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Genetics, environment, and their interactions impact autism spectrum disorder etiology. Smoking is a suspected autism spectrum disorder risk factor due to biological plausibility and high prevalence. Using two large epidemiological samples, we examined whether autism spectrum disorder was associated with prenatal paternal smoking in a Discovery sample (N = 10,245) and an independent Replication sample (N = 29,773). Paternal smoking was retrospectively assessed with questionnaires. Likelihood of having autism spectrum disorder was estimated with the Autism Spectrum Screening Questionnaire at three levels: low (<10), intermediate (10-14), and high ([greater than or equal to]15). Ordinal regression was used to examine the relationship between prenatal paternal smoking and likelihood of having autism spectrum disorder, adjusting for confounders. A total of 36.5% of Discovery sample fathers and 63.3% of Replication sample fathers smoked during the pregnancy period; 7% of the Replication sample smoker fathers smoked during the pre-conception period but quit during pregnancy period. Discovery sample prenatal paternal smoking significantly increased the likelihood of having autism spectrum disorder in their offspring (adjusted odds ratio=1.27). This was confirmed in the Replication sample with adjusted odds ratio of 1.15 among smoking pre-conception period + pregnancy period fathers; 14.4% and 11.1% increased high likelihood of autism spectrum disorder was attributable to prenatal paternal smoking in Discovery sample and Replication sample, respectively. Smoking prevention, especially in pregnancy planning, may decrease autism spectrum disorder risk in offspring.

While a growing number of studies indicate associations between experiences of bullying and autism spectrum disorder (ASD), it is not clear what roles comorbid behavioral problems may play. We investigated the experiences of children with ASD as victims and/or perpetrators of bullying. Children with ASD epidemiologically ascertained participated in a cross-sectional study. Although children with ASD showed significantly increased risk for bullying involvement compared to community children, after controlling for comorbid psychopathology and other demographic factors, increased risks for being perpetrators or victim-perpetrators disappeared while risk for being bullied/teased continued to be significantly elevated. This finding will help guide medical, educational and community personnel to effectively identify children with ASD at risk for school bullying and develop interventions.

BackgroundHeterogeneous mental health outcomes during the COVID-19 pandemic are documented in the general population. Such heterogeneity has not been systematically assessed in youth with autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDD). To identify distinct patterns of the pandemic impact and their predictors in ASD/NDD youth, we focused on pandemic-related changes in symptoms and access to services.MethodsUsing a naturalistic observational design, we assessed parent responses on the Coronavirus Health and Impact Survey Initiative (CRISIS) Adapted For Autism and Related neurodevelopmental conditions (AFAR). Cross-sectional AFAR data were aggregated across 14 European and North American sites yielding a clinically well-characterized sample of N = 1275 individuals with ASD/NDD (age = 11.0 ± 3.6 years; n females = 277). To identify subgroups with differential outcomes, we applied hierarchical clustering across eleven variables measuring changes in symptoms and access to services. Then, random forest classification assessed the importance of socio-demographics, pre-pandemic service rates, clinical severity of ASD-associated symptoms, and COVID-19 pandemic experiences/environments in predicting the outcome subgroups.ResultsClustering revealed four subgroups. One subgroup-broad symptom worsening only (20%)-included youth with worsening across a range of symptoms but with service disruptions similar to the average of the aggregate sample. The other three subgroups were, relatively, clinically stable but differed in service access: primarily modified services (23%), primarily lost services (6%), and average services/symptom changes (53%). Distinct combinations of a set of pre-pandemic services, pandemic environment (e.g., COVID-19 new cases, restrictions), experiences (e.g., COVID-19 Worries), and age predicted each outcome subgroup.LimitationsNotable limitations of the study are its cross-sectional nature and focus on the first six months of the pandemic.ConclusionsConcomitantly assessing variation in changes of symptoms and service access during the first phase of the pandemic revealed differential outcome profiles in ASD/NDD youth. Subgroups were characterized by distinct prediction patterns across a set of pre- and pandemic-related experiences/contexts. Results may inform recovery efforts and preparedness in future crises; they also underscore the critical value of international data-sharing and collaborations to address the needs of those most vulnerable in times of crisis.

