Role In Aetiology Of Autism Research Articles

Maternal diabetes and hypertensive disorders in association with autism spectrum disorder.

Previous studies have shown complications of pregnancy, often examined in aggregate, to be associated with autism spectrum disorder (ASD). Results for specific complications, such as maternal diabetes and hypertension, have not been uniformly consistent and should be investigated independently in relation to ASD in a large community-based sample. The Study to Explore Early Development (SEED), a US multisite case-control study, enrolled children born in 2003-2006 at 2-5 years of age. Children were classified into three groups based on confirmation of ASD (n = 698), non-ASD developmental delay (DD; n = 887), or controls drawn from the general population (POP; n = 979). Diagnoses of any diabetes or hypertensive disorder during pregnancy were identified from prenatal medical records and maternal self-report. Logistic regression models estimated adjusted odds ratios (aOR) and confidence intervals (CI) adjusting for maternal age, race/ethnicity, education, smoking during pregnancy, and study site. Models for hypertension were additionally adjusted for parity and plurality. Among 2,564 mothers, we identified 246 (9.6%) with any diabetes and 386 (15.1%) with any hypertension in pregnancy. After adjustment for covariates, any diabetes during pregnancy was not associated with ASD (aOR = 1.10 [95% CI 0.77, 1.56]), but any hypertension was associated with ASD (aOR = 1.69 [95% CI 1.26, 2.26]). Results were similar for DD, and any diabetes (aOR = 1.29 [95% CI 0.94, 1.78]) or any hypertension (aOR = 1.71 [95% CI 1.30, 2.25]). Some pregnancy complications, such as hypertension, may play a role in autism etiology and can possibly serve as a prompt for more vigilant ASD screening efforts. Autism Res 2019, 12: 967-975. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We studied if common complications in pregnancy are associated with autism spectrum disorder (ASD) in a large sample of mothers and children. Our results show an association between conditions marked by high blood pressure and ASD, but no association with conditions marked by high blood sugar and ASD. Associations were similar for children who had a developmental disorder that was not ASD, suggesting that this relationship may not be specific to ASD.

Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism.

Autism spectrum disorder (ASD) is a spectral neurodevelopment disorder affecting approximately 1% of the population. ASD is characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Multiple factors, including genetic/genomic, epigenetic/epigenomic and environmental, are thought to be necessary for autism development. Recent reviews have provided further insight into the genetic/genomic basis of ASD. It has long been suspected that epigenetic mechanisms, including DNA methylation, chromatin structures and long non-coding RNAs may play important roles in the pathology of ASD. In addition to genetic/genomic alterations and epigenetic/epigenomic influences, environmental exposures have been widely accepted as an important role in autism etiology, among which immune dysregulation and gastrointestinal microbiota are two prominent ones.

Use of Birth Certificates to Examine Maternal Occupational Exposures and Autism Spectrum Disorders in Offspring

The continuing rise in the prevalence of autism spectrum disorders has led to heightened interest in the role of nongenetic factors, including exogenous exposures, but little research has been conducted. To explore a possible role in autism etiology, we used data available from our prior studies to examine potential occupational exposures, as these may occur at higher levels than environmental exposures. Parental occupation was obtained from birth certificates for 284 children with autism and 659 controls, born in 1994 in the San Francisco Bay Area. Self-reported occupation and industry were coded into eight exposure/chemical groups based on potential neurotoxicity or reprotoxicity by a board-certified physician in occupational medicine and an industrial hygienist blinded to case-control status. Mothers of autistic children were twice as likely to work in occupations considered exposed (14.4%) as mothers of controls (7.2%) (adjusted odds ratio [AOR] 2.3 [95% confidence interval {CI} 1.3-4.2]). The exposure categories of the greatest frequency among case mothers were exhaust and combustion products (AOR = 12.0 [95% CI 1.4-104.6]) and disinfectants (AOR = 4.0 [95% CI 1.4-12.0]). Paternal occupational exposure was not associated with autism, potentially consistent with a direct in-utero exposure effect. There are several limitations of this hypothesis-generating study, including lack of detail on workplace and job duties, leading to possible misclassification and low proportion exposed. However, this misclassification would not be biased by case-control status and is unlikely to explain the associations we did find, suggesting that further research on exogenous exposures may yield useful etiologic clues.

