Autism Spectrum Disorder Risk Research Articles

Cell-type-specific effects of autism-associated chromosome 15q11.2-13.1 duplications in human brain.

Recurrent copy number variation represents one of the most well-established genetic drivers in neurodevelopmental disorders, including autism spectrum disorder (ASD). Duplication of 15q11.2-13.1 (dup15q) is a well-described neurodevelopmental syndrome that increases the risk of ASD by over 40-fold. However, the effects of this duplication on gene expression and chromatin accessibility in specific cell types in the human brain remain unknown. To identify the cell-type-specific transcriptional and epigenetic effects of dup15q in the human frontal cortex we conducted single-nucleus RNA-sequencing and multi-omic sequencing on dup15q cases (n=6) as well as non-dup15q ASD (n=7) and neurotypical controls (n=7). Cell-type-specific differential expression analysis identified significantly regulated genes, critical biological pathways, and differentially accessible genomic regions. Although there was overall increased gene expression across the duplicated genomic region, cellular identity represented an important factor mediating gene expression changes. Neuronal subtypes, showed greater upregulation of gene expression across a critical region within the duplication as compared to other cell types. Genes within the duplicated region that had high baseline expression in control individuals showed only modest changes in dup15q, regardless of cell type. Of note, dup15q and ASD had largely distinct signatures of chromatin accessibility, but shared the majority of transcriptional regulatory motifs, suggesting convergent biological pathways. However, the transcriptional binding factor motifs implicated in each condition implicated distinct biological mechanisms; neuronal JUN/FOS networks in ASD vs. an inflammatory transcriptional network in dup15q microglia. This work provides a cell-type-specific analysis of how dup15q changes gene expression and chromatin accessibility in the human brain and finds evidence of marked cell-type-specific effects of this genetic driver. These findings have implications for guiding therapeutic development in dup15q syndrome, as well as understanding the functional effects CNVs more broadly in neurodevelopmental disorders.

Exposure to maternal cannabis use disorder and risk of autism spectrum disorder in offspring: A data linkage cohort study

This study aimed to investigate the association between pre-pregnancy, prenatal and perinatal exposures to cannabis use disorder (CUD) and the risk of autism spectrum disoder (ASD) in offspring. Data were drawn from the New South Wales (NSW) Perinatal Data Collection (PDC), population-based, linked administrative health data encompassing all-live birth cohort from January 2003 to December 2005. This study involved 222 534 mother-offspring pairs. . The exposure variable (CUD) and the outcome of interest (ASD) were identified using the 10th international disease classification criteria, Australian Modified (ICD-10-AM). We found a three-fold increased risk of ASD in the offspring of mothers with maternal CUD compared to non-exposed offspring. In our sensitivity analyses, male offspring have a higher risk of ASD associated with maternal CUD than their female counterparts. In conclusion, exposure to maternal CUD is linked to a higher risk of ASD in offspring, with a stronger risk in male offspring. Further research is needed to understand these gender-specific effects and the relationship between maternal CUD and ASD risk in children.

Association between maternal antidepressant use during pregnancy and the risk of autism spectrum disorder and attention deficit hyperactivity disorder in offspring.

Prenatal antidepressant exposure has been reported to be associated with adverse neurodevelopmental outcomes, yet studies considering confounding factors in Asian populations are lacking. This study utilized a nationwide data base in Taiwan, enrolling all liveborn children registered in the National Health Insurance system between 2004 and 2016. Subjects were divided into two groups: antidepressant-exposed (n = 55,707)) and antidepressant-unexposed group (n = 2,245,689). The effect of antidepressant exposure during different trimesters on autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) was examined. Sibling controls and parallel comparisons by paternal exposure status were treated as negative controls. Additional sensitivity analyses were conducted to examine the effects of antidepressant exposure before and after pregnancy. Prenatal antidepressant exposure was associated with increased risks of ASD and ADHD in population-wide and adjusted analysis. However when comparing antidepressant-exposed children with their unexposed siblings, no differences were found for ASD (Hazard ratio [HR]: 1.04, 95% confidence interval [CI] 0.76-1.42 in first trimester; HR: 0.96, 95% CI 0.62-1.50 in second trimester; HR: 0.69, 95% CI 0.32-1.48 in third trimester) and ADHD (HR: 0.98, 95%CI 0.84-1.15 in first trimester; HR: 0.91, 95% CI 0.73-1.14 in second trimester; HR: 0.79, 95% CI 0.54-1.16 in third trimester). Increased risks for ASD and ADHD were also noted in paternal control, before and after pregnancy analyses. These results imply that the association between prenatal antidepressant exposure and ASD and ADHD is not contributed to by an intrauterine medication effect but more likely to be accounted for by maternal depression, genetic, and potential environmental factors.