ObjectivesHigher prevalence of suicidality has been reported in individuals with ASD. This study aimed to (1) Estimate the prevalence of suicidal ideation (SI) in epidemiologically-ascertained, population-based, samples of children with ASD or Autism Spectrum Screening Questionnaire (ASSQ) Screen Positivity (ASP); (2) Determine whether ASD/ASP is an independent risk factor for SI, controlling for known SI risk factors; and, (3) Develop an explanatory model for SI in children with ASD/ASP.MethodsParticipants came from three epidemiologically-ascertained samples of school-aged Korean children (n = 14,423; 3,702; 4,837). ASSQ ≥ 14 was the cutoff for ASP. A subsample (n = 86) was confirmed to have ASD. SI was based on parents' endorsement of items on the Behavioral Assessment System for Children-2-Parent Report Scale-Children. Logistic regressions were used to assess associations between SI and ASD/ASP, controlling for demographics, peer victimization, behavior problems, and depression. To develop an explanatory model for SI within ASD/ASP, the associations between SI and child characteristics (comorbid conditions, ASD symptoms, IQ, adaptive function) were tested.ResultsSI was higher in children with ASD (14%) and ASP (16.6-27.4%) than ASSQ Screen Negative (ASN) peers (3.4-6.9%). ASD/ASP was strongly predictive of SI (ORs: 2.87-5.67), after controlling for known SI risk factors compared to ASN. Within the ASD and ASP groups, anxiety was the strongest predictor of SI.ConclusionsSI prevalence was higher in non-clinical samples of children with ASD and ASP, relative to ASN peers. These results underscore the need for routine screening for SI in children with ASD and social difficulties, particularly those with high anxiety. HighlightsPopulation-based, epidemiologically-ascertained, school-aged childrenASD and ASP are independent risk factors for SI in school-aged childrenAnxiety is an independent risk factor for SI in children with ASD or ASP.

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene-environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene-environment studies.

Lay abstractWhat is Already Known about This Subject: Genetics, (including de novo mutations), environmental factors (including toxic exposures), and their interactions impact autism spectrum disorder etiology. Paternal smoking is a candidate risk for autism spectrum disorder due to biological plausibility, high prevalence, and potential intervention.What This Study Adds: This original study and its replication confirms that paternal factors can substantially contribute to autism spectrum disorder risk for their offspring. It specifically indicates that paternal smoking both before and during pregnancy contributes significantly to autism spectrum disorder risk.Implications for practice, research, or policy: Smoking prevention, especially in pregnancy planning, may decrease autism spectrum disorder risk in offspring.

BackgroundConcerns have been raised that scores on standard measures of autism spectrum disorder (ASD) symptoms may differ as a function of sex. However, these findings are hindered by small female samples studied thus far. The current study evaluated if, after accounting for age, IQ, and language level, sex affects ASD severity estimates from diagnostic measures among children with ASD.MethodsData were obtained from eight sources comprising 27 sites. Linear mixed-effects models, including a random effect for site, were fit for 10 outcomes (Autism Diagnostic Observation Schedule [ADOS] domain-level calibrated severity scores, Autism Diagnostic Interview-Revised [ADI-R] raw scores by age-based algorithm, and raw scores from the two indices on the Social Responsiveness Scale [SRS]). Sex was added to the models after controlling for age, NVIQ, and an indicator for language level.ResultsSex significantly improved model fit for half of the outcomes, but least square mean differences were generally negligible (effect sizes [ES]

BackgroundsWhether there is a true increase in autism spectrum disorder (ASD) frequency or not remains unclear. Additionally, the rates of co-existing neurodevelopmental disorders (NDD) in a total population sample has not been fully examined before. Therefore, using a total population sample in Japan, we aimed to estimate the prevalence and cumulative incidence of autism spectrum disorder (ASD) annually, to determine whether there is a true increase in ASD prevalence by estimating the cumulative incidence of ASD annually, and to examine the rates of co-existing neurodevelopmental disorders (NDD).MethodIn this cross-sectional sequential design study, all 5-year-old children in the catchment area underwent the screening annually from the year 2013-2016. Screen-positive children were invited to participate in a comprehensive assessment, including child and parent interview, behavioral observation, and cognitive and motor function testing. All cases were reviewed by a multidisciplinary research team.ResultsCaregivers of 3954 children returned the screening, among which 559 children underwent the assessment with 87 children receiving an ASD diagnosis. Adjusted ASD prevalence was 3.22% (95% confidence interval (CI) 2.66-3.76%). The male to female ratio of the crude prevalence was 2.2:1. The cumulative incidence of ASD up to 5 years of age for the total study years was 1.31% (95% CI 1.00-1.62%). A generalized linear model revealed no significant linear trends in 5-year cumulative incidence over the study years. Only 11.5% of children had ASD alone; the remaining 88.5% were found to have at least one co-existing NDD.LimitationsModest sample size for a total population study.ConclusionsOur findings demonstrate the stability of the 5-year cumulative incidence of ASD, implying no true rise in ASD incident cases over the 4-year study period in the study catchment area. High rates of co-existing NDDs reflect the importance of investigating broad developmental challenges in children with ASD.