Brief report: Plasma oxytocin is lower in children with Asperger syndrome and associated with autistic trait attention to detail

Aim: Autism spectrum disorders (ASD) are described as a continuum of severity gradient of autistic symptoms diffusing through particular ASD diagnoses, however the biological correlates among individuals with the different ASD diagnoses slightly or considerably differ. Oxytocin (OT) has been implicated to play an important role in autism etiology. Lower OT levels have been previously found in children with infantile autism, however in a group of high-functioning autistic subjects, no differences have been shown compared to controls. Moreover, whereas the opposite patterns of OT associations with social measures have been found in children with infantile autism compared to healthy children, no associations have been found in individuals with high-functioning autism. We aimed to find out the plasma OT differences between separate group of children with Asperger syndrome (AS) and healthy children and the associations of OT with particular autistic traits in a group of children with AS. Methods: We included 9 children (m = 6, f = 3) with AS at the age 9 to 12 years and 9 age- and gender-matched controls. OT levels were analyzed by ELISA method. Autistic traits in children with AS were evaluated by Autism Spectrum Quotient (AQ), child and adolescent versions. Results: Children with AS had significantly lower plasma OT levels compared to healthy children. We found the significant negative correlation of OT level and AQ Attention to detail area score. Conclusion: In spite of the lower OT level in children with AS, which is also previously found in children with infantile autism, the pattern of OT associations with autistic traits more resembles the pattern in non-autistic population. Our preliminary results support the hypothesis of continuum within the ASD particular diagnoses in the terms of biological correlates.

Awareness and knowledge of autism among pharmacists

BackgroundIn the past few decades, the prevalence of autism has increased tremendously in the United States. The prevalence of autism is now higher than the combined prevalence of juvenile diabetes, pediatric cancer, and pediatric AIDS. As health care professionals with a high visibility in a community, pharmacists are likely to encounter more and more families having a child affected by this disorder. ObjectivesThe purpose of this study was to assess pharmacists’ awareness and knowledge of autism. The study aimed to assess pharmacists’ familiarity with autism symptoms, treatment medications, and community resources devoted to this disorder. Further, pharmacists’ knowledge of common myths associated with autism, etiology, prognosis, and treatment were assessed. MethodsUsing a cross-sectional design, an online survey of pharmacists registered in the state of Mississippi (MS) was conducted, using the Qualtrics software program. Descriptive analysis of study items was conducted. ResultsA total of 147 usable responses (5.8%) were received. The results indicated gaps in pharmacists’ awareness and knowledge of autism. Approximately, 23% of pharmacists did not know that autism is a developmental disorder, and 32% did not believe that genetics has a major role in autism etiology. More than 18% believed that vaccines can cause autism. Most (>90%) felt that they could benefit from autism continuing education (CE). ConclusionPolicy makers and autism agencies should consider providing educational interventions or CE programs to increase pharmacists’ awareness and knowledge of autism.

Functionality of promoter microsatellites of arginine vasopressin receptor 1A (AVPR1A): implications for autism