Gestational exposure to benzodiazepines or z-hypnotics and neurodevelopmental disorders in offspring: Systematic review and meta-analysis.

Benzodiazepine (BDZP) and/or z-hypnotic dispensing during pregnancy has increased globally, as have rates of autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). This systematic review and meta-analysis aimed to estimate the association between gestational exposure to BDZP and/or z-hypnotics and diagnosis of ASD or ADHD in offspring. We searched MEDLINE, EMBASE, and SCOPUS from inception till December 2023 for relevant English-language articles. Outcomes of interest were risk of ASD and ADHD, two independent primary outcomes, in children exposed anytime during pregnancy to BDZP and/or z-hypnotics versus those unexposed. Secondary outcomes were trimester-wise analyses. Using a random effects model, we pooled the overall and trimester-wise hazard ratios (HRs), with 95% confidence intervals (CIs), separately for risk of ASD and ADHD. We found six eligible retrospective cohort studies and no case-control studies. There was no increased risk of ASD associated with anytime gestational BDZP and/or z-hypnotic exposure (primary outcome, HR, 1.10; 95% CI, 0.81-1.50; 4 studies; n = 3,783,417; 80,270 exposed, 3,703,147 unexposed) nor after first trimester exposure (HR, 1.15; 95% CI, 0.83-1.58; 3 studies; n = 1,539,335; 70,737 exposed, 1,468,598 unexposed) or later trimester exposures. A very small but significantly increased risk of ADHD was noted with anytime gestational exposure to these drugs (primary outcome, HR, 1.07; 95% CI, 1.03-1.12; 4 studies; n = 2,000,777; 78,912 exposed, 1,921,865 unexposed) and also with (only) second trimester exposure (HR, 1.07; 95% CI, 1.03-1.12; 3 studies; n = 1,539,281; 33,355 exposed, 1,505,926 unexposed). Findings were consistent in sensitivity analyses. Gestational exposure to benzodiazepines or z-hypnotics was not associated with an increased risk of ASD and with only a marginally increased risk of ADHD in offspring. Given the likelihood of confounding by indication and by unmeasured variables in the original studies, our findings should reassure women who need these medications for severe anxiety or insomnia during pregnancy.

Investigating gene-environment interaction on attention in a double-hit model for Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a neurodevelopmental behavioral disorder characterized by social, communicative, and motor deficits. There is no single etiological cause for ASD, rather, there are various genetic and environmental factors that increase the risk for ASD. It is thought that some of these factors influence the same underlying neural mechanisms, and that an interplay of both genetic and environmental factors would better explain the pathogenesis of ASD. To better appreciate the influence of genetic-environment interaction on ASD-related behaviours, rats lacking a functional copy of the ASD-linked gene Cntnap2 were exposed to maternal immune activation (MIA) during pregnancy and assessed in adolescence and adulthood. We hypothesized that Cntnap2 deficiency interacts with poly I:C MIA to aggravate ASD-like symptoms in the offspring. In this double-hit model, we assessed attention, a core deficit in ASD due to prefrontal cortical dysfunction. We employed a well-established attentional paradigm known as the 5-choice serial reaction time task (5CSRTT). Cntnap2-/- rats exhibited greater perseverative responses which is indicative of repetitive behaviors. Additionally, rats exposed to poly I:C MIA exhibited premature responses, a marker of impulsivity. The rats exposed to both the genetic and environmental challenge displayed an increase in impulsive activity; however, this response was only elicited in the presence of an auditory distractor. This implies that exacerbated symptomatology in the double-hit model may situation-dependent and not generally expressed.