Through this meta-analysis, we sought to examine the prevalence of, risks for, and factors associated with bullying involvement (victimization, perpetration, perpetration-victimization) among students with autism spectrum disorder (ASD). Additionally, we attempted to examine sources of variance in the prevalence and effect sizes of bullying in students with ASD across studies. Systematic database and literature review identified 34 relevant studies (31 for Western countries, three for Eastern countries). Pooled prevalence estimates for victimization, perpetration, and perpetration-victimization in general were 67%, 29%, and 14%, respectively. The risk of victimization in students with ASD was significantly higher than that in typically developing students and students with other disabilities. Further, deficits in social interaction and communication, externalizing symptoms, internalizing symptoms, and integrated inclusive school settings were related to higher victimization, and externalizing symptoms were related to higher perpetration. Finally, moderation analyses revealed significant variations in the pooled prevalences thereof depending on culture, age, school settings, and methodological quality and in the pooled effect sizes according to publication year and methodological quality. Our results highlight needs for bullying intervention for students with ASD, especially those who are younger, are in an inclusive school setting, and have higher social difficulties and externalizing/internalizing symptoms; for intensive research of bullying experiences among students with ASD in Eastern countries; and for efforts to improve the methodological quality of such research.

Whole-genome sequencing (WGS) has facilitated the first genome-wide evaluations of the contribution of de novo noncoding mutations to complex disorders. Using WGS, we identified 255,106 de novo mutations among sample genomes from members of 1902 quartet families in which one child, but not a sibling or their parents, was affected by autism spectrum disorder (ASD). In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, was significantly associated with ASD. Casting noncoding variation in the context of a de novo risk score across multiple annotation categories, however, did demonstrate association with mutations localized to promoter regions. We found that the strongest driver of this promoter signal emanates from evolutionarily conserved transcription factor binding sites distal to the transcription start site. These data suggest that de novo mutations in promoter regions, characterized by evolutionary and functional signatures, contribute to ASD.

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive-compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes.

While a growing number of studies indicate associations between experiences of bullying and autism spectrum disorder (ASD), it is not clear what roles comorbid behavioral problems may play. We investigated the experiences of children with ASD as victims and/or perpetrators of bullying. Children with ASD epidemiologically ascertained participated in a cross-sectional study. Although children with ASD showed significantly increased risk for bullying involvement compared to community children, after controlling for comorbid psychopathology and other demographic factors, increased risks for being perpetrators or victim-perpetrators disappeared while risk for being bullied/teased continued to be significantly elevated. This finding will help guide medical, educational and community personnel to effectively identify children with ASD at risk for school bullying and develop interventions.

ObjectivesTo evaluate whether Asian (Korean children) populations can be validly diagnosed with autism spectrum disorder (ASD) using Western-based diagnostic instruments and criteria based on Diagnostic and Statistical Manual on Mental Disorders, 5th edition (DSM-5).MethodsParticipants included an epidemiologically ascertained 7-14-year-old (N = 292) South Korean cohort from a larger prevalence study (N = 55,266). Main outcomes were based on Western-based diagnostic methods for Korean children using gold standard instruments, Autism Diagnostic Interview-Revised, and Autism Diagnostic Observation Schedule. Factor analysis and ANOVAs were performed to examine factor structure of autism symptoms and identify phenotypic differences between Korean children with ASD and non-ASD diagnoses.ResultsUsing Western-based diagnostic methods, Korean children with ASD were successfully identified with moderate-to-high diagnostic validity (sensitivities/specificities ranging 64%-93%), strong internal consistency, and convergent/concurrent validity. The patterns of autism phenotypes in a Korean population were similar to those observed in a Western population with two symptom domains (social communication and restricted and repetitive behavior factors). Statistically significant differences in the use of socially acceptable communicative behaviors (e.g., direct gaze, range of facial expressions) emerged between ASD versus non-ASD cases (mostly p

