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Three-dimensional chromatin interactions regulate gene expressions. The significance of de novo mutations (DNMs) in chromatin interactions remains poorly understood for autism spectrum disorder (ASD). We generated 813 whole-genome sequences from 242 Korean simplex families to detect DNMs, and identified target genes which were putatively affected by non-coding DNMs in chromatin interactions. Non-coding DNMs in chromatin interactions were significantly involved in transcriptional dysregulations related to ASD risk. Correspondingly, target genes showed spatiotemporal expressions relevant to ASD in developing brains and enrichment in biological pathways implicated in ASD, such as histone modification. Regarding clinical features of ASD, non-coding DNMs in chromatin interactions particularly contributed to low intelligence quotient levels in ASD probands. We further validated our findings using two replication cohorts, Simons Simplex Collection (SSC) and MSSNG, and showed the consistent enrichment of non-coding DNM-disrupted chromatin interactions in ASD probands. Generating human induced pluripotent stem cells in two ASD families, we were able to demonstrate that non-coding DNMs in chromatin interactions alter the expression of target genes at the stage of early neural development. Taken together, our findings indicate that non-coding DNMs in ASD probands lead to early neurodevelopmental disruption implicated in ASD risk via chromatin interactions.

With the increasing number of sequencing projects involving families, quality control tools optimized for family genome sequencing are needed. However, accurately quantifying contamination in a DNA mixture is particularly difficult when genetically related family members are the sources. We developed TrioMix, a maximum likelihood estimation (MLE) framework based on Mendel's law of inheritance, to quantify DNA mixture between family members in genome sequencing data of parent–offspring trios. TrioMix can accurately deconvolute any intrafamilial DNA contamination, including parent–offspring, sibling–sibling, parent–parent, and even multiple familial sources. In addition, TrioMix can be applied to detect genomic abnormalities that deviate from Mendelian inheritance patterns, such as uniparental disomy (UPD) and chimerism. A genome-wide depth and variant allele frequency plot generated by TrioMix facilitates tracing the origin of Mendelian inheritance deviations. We showed that TrioMix could accurately deconvolute genomes in both simulated and real data sets.

IMPORTANCE: Pediatric patients often encounter anxiety and distress in hospital settings, and virtual reality education, providing a vivid, immersive, and realistic experience, has been introduced to mitigate these anxiety responses. OBJECTIVE: To evaluate whether virtual reality education for pediatric patients before chest radiography could reduce anxiety and distress in children and improve the radiographic process. DESIGN, SETTING, AND PARTICIPANTS: This prospective randomized clinical trial was conducted in a tertiary academic hospital in Seongnam, Republic of Korea. Participants (n = 112) were children aged 4 to 8 years who underwent chest radiography between July 20, 2018, and September 11, 2018. Analysis was performed from October 2, 2018, to April 23, 2019. INTERVENTIONS: Children were randomized to simple verbal instruction (control group) or 3-minute virtual reality education explaining the process of chest radiography in detail and leading to appropriate cooperation (virtual reality group). MAIN OUTCOMES AND MEASURES: The primary outcome was anxiety and distress among pediatric patients based on behavioral observations using the amended version of the Observational Scale of Behavioral Distress scale for radiology procedures (total score of 30, with a score <5 indicating less distressed and a score ≥5 indicating more distressed). Secondary outcomes were the need of parental presence, parental satisfaction score, procedure time, number of repeated images, and process difficulty score. RESULTS: Of 99 children included in the final analysis, 50 (50.5%) were allocated to the control group (mean [SD] age, 5.6 [1.2] years; 26 boys [52.0%]) and 49 (49.5%) to the virtual reality group (mean [SD] age, 5.8 [1.3] years; 32 boys [65.3%]). The mean (SD) score for anxiety and distress (2.0 [3.7] vs 5.0 [6.1]; mean difference, 3.0 [95% CI, 1.0-5.0]; P = .004), need for parental presence (8 cases with parents present [16.3%] vs 18 cases with parents present [36.0%]), and mean (SD) procedure time (55.1 [21.6] seconds vs 75.0 [42.0] seconds) were lower in the virtual reality group than in the control group. The mean (SD) score for parental satisfaction (9.4 [1.4] vs 8.6 [2.0]) was higher in the virtual reality group than in the control group. CONCLUSIONS AND RELEVANCE: Virtual reality education before chest radiography improved the radiography experience among pediatric patients by reducing anxiety, distress, and procedure time while increasing parents’ satisfaction. TRIAL REGISTRATION: UMIN Clinical Trials Registry: UMIN000030663

Detecting genetic interactions associated with complex disease is a major issue in genetic studies. Although a number of methods to detect gene-gene interactions for population-based Genome-Wide Association Studies (GWAS) have been developed, the statistical methods for family-based GWAS have been limited. In this study, we propose a new Bayesian approach called MB-TDT to find high-order genetic interactions for pedigree data. The MB-TDT method combines the Markov blanket algorithm with classical Transmission Disequilibrium Test (TDT) statistic. The Incremental Association Markov Blanket (IAMB) algorithm was adopted for large-scale Markov blanket discovery. We evaluated the proposed method using both real and simulated data sets. In a simulation study, we compared the power of MB-TDT with conditional logistic regression, Multifactor Dimensionality Reduction (MDR) and MDR-pedigree disequilibrium test (MDR-PDT). We demonstrated the superior power of MB-TDT in many cases. To demonstrate the approach, we analysed the Korean autism disorder GWAS data. The MB-TDT method can identify a minimal set of causal SNPs associated with a specific disease, thus avoiding an exhaustive search.