M-CHAT-R: UTILIZING FOR SCREENING AUTISM SPECTRUM DISORDER

Background: Autism Spectrum Disorder (ASD) is a multifaceted condition marked by challenges in communication and social interactions, behavioral restrictions, and repetitive actions. Identifying children who may be at risk of ASD early on is crucial for prompt consultation, monitoring, and intervention. Objectives: Determine the rate of Autism Spectrum Disorder in children between the ages of 18 and 36 months by utilizing the M-CHAT-R scale at the clinic of Can Tho Children's Hospital. And identify the associated risk factors for that rate of Autism Spectrum Disorder. Materials and methods: A descriptive cross-sectional study conducted on 608 children aged 18-36 months who were examined at the clinic of Can Tho Children's Hospital. Results: The majority of children in the study, comprising 88.3%, fell within the age range of 24-36 months, with proportions of boys and girls at 57.6% and 42.4%, respectively. Among the children, 94.7% (576/608 children) were classified as low risk, while medium risk and high risk accounted for 4.28% (26/608 children) and 1.02% (6/608 children), respectively. Questions with notably high positive rates among at-risk children were item 2 (38.9%), item 5 (15.2%), item 12 (16.2%), item 11 (4.8%). Conversely, the least common symptom was indicated in question 9, where children showed a preference for moving activities, accounting for only 2.7%. Associations were observed between the risk of Autism Spectrum Disorder and factors such as gender (p=0.04), father’age (p=0.024), alcohol consumption (p=0.047), birth asphyxia (p=0.036), seizures due to high fever/unknown cause (p=0.035). Conclusion: In the study, the rate of positive M-CHAT-R was 5.3% (32 out of 608 children), predominantly observed in the low-risk group, accounting for 94.7%. The majority of positive cases fell within the 24-36 month age group, comprising 26 out of the 32 children. The risk of Autism Spectrum Disorder showed correlations with gender, father’s age older or equal to 35 years old, alcohol consumption, birth asphyxia and seizures triggered by high fever or unknown causes. However, there was no observed relationship between the risk of Autism Spectrum Disorder and age group factors.

Mendelian randomization analyses reveal causal relationships between brain functional networks and risk of psychiatric disorders.

Dysfunction of brain resting-state functional networks has been widely reported in psychiatric disorders. However, the causal relationships between brain resting-state functional networks and psychiatric disorders remain largely unclear. Here we perform bidirectional two-sample Mendelian randomization (MR) analyses to investigate the causalities between 191 resting-state functional magnetic resonance imaging (rsfMRI) phenotypes (n = 34,691 individuals) and 12 psychiatric disorders (n = 14,307 to 698,672 individuals). Forward MR identified 8 rsfMRI phenotypes causally associated with the risk of psychiatric disorders. For example, the increase in the connectivity of motor, subcortical-cerebellum and limbic network was associated with lower risk of autism spectrum disorder. In adddition, increased connectivity in the default mode and central executive network was associated with lower risk of post-traumatic stress disorder and depression. Reverse MR analysis revealed significant associations between 4 psychiatric disorders and 6 rsfMRI phenotypes. For instance, the risk of attention-deficit/hyperactivity disorder increases the connectivity of the attention, salience, motor and subcortical-cerebellum network. The risk of schizophrenia mainly increases the connectivity of the default mode and central executive network and decreases the connectivity of the attention network. In summary, our findings reveal causal relationships between brain functional networks and psychiatric disorders, providing important interventional and therapeutic targets for psychiatric disorders at the brain functional network level.