The Social Responsiveness Scale (SRS) is an autism rating scales in widespread use, with over 20 official foreign language translations. It has proven highly feasible for quantitative ascertainment of autistic social impairment in public health settings, however, little is known about the validity of the reinforcement in Asia populations or in references to DSM5. The current study aims to evaluate psychometric properties and cross-cultural aspects of the SRS-Korean version (K-SRS).The study subjects were ascertained from three samples: a general sample from 3 regular education elementary schools (n=790), a clinical sample (n=154) of 6-12-year-olds from four psychiatric clinics, and an epidemiological sample of children with ASD, diagnosed using both DSM IV PDD, DSM5 ASD and SCD criteria (n=151). Their parents completed the K-SRS and the Autism Spectrum Screening Questionnaire(ASSQ). Descriptive statistics, correlation analyses and principal components analysis (PCA) were performed on the total population. Mean total scores on the K-SRS differed significantly between the three samples. ASSQ scores were significantly correlated with the K-SRS T-scores. PCA suggested a one-factor solution for the total population.Our results indicate that the K-SRS exhibits adequate reliability and validity for measuring ASD symptoms in Korean children with DSM IV PDD and DSM5 ASD. Our findings further suggest that it is difficult to distinguish SCD from other child psychiatric conditions using the K-SRS.This is the first study to examine the relationship between the SRS subscales and DSM5-based clinical diagnoses. This study provides cross-cultural confirmation of the factor structure for ASD symptoms and traits measured by the SRS. Autism Res 2016, 9: 970-980. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Understanding the pathogenesis of neurodevelopmental disorders has proven to be challenging. Using autism spectrum disorder (ASD) as a paradigmatic neurodevelopmental disorder, this article reviews the existing literature on the etiological substrates of ASD and explores how genetic epidemiology approaches including gene-environment interactions (G×E) can play a role in identifying factors associated with ASD etiology. New genetic and bioinformatics strategies have yielded important clues to ASD genetic substrates. The next steps for understanding ASD pathogenesis require significant effort to focus on how genes and environment interact with one another in typical development and its perturbations. Along with larger sample sizes, future study designs should include sample ascertainment that is epidemiologic and population-based to capture the entire ASD spectrum with both categorical and dimensional phenotypic characterization; environmental measurements with accuracy, validity, and biomarkers; statistical methods to address population stratification, multiple comparisons, and G×E of rare variants; animal models to test hypotheses; and new methods to broaden the capacity to search for G×E, including genome-wide and environment-wide association studies, precise estimation of heritability using dense genetic markers, and consideration of G×E both as the disease cause and a disease course modifier. Although examination of G×E appears to be a daunting task, tremendous recent progress in gene discovery has opened new horizons for advancing our understanding of the role of G×E in the pathogenesis of ASD and ultimately identifying the causes, treatments, and even preventive measures for ASD and other neurodevelopmental disorders.

ObjectiveChanges in autism diagnostic criteria found in DSM-5 may affect autism spectrum disorder (ASD) prevalence, research findings, diagnostic processes, and eligibility for clinical and other services. Using our published, total-population Korean prevalence data, we compute DSM-5 ASD and social communication disorder (SCD) prevalence and compare them with DSM-IV pervasive developmental disorder (PDD) prevalence estimates. We also describe individuals previously diagnosed with DSM-IV PDD when diagnoses change with DSM-5 criteria.MethodThe target population was all children from 7 to 12 years of age in a South Korean community (N = 55,266), those in regular and special education schools, and a disability registry. We used the Autism Spectrum Screening Questionnaire for systematic, multi-informant screening. Parents of screen-positive children were offered comprehensive assessments using standardized diagnostic procedures, including the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. Best-estimate clinical diagnoses were made using DSM-IV PDD and DSM-5 ASD and SCD criteria.ResultsDSM-5 ASD estimated prevalence was 2.20% (95% confidence interval = 1.77-3.64). Combined DSM-5 ASD and SCD prevalence was virtually the same as DSM-IV PDD prevalence (2.64%). Most children with autistic disorder (99%), Asperger disorder (92%), and PDD-NOS (63%) met DSM-5 ASD criteria, whereas 1%, 8%, and 32%, respectively, met SCD criteria. All remaining children (2%) had other psychopathology, principally attention-deficit/hyperactivity disorder and anxiety disorder.ConclusionOur findings suggest that most individuals with a prior DSM-IV PDD meet DSM-5 diagnostic criteria for ASD and SCD. PDD, ASD or SCD; extant diagnostic criteria identify a large, clinically meaningful group of individuals and families who require evidence-based services.