BackgroundArginine vasopressin (AVP) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. The arginine vasopressin receptor 1A gene (AVPR1A) is widely expressed in the brain and is considered to be a key receptor for regulation of social behaviour. Moreover, genetic variation at AVPR1A has been reported to be associated with autism. Evidence from non-human mammals implicates variation in the 5'-flanking region of AVPR1A in variable gene expression and social behaviour.MethodsWe examined four tagging single nucleotide polymorphisms (SNPs) (rs3803107, rs1042615, rs3741865, rs11174815) and three microsatellites (RS3, RS1 and AVR) at the AVPR1A gene for association in an autism cohort from Ireland. Two 5'-flanking region polymorphisms in the human AVPR1A, RS3 and RS1, were also tested for their effect on relative promoter activity.ResultsThe short alleles of RS1 and the SNP rs11174815 show weak association with autism in the Irish population (P = 0.036 and P = 0.008, respectively). Both RS1 and RS3 showed differences in relative promoter activity by length. Shorter repeat alleles of RS1 and RS3 decreased relative promoter activity in the human neuroblastoma cell line SH-SY5Y.ConclusionsThese aligning results can be interpreted as a functional route for this association, namely that shorter alleles of RS1 lead to decreased AVPR1A transcription, which may proffer increased susceptibility to the autism phenotype.

The Role of Prenatal, Obstetric and Neonatal Factors in the Development of Autism

We conducted a linked database cohort study of infants born between 1990 and 2002 in Nova Scotia, Canada. Diagnoses of autism were identified from administrative databases with relevant diagnostic information to 2005. A factor representing genetic susceptibility was defined as having an affected sibling or a mother with a history of a psychiatric or neurologic condition. Among 129,733 children, there were 924 children with an autism diagnosis. The results suggest that among those with low genetic susceptibility, some maternal and obstetric factors may have an independent role in autism etiology whereas among genetically susceptible children, these factors appear to play a lesser role. The role of pre-pregnancy obesity and excessive weight gain during pregnancy on autism risk require further investigation.

Perinatal Exposure to Hazardous Air Pollutants and Autism Spectrum Disorders at Age 8

Hazardous air pollutants are plausible candidate exposures for autism spectrum disorders. They have been explored in recent studies for their role in the development of these disorders. We used a prevalent case-control design to screen perinatal exposure to 35 hazardous air pollutants for further investigation in autism etiology. We included 383 children with autism spectrum disorders and, as controls, 2,829 children with speech and language impairment. All participants were identified from the records-based surveillance of 8-year-old children conducted by the Autism and Developmental Disabilities Monitoring Network in North Carolina (for children born in 1994 and 1996) and West Virginia (born in 1992 and 1994). Exposures to ambient concentrations of metal, particulate, and volatile organic air pollutants in the census tract of the child's birth residence were assigned from the 1996 National Air Toxics Assessment annual-average model. We estimated odds ratios (ORs) for autism spectrum disorders and corresponding 95% confidence intervals (CIs), comparing across the 20th and 80th percentiles of log-transformed hazardous air pollutant concentration among the selected controls, using semi-Bayes logistic models and adjusting for sampling variables (surveillance year and state), a priori demographic confounders from the birth certificate and census, and covarying air pollutants. We estimated many near-null ORs, including those for metals, established human neurodevelopmental toxicants, and several pollutants that were elevated in a similar study in California. Hazardous air pollutants with more precise and elevated OR estimates included methylene chloride, 1.4 (95% CI = 0.7-2.5), quinoline, 1.4 (1.0-2.2), and styrene, 1.8 (1.0-3.1). Our screening design was limited by exposure misclassification of air pollutants and the use of an alternate developmental disorder as the control group, both of which may have biased results toward the null. Despite these limitations, methylene chloride, quinoline, and styrene emerged (based on this analysis and prior epidemiologic evidence) as candidates that warrant further investigation for a possible role in autism etiology.

Oxytocin receptor (OXTR) does not play a major role in the aetiology of autism: Genetic and molecular studies