Prenatal & Perinatal Risk Factors of Autism Spectrum Disorder

Background: Autism spectrum disorder (ASD) is lifelong neurodevelopmental disorder characterized by impairments in social function, communication, and certain behaviors. The etiology of ASD is unclear & it is believed to be multi-factorial, among those several prenatal & perinatal factors are found to be significant. So, the necessity of this study is to detect the presence of known risk factors of ASD which in turn may help in the early diagnosis and intervention for better long-term outcomes. Objective: To find out prenatal and perinatal risk factors of ASD. Method: A case control study was conducted with 112 cases of ASD and 201 controls of 2-6 years of age. The study was carried out in Center for Neurodevelopment and Autism in Children (CNAC), in the department of Paediatrics, Bangabandhu Sheikh Mujib Medical University and Autism Welfare Foundation (AWF). ASD was diagnosed by DSM-IV TR criteria. Mothers were interviewed and data were collected by semistructured questionnaires. Results: Total 5 risk factors were identified as the risk factors of ASD. They were: advanced paternal age (OR=2.84) and maternal age (OR=1.87); male baby (OR=2.01); environmental stress during pregnancy (OR=1.61) and preterm delivery (OR=1.80). Conclusions: It is concluded that advanced paternal age, maternal age, male baby, environmental stress during pregnancy and preterm delivery are associated with increased risk of ASD. BANGLADESH J CHILD HEALTH 2022; VOL 46 (3) : 115-121

Cross-Cultural Generalizability of the First Year Inventory for Early ASD Screening in China.

The First Year Inventory (FYI) is a parent report screening measure, aimed at identifying the risk of autism spectrum disorder (ASD) in 12-month-old infants. This study aimed to investigate the utility of FYI within the Chinese community and develop a short version, encompassing both a low-risk sample and a high-risk sample comprising infants with older siblings diagnosed with ASD. Parents of 53 high-risk (HR) infants and 519 low-risk (LR) infants, aged 11 to 13 months, were recruited. After comparing response distributions across Chinese and American samples, a new factorial structure was developed according to the factor analyses. The construct validity and internal consistency of the two FYI versions were examined. The implementation of FYI in the HR sample was also assessed. Noteworthy disparities in response distribution were observed between the Chinese and American samples. Both FYI 2.0 and the FYI short version demonstrated moderate construct validity and internal consistency, with the FYI short version exhibiting better predictive ability in the HR sample. Significant lower risk scores was observed in the HR sample compared to the LR sample. These findings substantiate the applicability and validity of the Chinese short version of FYI. Future research should include follow-up assessments with the Chinese sample to evaluate cutoff scores, considering the cutoff between sensitivity and specificity and the sample?s characteristics.

Cortical dysmorphology and reduced cortico-collicular projections in an animal model of autism spectrum disorder.

Autism spectrum disorder is a neurodevelopmental disability that includes sensory disturbances. Hearing is frequently affected and ranges from deafness to hypersensitivity. In utero exposure to the antiepileptic valproic acid is associated with increased risk of autism spectrum disorder in humans and timed valproic acid exposure is a biologically relevant and validated animal model of autism spectrum disorder. Valproic acid-exposed rats have fewer neurons in their auditory brainstem and thalamus, fewer calbindin-positive neurons, reduced ascending projections to the midbrain and thalamus, elevated thresholds, and delayed auditory brainstem responses. Additionally, in the auditory cortex, valproic acid exposure results in abnormal responses, decreased phase-locking, elevated thresholds, and abnormal tonotopic maps. We therefore hypothesized that in utero, valproic acid exposure would result in fewer neurons in auditory cortex, neuronal dysmorphology, fewer calbindin-positive neurons, and reduced connectivity. We approached this hypothesis using morphometric analyses, immunohistochemistry, and retrograde tract tracing. We found thinner cortical layers but no changes in the density of neurons, smaller pyramidal and non-pyramidal neurons in several regions, fewer neurons immunoreactive for calbindin-positive, and fewer cortical neurons projecting to the inferior colliculus. These results support the widespread impact of the auditory system in autism spectrum disorder and valproic acid-exposed animals and emphasize the utility of simple, noninvasive auditory screening for autism spectrum disorder.