Recent advances in the genetics of neurodevelopmental disorder (NDD) have demonstrated that rare mutations play a role not only in Mendelian syndromes, but in complex, common forms of NDDs as well. Strikingly, both common polymorphisms and rare variations in a single gene or genetic locus have been found to carry risk for conditions previously considered to be clinically and aetiologically distinct. Recent developments in the methods and tools available for studying complex NDDs have led to systematic and reliable genome-wide variant discovery. Both common as well as rare, and structural as well as sequence, genetic variations have been identified as contributing to NDDs. There are multiple examples in which the identical variant had been found to contribute to a wide range of formerly distinct diagnoses, including autism, schizophrenia, epilepsy, intellectual disability and language disorders. These include variations in chromosomal structure at 16p11.2, rare de novo point mutations at the gene SCN2A, and common single nucleotide polymorphisms (SNPs) mapping near loci encoding the genes ITIH3, AS3MT, CACNA1C and CACNB2. These selected examples point to the challenges to current diagnostic approaches. Widely used categorical schema have been adequate to provide an entré into molecular mechanisms of NDDs, but there is a need to develop an alternative, more biologically-relevant nosology. Thus recent advances in gene discovery in the area of NDDs are leading to a re-conceptualization of diagnostic boundaries. Findings suggest that epidemiological samples may provide important new insights into the genetics and diagnosis of NDDs and that other areas of medicine may provide useful models for developing a new diagnostic nosology, one that simultaneously integrates categorical diagnoses, biomarkers and dimensional variables.

Background: Existing reviews of screening tools for Autism Spectrum Disorder (ASD) focus on young children, and not all screening tools have been examined against validated diagnostic procedures.Aims: To examine the validity of screening tools for ASD in non-young children and adults to provide clinical recommendations about the use of these tools in a variety of clinical settings.Methods and Procedures: Electronic databases, including MEDLINE, EMBASE, PsychINFO, Cochrane Library and CINAHL, were searched through March 2017. Studies examining the validity of ASD screening tools against the Autism Diagnostic Observation Schedule and/or the Autism Diagnostic Interview - Revised in non-young children (age 4 or above) and adults were included. Three authors independently reviewed each article for data extraction and quality assessment.Outcomes and Results: 14 studies met the inclusion criteria, of which 11 studies were with children (4-18 years of age) and 3 studies included adults only (19 years of age and above). Included studies were conducted in a general population/low-risk sample (N = 3) and a clinically referred/high-risk sample (N = 11). In total 11 tools were included.Conclusions and Implications: Only three screening tools (the Autism-Spectrum Quotient, the Social Communication Questionnaire, and the Social Responsiveness Scale) were examined in more than 2 studies. These tools may assist in differentiating ASD from other neurodevelopmental and psychiatric disorders or typically developed children. In young adult populations, the paucity of the existing research in this group limits definitive conclusion and recommendations. [ABSTRACT FROM AUTHOR]

Background: Studies of copy number variation (CNV) have characterized loci and molecular pathways in a range of neuropsychiatric conditions. We analyzed rare CNVs in Tourette syndrome (TS) to identify novel risk regions and relevant pathways, to evaluate burden of structural variation in cases versus controls, and to assess overlap of identified variations with those in other neuropsychiatric syndromes. Methods: We conducted a case-control study of 460 individuals with TS, including 148 parent-child trios and 1131 controls. CNV analysis was undertaken using 370 K to 1 M probe arrays, and genotyping data were used to match cases and controls for ancestry. CNVs present in < 1% of the population were evaluated. Results: While there was no significant increase in the number of de novo or transmitted rare CNVs in cases versus controls, pathway analysis using multiple algorithms showed enrichment of genes within histamine receptor (subtypes 1 and 2) signaling pathways (p = 5.8 × 10−4 − 1.6 × 10−2), as well as axon guidance, cell adhesion, nervous system development, and synaptic structure and function processes. Genes mapping within rare CNVs in TS showed significant overlap with those previously identified in autism spectrum disorders but not intellectual disability or schizophrenia. Three large, likely pathogenic, de novo events were identified, including one disrupting multiple gamma-aminobutyric acid receptor genes. Conclusions: We identify further evidence supporting recent findings regarding the involvement of histaminergic and gamma-aminobutyric acidergic mechanisms in the etiology of TS and show an overlap of rare CNVs in TS and autism spectrum disorders. [ABSTRACT FROM AUTHOR]

An abstract of the article "3.38 Autism and Mental Illness in a Korean-American Evangelical Community: A Mixed Methods Approach" by Patricia S. Hong and colleagues is presented.