neurodevelopmental disorders. Stratification by preexisting maternal thyroid disorders did not affect the results. We found no evidence for associations between first trimester maternal thyroid hormone levels and child's school performance, or risk of ADHD or ASD.

Febrile seizure (FS) is the most prevalent childhood seizure; it is significantly related to subsequent epilepsy and has possible links to childhood neurodevelopmental disorders. Separately, premature births are believed to increase the risk of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Therefore, this study investigated whether preterm birth is a risk factor for subsequent epilepsy, ASD, and ADHD in children with FS. We retrospectively collected data for children aged < 5 years with FS from 1 January 2005, to 31 December 2013. We divided these children into two groups—the premature birth group and the full-term group—and compared their incidence rates of epilepsy, ASD and ADHD. The data of 426 patients with history of febrile convulsion were retrospectively collected. The premature birth group (FS+/preterm+) had 108 patients and the full-term group (FS+/preterm−) had 318 patients. The overall epilepsy risk in the FS+/preterm+ group was higher than in the FS+/preterm− group (odds ratio [OR], 2.52; 95% confidence interval [CI], 1.14–5.58; p = 0.02). The overall risk of ADHD in the FS+/preterm+ group was higher than that in the FS+/preterm− group (OR, 6.41; 95% CI, 3.39–12.09; p = 0.0001). In addition, children with FS+/preterm+ had 16.9 times (95% CI, 4.79–59.7; p = 0.0001) higher odds of having ASD compared with those with FS+/preterm−. Preterm birth may be a risk factor for subsequent epilepsy, ASD and ADHD in children with FS.

Children with Autism Spectrum Disorder (ASD) or Attention Deficit Hyperactivity Disorder (ADHD) have shown an increased risk for violence and victimization. However, research on exposure to multiple forms of victimization in different contexts are scarce. Hence, the current aim is to review the evidence about polyvictimization among children with ASD or ADHD. PsycInfo, ERIC, ERC, Scopus, and PubMed databases were systematically searched until 12 March 2019 to identify empirical studies with reported prevalence rates of at least four forms of victimization among children with ASD or ADHD. A total of 6/1300 articles were included in the review, ranging in sample sizes from 92 to 4114. The reported prevalence rates for polyvictimization were 1.8% and 23.1% for children with ASD and 7.3% for children with ADHD. The results emphasize the high prevalence of violence and victimization, including polyvictimization, among children with ASD or ADHD. Polyvictimization among children with ASD or ADHD is a highly under researched area. Significant knowledge gaps and important methodological considerations that provide important implications for future research include lack of information on cyber bullying, frequency or intensity of victimization, and the failure to include children as informants and to report health outcomes associated with polyvictimization.

Background: Prenatal maternal stress (PNMS) is defined as the experience of significant levels of prenatal stress, depression or anxiety during pregnancy. PNMS has been associated with increased risk of autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) in exposed offspring. However, these findings are inconsistent and other studies found no association, meaning a clear consensus on the impact of PNMS on ASD and ADHD risk is required. The purpose of this systematic review and meta-analysis is to summarize and critically review the existing literature on the effects of PNMS on ASD and ADHD risk. Methods: Electronic databases (PubMed, PsycINFO, Web of Science, Scopus and EMBASE) will be searched for articles following a detailed search strategy. We will include cohort, case-control and cross-sectional studies that assessed maternal exposure to psychological and/or environmental stress and had ASD or ADHD as an outcome. Two reviewers will independently screen the titles, abstracts and full articles to identify eligible studies. We will use a standardised data extraction form for extracting data and a bias classification tool for assessing study quality. This systematic review will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). The generic inverse variance method will be used if possible to perform meta-analyses. Ethics and dissemination: Ethical approval is not required for this study because it will not involve the conduct or inclusion of any experimental or personal data that would require informed consent. The systematic review will be disseminated in peer-reviewed journals. PROSPERO registration number: CRD42018084222.