Association between maternal genitourinary infections and the risk of attention deficit hyperactivity disorder and autism spectrum disorder in children according to a systematic review

Introduction. Autism spectrum disorders and attention deficit hyperactivity disorder are among the most significant and widespread mental disorders that manifest in childhood and adolescence. Their etiology and pathogenesis have not been studied enough and most likely a complex of factors leads to their formation. Among other things, data are accumulating on the role of various hazards and diseases of the mother, which increase the risk of neuropsychiatric disorders in offspring. These include genitourinary infections, whose contribution to the development of autism spectrum disorders and attention deficit hyperactivity disorder has not yet been systematically studied.Aim. To establish the contribution of maternal genitourinary infections to the formation of autism spectrum disorders and attention deficit hyperactivity disorder in children.Materials and methods. An electronic search was conducted in the Scopus and Pubmed databases to obtain relevant literature by August 2022. The search strategy included a combination of keywords and MESH terms: urogenital infections, and autism, and autism spectrum disorders, and attention deficit hyperactivity disorder, and maternal infections.Results. On this topic 10 papers have been identified in the available literature – 6 on autism spectrum disorders and 4 on attention deficit hyperactivity disorder. In all the papers on attention deficit hyperactivity disorder included in the analysis, an association between genitourinary infections and neuropsychiatric disorders was revealed. In the case of autism spectrum disorders, the data obtained were more contradictory. The heterogeneity of the available data (different designs, different deficits and approaches to the diagnosis of genitourinary infections) did not allow for a meta-analysis.Conclusions. Genitourinary infections play a pathogenetic role in the formation of attention deficit hyperactivity disorder, while the effect of genitourinary infections on the development of autism spectrum disorders seems less unambiguous. It is necessary to continue work in this area with a more unified design to form practical recommendations for the prevention of neuropsychiatric disorders.

Quantitative proteomics of dorsolateral prefrontal cortex reveals an early pattern of synaptic dysmaturation in children with idiopathic autism.

Autism spectrum disorder (ASD) is a developmental disorder with a rising prevalence and unknown etiology presenting with deficits in cognition and abnormal behavior. We hypothesized that the investigation of the synaptic component of prefrontal cortex may provide proteomic signatures that may identify the biological underpinnings of cognitive deficits in childhood ASD. Subcellular fractions of synaptosomes from prefrontal cortices of age-, brain area-, and postmortem-interval-matched samples from children and adults with idiopathic ASD vs. controls were subjected to HPLC-tandem mass spectrometry. Analysis of data revealed the enrichment of ASD risk genes that participate in slow maturation of the postsynaptic density (PSD) structure and function during early brain development. Proteomic analysis revealed down regulation of PSD-related proteins including AMPA and NMDA receptors, GRM3, DLG4, olfactomedins, Shank1-3, Homer1, CaMK2α, NRXN1, NLGN2, Drebrin1, ARHGAP32, and Dock9 in children with autism (FDR-adjusted P < 0.05). In contrast, PSD-related alterations were less severe or unchanged in adult individuals with ASD. Network analyses revealed glutamate receptor abnormalities. Overall, the proteomic data support the concept that idiopathic autism is a synaptopathy involving PSD-related ASD risk genes. Interruption in evolutionarily conserved slow maturation of the PSD complex in prefrontal cortex may lead to the development of ASD in a susceptible individual.

Environmental Risk Factors in Autism Spectrum Disorder: A Narrative Review.

