Association of Genetic Risks with Autism Spectrum Disorder and Early Neurodevelopmental Delays among Children without Intellectual Disability

IMPORTANCE Autism spectrum disorder (ASD) is highly heritable, and modest contributions of common genetic variants to ASD have been reported. However, the association of genetic risks derived from common risk variants with ASD traits in children from the general population is not clear, and the association of these genetic risks with neurodevelopment in infants has not been well understood. OBJECTIVE To test whether a polygenic risk score (PRS) for ASD is associated with neurodevelopmental progress at age 18 months and ASD traits at age 6 years among children from the general population. DESIGN, SETTING, AND PARTICIPANTS In this cohort study, 876 children in the Hamamatsu Birth Cohort for Mothers and Children in Hamamatsu, Japan, underwent testing for the association of an ASD PRS with neurodevelopmental progress and ASD traits. Data collection began in December 2007 and is ongoing. Data analysis was conducted from April to December 2019. MAIN OUTCOMES AND MEASURES Summary data from the largest genome-wide association study were used to generate ASD PRSs, and significance of thresholds was calculated for each outcome. The Autism Diagnostic Observation Schedule 2 was used to measure ASD traits at age 6 years, and the Mullen Scales of Early Learning was used to measure neurodevelopmental progress at age 18 months. RESULTS Of 876 participants (mean [SD] gestational age at birth, 38.9 [1.6] weeks; 438 [50.0%] boys; 868 [99.1%] Japanese), 734 were analyzed. The ASD PRS was associated with ASD traits (R2 = 0.024; β, 0.71; SE, 0.24; P = .03). The association of ASD PRS with infant neurodevelopment was most pronounced in gross motor (R2 = 0.015; β, −1.25; SE, 0.39; P = .01) and receptive language (R2 = 0.014; β, −1.19; SE, 0.39; P = .02) scores on the Mullen Scales of Early Learning. Gene set enrichment analyses found that several pathways, such as cell maturation (R2 = 0.057; β, −5.28; SE, 1.40; P \u3c .001) and adenylyl cyclase activity and cyclic adenosine monophosphate concentration (R2 = 0.064; β, −5.30; SE 1.30; P \u3c .001), were associated with ASD traits. Gene sets associated with inflammation were commonly enriched with ASD traits and gross motor skills (eg, chemokine motif ligand 2 production: R2 = 0.051; β, −6.04; SE, 1.75; P = .001; regulation of monocyte differentiation: R2 = 0.052; β, −6.63; SE, 1.90; P = .001; and B-cell differentiation: R2 = 0.051; β, 7.37; SE, 2.15; P = .001); glutamatergic signaling–associated gene sets were commonly enriched with ASD traits and receptive language skills (eg, regulation of glutamate secretion: R2 = 0.052; β, −5.82; SE, 1.68; P = .001; ionotropic glutamate receptor signaling pathway: R2 = 0.047; β, 3.54; SE, 1.09; P = .001; and negative regulation of glutamate secretion: R2 = 0.045; β, −5.38; SE, 1.74; P = .002). CONCLUSIONS AND RELEVANCE In this study, the ASD PRS was associated with ASD traits among children from the general population. Genetic risks for ASD might be associated with delays in some neurodevelopmental domains, such as gross motor and receptive language skills

Broader autism phenotype as a risk factor for postpartum depression: Hamamatsu Birth Cohort (HBC) Study

AbstractThe broader autism phenotype (BAP), which refers to the expression of behavioral and cognitive propensities that are milder but qualitatively similar to those defining autism spectrum disorder, can play a crucial role in postpartum depression (PPD). We investigated whether pregnant women's BAP would increase the risk for PPD, using a representative birth cohort in Japan. Pregnant women were enrolled in the Hamamatsu Birth Cohort (HBC) Study during their mid-gestation (N=841) and were followed up until 3 months after delivery. BAP was measured mainly during the 2nd trimester of the pregnancy by using the Broader Phenotype Autism Symptoms Scale. Participants scoring 9 points or higher on the Edinburgh Postnatal Depression Scale at least once during the first 3 months after childbirth were diagnosed with PPD. Among participants, 128 (15.2%) women were found to have PPD. Multiple logistic regression analyses showed that BAP were associated with PPD (OR=1.19, 95% CI [1.07–1.31]), even after controlling for other potential confounders. In addition, the association was not moderated by history of depression and/or anxiety disorders, including concurrent depressive and anxiety symptoms during pregnancy. The findings suggest that pregnant women with BAP have an elevated risk for PPD

Plasma Cytokine Profiles in Subjects with High-Functioning Autism Spectrum Disorders

Accumulating evidence suggests that dysregulation of the immune system is involved in the pathophysiology of autism spectrum disorders (ASD). The aim of the study was to explore immunological markers in peripheral plasma samples from non-medicated subjects with high-functioning ASD.A multiplex assay for cytokines and chemokines was applied to plasma samples from male subjects with high-functioning ASD (n = 28) and matched controls (n = 28). Among a total of 48 analytes examined, the plasma concentrations of IL-1β, IL-1RA, IL-5, IL-8, IL-12(p70), IL-13, IL-17 and GRO-α were significantly higher in subjects with ASD compared with the corresponding values of matched controls after correction for multiple comparisons.The results suggest that abnormal immune responses as assessed by multiplex analysis of cytokines may serve as one of the biological trait markers for ASD