Oxytocin (OXT) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. It is postulated that OXT reduces activation of the amygdala, inhibiting social anxiety, indicating a neural mechanism for the effects of OXT in social cognition. Genetic variation at the oxytocin receptor gene (OXTR) has been reported to be associated with autism. We examined 18 SNPs at the OXTR gene for association in three independent autism samples from Ireland, Portugal and the United Kingdom. We investigated cis-acting genetic effects on OXTR expression in lymphocytes and amygdala region of the brain using an allelic expression imbalance (AEI) assay and by investigating the correlation between RNA levels and genotype in the amygdala region. No marker survived multiple correction for association with autism in any sample or in a combined sample (n=436). Results from the AEI assay performed in the lymphoblast cell lines highlighted two SNPs associated with relative allelic abundance in OXTR (rs237897 and rs237895). Two SNPs were found to be effecting cis-acting variation through AEI in the amygdala. One was weakly correlated with total gene expression (rs13316193) and the other was highlighted in the lymphoblast cell lines (rs237895). Data presented here does not support the role of common genetic variation in OXTR in the aetiology of autism spectrum disorders in Caucasian samples.

MECP2 coding sequence and 3′UTR variation in 172 unrelated autistic patients

Mutations in the coding sequence of the methyl-CpG-binding protein 2 gene (MECP2), which cause Rett syndrome (RTT), have been found in male and female autistic subjects without, however, a causal relation having unequivocally been established. In this study, the MECP2 gene was scanned in a Portuguese autistic population, hypothesizing that the phenotypic spectrum of mutations extends beyond the traditional diagnosis of RTT and X-linked mental retardation, leading to a non-lethal phenotype in male autistic patients. The coding region, exon-intron boundaries, and the whole 3'UTR were scanned in 172 patients and 143 controls, by Detection of Virtually All Mutations-SSCP (DOVAM-S). Exon 1 was sequenced in 103 patients. We report 15 novel variants, not found in controls: one missense, two intronic, and 12 in the 3'UTR (seven in conserved nucleotides). The novel missense change, c.617G > C (p.G206A), was present in one autistic male with severe mental retardation and absence of language, and segregates in his maternal family. This change is located in a highly conserved residue within a region involved in an alternative transcriptional repression pathway, and likely alters the secondary structure of the MeCP2 protein. It is therefore plausible that it leads to a functional modification of MeCP2. MECP2 mRNA levels measured in four patients with 3'UTR conserved changes were below the control range, suggesting an alteration in the stability of the transcripts. Our results suggest that MECP2 can play a role in autism etiology, although very rarely, supporting the notion that MECP2 mutations underlie several neurodevelopmental disorders.

Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels

Autism is a neurodevelopmental disorder of unclear etiology. The consistent finding of platelet hyperserotonemia in a proportion of patients and its heritability within affected families suggest that genes involved in the serotonin system play a role in this disorder. The role in autism etiology of seven candidate genes in the serotonin metabolic and neurotransmission pathways and mapping to autism linkage regions (SLC6A4, HTR1A, HTR1D, HTR2A, HTR5A, TPH1 and ITGB3) was analyzed in a sample of 186 nuclear families. The impact of interactions among these genes in autism was assessed using the multifactor-dimensionality reduction (MDR) method in 186 patients and 181 controls. We further evaluated whether the effect of specific gene variants or gene interactions associated with autism etiology might be mediated by their influence on serotonin levels, using the quantitative transmission disequilibrium test (QTDT) and the restricted partition method (RPM), in a sample of 109 autistic children. We report a significant main effect of the HTR5A gene in autism (P = 0.0088), and a significant three-locus model comprising a synergistic interaction between the ITGB3 and SLC6A4 genes with an additive effect of HTR5A (P < 0.0010). In addition to the previously reported contribution of SLC6A4, we found significant associations of ITGB3 haplotypes with serotonin level distribution (P = 0.0163). The most significant models contributing to serotonin distribution were found for interactions between TPH1 rs4537731 and SLC6A4 haplotypes (P = 0.002) and between HTR1D rs6300 and SLC6A4 haplotypes (P = 0.013). In addition to the significant independent effects, evidence for interaction between SLC6A4 and ITGB3 markers was also found. The overall results implicate SLC6A4 and ITGB3 gene interactions in autism etiology and in serotonin level determination, providing evidence for a common underlying genetic mechanism and a molecular explanation for the association of platelet hyperserotonemia with autism.