Existing evidence indicates that environmental factors might contribute up to 50% of the variance in autism spectrum disorder (ASD) risk. This structured narrative review offers a comprehensive synthesis of current knowledge on environmental risk factors in ASD, including evaluation of conflicting evidence, exploration of underlying mechanisms, and suggestions for future research directions. Analysis of diverse epidemiological investigations indicates that certain environmental factors, including advanced parental age, preterm birth, delivery complications, and exposure to toxic metals, drugs, air pollutants, and endocrine-disrupting chemicals, are linked to an increased ASD risk through various mechanisms such as oxidative stress, inflammation, hypoxia, and its consequences, changes in neurotransmitters, disruption of signaling pathways and some others. On the other hand, pregnancy-related factors such as maternal diabetes, maternal obesity, and caesarian section show a weaker association with ASD risk. At the same time, other environmental factors, such as vaccination, maternal smoking, or alcohol consumption, are not linked to the risk of ASD. Regarding nutritional elements data are inconclusive. These findings highlight the significance of environmental factors in ASD etiology and emphasize that more focused research is needed to target the risk factors of ASD. Environmental interventions targeting modifiable risk factors might offer promising avenues for ASD prevention and treatment.

Copy-number variants and polygenic risk for intelligence confer risk for autism spectrum disorder irrespective of their effects on cognitive ability.

Rare copy number variants (CNVs) and polygenic risk for intelligence (PRS-IQ) both confer susceptibility for autism spectrum disorder (ASD) but have opposing effects on cognitive ability. The field has struggled to disentangle the effects of these two classes of genomic variants on cognitive ability from their effects on ASD susceptibility, in part because previous studies did not include controls with cognitive measures. We aim to investigate the impact of these genomic variants on ASD risk while adjusting for their known effects on cognitive ability. In a cohort of 8,426 subjects with ASD and 169,804 controls with cognitive assessments, we found that rare coding CNVs and PRS-IQ increased ASD risk, even after adjusting for their effects on cognitive ability. Bottom decile PRS-IQ and CNVs both decreased cognitive ability but had opposing effects on ASD risk. Models combining both classes of variants showed that the effects of rare CNVs and PRS-IQ on ASD risk and cognitive ability were largely additive, further suggesting that susceptibility for ASD is conferred independently from its effects on cognitive ability. Despite imparting mostly additive effects on ASD risk, rare CNVs and PRS-IQ showed opposing effects on core and associated features and developmental history among subjects with ASD. Our findings suggest that cognitive ability itself may not be the factor driving the underlying liability for ASD conferred by these two classes of genomic variants. In other words, ASD risk and cognitive ability may be two distinct manifestations of CNVs and PRS-IQ. This study also highlights the challenge of understanding how genetic risk for ASD maps onto its dimensional traits.

Sex-Differential Gene Expression in Developing Human Cortex and Its Intersection With Autism Risk Pathways

BackgroundSex-differential biology may contribute to the consistently male-biased prevalence of autism spectrum disorder (ASD). Gene expression differences between males and females in the brain can indicate possible molecular and cellular mechanisms involved, although transcriptomic sex differences during human prenatal cortical development have been incompletely characterized, primarily due to small sample sizes. MethodsWe performed a meta-analysis of sex-differential expression and co-expression network analysis in 2 independent bulk RNA sequencing datasets generated from cortex of 273 prenatal donors without known neuropsychiatric disorders. To assess the intersection between neurotypical sex differences and neuropsychiatric disorder biology, we tested for enrichment of ASD–associated risk genes and expression changes, neuropsychiatric disorder risk genes, and cell type markers within identified sex-differentially expressed genes (sex-DEGs) and sex-differential co-expression modules. ResultsWe identified 101 significant sex-DEGs, including Y-chromosome genes, genes impacted by X-chromosome inactivation, and autosomal genes. Known ASD risk genes, implicated by either common or rare variants, did not preferentially overlap with sex-DEGs. We identified 1 male-specific co-expression module enriched for immune signaling that is unique to 1 input dataset. ConclusionsSex-differential gene expression is limited in prenatal human cortex tissue, although meta-analysis of large datasets allows for the identification of sex-DEGs, including autosomal genes that encode proteins involved in neural development. Lack of sex-DEG overlap with ASD risk genes in the prenatal cortex suggests that sex-differential modulation of ASD symptoms may occur in other brain regions, at other developmental stages, or in specific cell types, or may involve mechanisms that act downstream from mutation-carrying genes.