Advances in Our Understanding of Genetic Risk Factors for Autism Spectrum Disorders

Attention problems are common in youngsters with attention deficit hyperactivity disorder (ADHD) as well as in adolescents with combined autism spectrum disorder (ASD) and ADHD. However, it is unknown whether there is psychophysiological overlap and/or a difference in electroencephalogram (EEG) power spectra between ADHD and comorbid ASD and ADHD (ASD + ADHD), on and off stimulant medication. To explore potential differences and overlap, measures of theta and beta power in adolescents diagnosed with ADHD (n = 33) versus adolescents with combined ASD + ADHD (n = 20), categorized by stimulant medication use (57 % of the total sample), were compared. EEG measures were acquired in three conditions: (1) resting state, eyes closed (2) resting state, eyes open and (3) during an oddball task. In addition, performance on the d2 attention test was analyzed. Adolescents with ADHD displayed more absolute theta activity than adolescents with ASD + ADHD during the eyes open and task conditions, independent of stimulant medication use. In addition, only the adolescents with ADHD showed an association between diminished attention test performance and increased theta in the eyes open condition. Results of the current study suggest that although there is behavioral overlap between ADHD characteristics in adolescents with ADHD and adolescents with combined ASD + ADHD, the underlying psychophysiological mechanisms may be different. Adolescents with ASD + ADHD exhibited fewer of the EEG physiological signs usually associated with ADHD, although there was an overlap in attentional problems between the groups. This may indicate that treatments developed for ADHD work differently in some adolescents with ASD + ADHD and adolescents with ADHD only.

Studies on neurodevelopmental outcomes in individuals with congenital anomalies who undergo neonatal surgery are scarce and have reported contradictory findings based on small study groups. The congenital condition VACTERL association includes at least three malformations: vertebral anomalies, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal anomalies and limb deformities. Most of these patients undergo surgery during their first days of life. Neurodevelopmental disorders include a broad group of disabilities involving some form of disruption to brain development. Attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD) and intellectual disability (ID) are diagnoses included in this group. The aim of the study was to investigate the risk of ADHD, ASD and ID in a cohort of individuals with VACTERL association. Data was obtained from four Swedish national health registers and analyzed using the Cox proportional hazards model. Patients born 1973-2018 in Sweden with the diagnosis of VACTERL association were included in the study. For each case five healthy controls matched for sex, gestational age at birth, birth year and birth county were obtained. The study included 136 individuals with VACTERL association and 680 controls. Individuals with VACTERL had significantly higher risk of ADHD, ASD and ID than the controls; 2.25 (95% CI, 1.03-4.91), 5.15 (95% CI, 1.93-13.72) and 8.13 (95% CI, 2.66-24.87) times respectively. A higher risk of ADHD, ASD and ID was found among individuals with VACTERL association compared to controls. These results are of importance to caregivers and to professionals participating in follow ups of these patients in providing early diagnosis and support, aiming to optimize the quality of life of these patients.

Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorders (ASD) are two of the most represented neurodevelopmental conditions in childhood. The diagnostic shift introduced by the DSM-5, allowing a combined diagnosis of ADHD and ASD, poses different clinical challenges related to diagnostic overshadowing, accuracy of clinical judgment and potential delay in an ASD diagnosis in children presenting with ADHD. Here we tried to disentangle the clinical phenotype and specificity of the two co-occurring conditions in relation to autism traits and empathy, by comparing children with ASD with and without comorbid ADHD with children presenting ADHD only and children with typical development. The child versions of the Autism Quotient (C-AQ) and Empathy Quotient (C-EQ) were administered to a total sample of 198 male children between 6 and 14 years old with age appropriate language skills and normal intelligence. Univariate analysis demonstrated no significant differences in the C-AQ total and subscale scores as well as the C-EQ between children with ASD and children with ASD+ADHD, while children with ADHD alone presented an intermediate phenotype between ASD and TD. Furthermore, a receiver operating characteristic (ROC) analysis was applied to discriminate among the different phenotypes. We found that the C-AQ and C-EQ were accurate at distinguishing with satisfactory reliability between: a) ASD versus non- ASD (N-ASD) groups comprising both ADHD and TD children (Area Under the Curve AUC 88% for C-AQ and 81% for C-EQ); b) ASD and TD (AUC 92% for C-AQ and 95% for C-EQ); c) ASD and ADHD (AUC 80% for C-AQ and 68% for C-EQ). Our data confirm the reliability of the C-AQ and C-EQ as behavioural markers to differentiate ASD (regardless of comorbid ADHD) from an ADHD condition and TD. Interestingly, in our sample an ADHD condition does not increase the severity of the clinical phenotype in terms of autism traits distribution and empathy, suggesting that the psychological measures detected by the two quantitative instruments are independent of ADHD traits. This evidence will contribute to the translational efforts in developing better tailored treatments and preventive strategies.