Jiko-shisen-kyofu (fear of one's own glance), but not taijin-kyofusho (fear of interpersonal relations), is an east Asian culture-related specific syndrome

Objective: According to the DSM-IV-TR, the concept of taijin-kyofusho (fear of interpersonal relations) is both unique to East Asia and a culture-bound syndrome. In the indigenous diagnostic classification system in Japan, taijin-kyofusho consists of four subtypes, i.e. sekimen-kyofu (phobia of blushing), shubo-kyofu (phobia of a deformed face/body), jiko-shu-kyofu (phobia of one's own foul body odour), and jiko-shisen-kyofu (phobia of one's own glance). Each subtype except for phobia of one's own glance can be adequately assigned to a respective existing category in the DSM-IV-TR. The aim of the study was to introduce clinical features of phobia of one's own glance to western psychiatrists. Methods: Description of a series of cases with jiko-shisen-kyofu (phobia of one's own glance). Results: All of our cases shared the unique feature that they suffered from the preoccupation that their own glance was offensive to others, and as a result were socially withdrawn themselves. Conclusions: To our best knowledge, no cases with a clear picture of phobia of one's own glance have been reported in the West to date. The controversial issue of the classification of phobia of one's own glance as an east Asian culture-related specific syndrome was addressed. © 2011 The Royal Australian and New Zealand College of Psychiatrists.link_to_subscribed_fulltex

Season of Birth Predicts Emotional and Behavioral Regulation in 18-Month-Old Infants: Hamamatsu Birth Cohort for Mothers and Children (HBC Study)

Background: Previous research has demonstrated that the season of birth may predict development of emotional and behavioral regulation during childhood or adolescence. This study examined whether the season of birth predicts effortful control (i.e., the ability to voluntarily choose course of actions during conflict and to plan for the future) and aggression (i.e., the use of physical force and expression of anger toward others) in 18-month-old infants.Methods: Participants included 885 infants who were enrolled in the Hamamatsu Birth Cohort for Mothers and Children in Hamamatsu, Japan. Seasons of birth were categorized into winter (December, January, and February), spring (March, April, and May), summer (June, July, and August), and autumn (September, October, and November). At 18 months of age, effortful control was assessed using the Early Childhood Behavior Questionnaire, and aggression was measured using the Cardiff Infant Contentiousness Scale. Structural equation modeling analysis with measurement and structural equations was conducted to test our prediction.Results: Effortful control was higher in infants born in spring (B = 0.095, 95% CI [0.014 to 0.175], p = 0.021, = 0.146) and summer (B = 0.078, 95% CI [0.001 to 0.156], p = 0.049, = 0.118) than in those born in winter. In addition, aggression was lower in those born in spring (B = −0.286, 95% CI [−0.551 to −0.021], p = 0.035, = −0.135) than those born in winter, even after controlling for seven covariates.Conclusion: The findings suggest that season of birth may determine development of emotional and behavioral regulation skills during early infancy. Future research should pay more attention to the underlying mechanisms of the effects of birth season on development of emotional and behavioral regulation during infancy

Interaction of genetic liability for attention deficit hyperactivity disorder (ADHD) and perinatal inflammation contributes to ADHD symptoms in children

Objective: Genetic and environmental factors contribute to the development of Attention Deficit/Hyperactivity Disorder (ADHD). Perinatal inflammation is one of the promising environmental risk factors for ADHD, but the relationship between the genetic risk for ADHD and perinatal inflammation requires further examination. Methods: A possible gene-environmental interaction between perinatal inflammation and ADHD polygenic risk score (ADHD-PRS) on ADHD symptoms was investigated in children aged 8–9 from the Hamamatsu Birth Cohort for Mothers and Children (N = 531). Perinatal inflammation was evaluated by the level of concentration of three cytokines assayed in umbilical cord blood. The genetic risk for ADHD was assessed by calculating ADHD-PRS for each individual using a previously collected genome-wide association study of ADHD. Results: Perinatal inflammation (β [SE], 0.263 [0.017]; P < 0.001), ADHD-PRS (β [SE], 0.116[0.042]; P = 0.006), and an interaction between the two (β [SE], 0.031[0.011]; P = 0.010) were associated with ADHD symptoms. The association between perinatal inflammation and ADHD symptoms measured by ADHD-PRS was evident only in the two higher genetic risk groups (β [SE], 0.623[0.122]; P < 0.001 for the medium-high risk group; β [SE], 0.664[0.152]; P < 0.001 for the high-risk group). Conclusion: Inflammation in the perinatal period both directly elevated ADHD symptoms and magnified the impact of genetic vulnerability on ADHD risk particularly among children aged 8–9 with genetically higher risk for ADHD

List of analytes in the multiplex assay.

<p>Concentrations of analytes are shown in [pg/ml]. Note the statistically significant difference between the two groups (*<i>P</i><0.05 after FDR correction for multiple comparisons). Abbreviations: ASD, autism spectrum disorder; BDR, below the detection range; FDR, false discovery rate; and SD, standard deviation.</p