Food, nutrition, and autism: from soil to fork

Food and nutrition-related factors have the potential to impact development of autism spectrum disorder (ASD) and quality of life for people with ASD, but gaps in evidence exist. On 10 November 2022, Tufts University’s Friedman School of Nutrition Science and Policy and Food and Nutrition Innovation Institute hosted a 1-d meeting to explore the evidence and evidence gaps regarding the relationships of food and nutrition with ASD. This meeting report summarizes the presentations and deliberations from the meeting. Topics addressed included prenatal and child dietary intake, the microbiome, obesity, food-related environmental exposures, mechanisms and biological processes linking these factors and ASD, food-related social factors, and data sources for future research. Presentations highlighted evidence for protective associations with prenatal folic acid supplementation and ASD development, increases in risk of ASD with maternal gestational obesity, and the potential for exposure to environmental contaminants in foods and food packaging to influence ASD development. The importance of the maternal and child microbiome in ASD development or ASD-related behaviors in the child was reviewed, as was the role of discrimination in leading to disparities in environmental exposures and psychosocial factors that may influence ASD. The role of child diet and high prevalence of food selectivity in children with ASD and its association with adverse outcomes were also discussed. Priority evidence gaps identified by participants include further clarifying ASD development, including biomarkers and key mechanisms; interactions among psychosocial, social, and biological determinants; interventions addressing diet, supplementation, and the microbiome to prevent and improve quality of life for people with ASD; and mechanisms of action of diet-related factors associated with ASD. Participants developed research proposals to address the priority evidence gaps. The workshop findings serve as a foundation for future prioritization of scientific research to address evidence gaps related to food, nutrition, and ASD.

Association of Breastfeeding Duration with Neurodevelopmental Outcomes in an Enriched Familial Likelihood Cohort for Autism Spectrum Disorder.

This study aimed to compare the breastfeeding (BF) duration of the younger siblings of children with ASD in an enriched-likelihood cohort for autism spectrum disorder (ASD), and to determine whether longer BF duration was associated with differences in neurodevelopmental outcomes in this cohort. Information on BF practices was collected via surveys in the MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) study. Developmental evaluations, including the Mullen Scales of Early Learning and the Autism Diagnostic Observation Schedule, were conducted by expert clinicians. Participants' neurodevelopmental outcome was classified by an algorithm into three groups: typical development, ASD, and non-typical development. The median duration of BF was 10.70months (interquartile range of 12.07months). There were no significant differences in the distribution of duration of BF among the three neurodevelopmental outcome categories. Children in this enriched-likelihood cohort who were breastfed for > 12months had significantly higher scores on cognitive testing compared to those who were breastfed for 0-3months. There was no significant difference in ASD symptomatology or ASD risk based on BF duration.

Association between parental psychiatric disorders and risk of offspring autism spectrum disorder: a Swedish and Finnish population-based cohort study

Roughly more than one in six adults worldwide suffer from psychiatric conditions. Sporadic studies have associated parental psychiatric disorders with autism spectrum disorder in offspring. Comprehensively examining the association between parental psychiatric disorders and offspring autism spectrum disorder is needed to guide health policies, and to inform etiologic studies. We included all children born in Sweden and Finland 1997-2016. Diagnoses were clinically ascertained from National Registers through 2017. We calculated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for autism spectrum disorder in offspring of fathers and mothers with psychiatric disorders, in both parents jointly and across co-occurring conditions. Among 2,505,842 children, 33,612 were diagnosed with autism spectrum disorder, of which 20% had a parent with psychiatric disorders. The risk of autism spectrum disorder was increased across all psychiatric disorders in fathers (Sweden: aHR=2.02, 95% CI=1.92-2.12; Finland: aHR=1.63, 95% CI=1.50-1.77), mothers (Sweden: aHR=2.34, 95% CI=2.24-2.43; Finland aHR=2.12, 95% CI=1.92-2.28), or both parents (Sweden: aHR=3.76, 95% CI=3.48-4.07; Finland aHR=3.61, 95% CI=3.20-4.07), compared to neither parents. Co-occurrence of parental psychiatric disorders further increased risk (e.g., Sweden: for one, two or≥three different diagnostic categories compared to no diagnosis, in fathers aHR=1.81, 2.07, 2.52; in mothers aHR=2.05, 2.63, 3.57). Psychiatric disorders in both parents conveyed the highest risk of offspring autism spectrum disorder, followed by mothers and then fathers. The risk increased with number of co-occurring disorders. All parental psychiatric disorders were associated with increased the risk of autism spectrum disorder. To reliably assess the risk of autism spectrum disorder in children, a comprehensive history incorporating the full range of parental psychiatric disorders is needed beyond solely focusing on familial autism spectrum disorder. Swedish-Research-Council-2021-0214.

Maternal Immune Activation and Autism Spectrum Disorder: Complex Interactions and Therapeutic Possibilities

This review examines the intricate association between maternal immune activation (MIA) and autism spectrum disorder (ASD), emphasizing the impact of maternal infections during pregnancy. Epidemiological studies link viral and bacterial infections to an elevated risk of ASD, revealing the complex interplay between environmental factors and neurodevelopmental outcomes. Immunological mechanisms, including cytokine dysregulation and neuroinflammation, involve key players such as interleukin-6 and tumor necrosis factor-alpha, influencing fetal brain development and ASD risk. Genetic and environmental interactions contribute to individual susceptibility, with specific variants influencing MIA's impact on ASD risk. Epigenetic modifications provide a molecular link between environmental exposures, including MIA, and enduring neurodevelopmental changes. Recognizing critical periods during fetal neurodevelopment susceptible to MIA is crucial. Long-term studies highlight enduring consequences on behavior and cognition into childhood and adolescence. Exploring potential therapeutic interventions, including immunomodulatory strategies during pregnancy, offers hope for mitigating MIA's impact on ASD outcomes. Despite progress, knowledge gaps persist, motivating future research guided by emerging technologies and interdisciplinary approaches to unravel the intricate MIA-ASD relationship.

Genetically identified mediators associated with increased risk of stroke and cardiovascular disease in individuals with autism spectrum disorder

Growing evidence suggested that individuals with autism spectrum disorder (ASD) associated with stroke and cardiovascular disease (CVD). However, the causal association between ASD and the risk of stroke and CVD remains unclear. To validate this, we performed two-sample Mendelian randomization (MR) and two-step mediation MR analyses, using relevant genetic variants sourced from the largest genome-wide association studies (GWASs). Two-sample MR evidence indicated causal relationships between ASD and any stroke (OR = 1.1184, 95% CI: 1.0302–1.2142, P < 0.01), ischemic stroke (IS) (OR = 1.1157, 95% CI: 1.0237–1.2160, P = 0.01), large-artery atherosclerotic stroke (LAS) (OR = 1.2902, 95% CI: 1.0395–1.6013, P = 0.02), atrial fibrillation (AF) (OR = 1.0820, 95% CI: 1.0019–1.1684, P = 0.04), and heart failure (HF) (OR = 1.1018, 95% CI: 1.0007–1.2132, P = 0.05). Additionally, two-step mediation MR suggested that type 2 diabetes mellitus (T2DM) partially mediated this effect (OR = 1.14, 95%CI: 1.02–1.28, P = 0.03). The mediated proportion were 10.96% (95% CI: 0.58%–12.10%) for any stroke, 11.77% (95% CI: 10.58%–12.97%) for IS, 10.62% (95% CI: 8.04%–13.20%) for LAS, and 7.57% (95% CI: 6.79%–8.36%) for HF. However, no mediated effect was observed between ASD and AF risk. These findings have implications for the development of prevention strategies and interventions for stroke and CVD in patients with ASD.