We examined the association between the selected polymorphisms in two candidate genes, the arsenite methyltransferase gene (AS3MT, rs11191454) and the inter--trypsin inhibitors heavy chain-3 gene (ITIH3, rs2535629), and attention-deficit hyperactivity disorder (ADHD) in a Korean population. A total of 238 patients with ADHD, along with both of their biological parents, were recruited. The children were administered intelligence quotient tests, whereas their parents completed the Child Behavior Checklist. In the transmission disequilibrium test on 181 trios, we found overtransmission of the A allele at the AS3MTrs11191454 polymorphism in children with ADHD (2=8.81, P=0.003). However, there was no preferential transmission at the ITIH3rs52535629 polymorphism (2=0.14, P=0.707). Our results provide preliminary evidence for the overtransmission of the A allele at the AS3MTrs11191454 polymorphism in ADHD.

We evaluated the effect of OROS methylphenidate (MPH) on sleep quality and architecture in children with attention-deficithyperactivity disorder (ADHD) using both a parental sleep questionnaire and polysomnography. Twenty-four ADHD children who had no comorbid psychiatric or sleep disorders except for oppositional defiant disorder completed the 6-week, prospective, open-label, flexible-dose trial with OROS MPH (Concerta) monotherapy. After OROS MPH administration, the polysomnography data indicated that the percentage of stage 2 sleep was increased (P0.024) and the Number of Awakenings was decreased (P0.047). Relative to baseline, Parasomnias of the Children's Sleep Habits Questionnaire were decreased (P0.033). Sleep Onset Latency was not changed during the treatment in general, but was increased in six children with subjective sleep difficulties (F15.832, P0.025, ηp20.226). Bedtime Resistance and Sleep Onset Delay in Children's Sleep Habits Questionnaire were also increased during the treatment with OROS MPH only in individuals with sleep complaints (F15.001, P0.036, ηp20.185; F17.237, P0.013, ηp20.248). These results suggest that OROS MPH in open-label treatment does not seem to impair sleep and may even improve some aspects of sleep.

AbstractBackground: The objective of this study was to evaluate the relationship between symptoms of attention deficit hyperactivity disorder (ADHD) and biogenetic temperament, as assessed by the Junior Temperament and Character Inventory (JTCI) in Korean elementary school children. Sampling and Methods: Five hundred and sixteen elementary school students (254 boys and 262 girls; age range 9–14 years, mean age 11.0 ± 1.0 years) were studied. The Junior Temperament and Character Inventory, both the self-rating and parent rating scales, the DuPaul ADHD rating scale (ARS-IV) for parents and teachers and the Child Behavior Checklist have been completed by study subjects. Children with high ARS-IV scores (the upper 10th percentile, n = 52) were defined to have ADHD. Fifty-two age- and sex-matched non-ADHD control subjects were selected randomly from a pool of 464 subjects. Results: Inattention and hyperactivity/impulsivity symptoms correlated positively with Novelty Seeking in both children and parent ratings. These symptoms correlated negatively with Persistence, Self-Directedness and Cooperativeness. Novelty Seeking also had significant correlations with attention problems, delinquent behavior, aggressive behavior, externalizing problems and social problems in the Child Behavior Checklist. The ADHD group (n = 52) had higher scores of Novelty Seeking and lower scores of Self-Directedness and Cooperativeness, compared with the control group. Conclusions: There were significant correlations between ADHD symptoms and Novelty Seeking. Current findings suggest that Novelty Seeking and ADHD share biogenetic backgrounds.Copyright © 2006 S. Karger AG, Basel

The dopamine (DA) system has been implicated in attention deficit hyperactivity disorder (ADHD) based on pharmacologic evidence. Because of an interaction between the serotonin (5‐HT) and DA systems, the serotonin transporter gene (SLC6A4) has been considered as a candidate ADHD susceptibility gene. Two common polymorphisms, 5‐HTTLPR and the intron 2 VNTR, have been studied for association in ADHD, with both positive (increased frequency of long allele of 5‐HTTLPR and decreased frequency of 12 repeats of the intron 2 VNTR) and negative findings. However, there has not been an association study in an East Asian ADHD population. In this study, we examined the genotypes of these two polymorphisms in 126 Korean ADHD families and investigated linkage disequilibrium (LD) between SLC6A4 and ADHD, using the transmission disequilibrium test (TDT) and haplotype analysis. Additionally, association with quantitative measures of inattention, hyperactivity‐impulsivity, and overall severity was tested using logistic regression and QTDT analysis. TDT of both polymorphisms and haplotype analysis failed to detect LD. However, after excluding ADHD NOS subtype, TDT revealed nominally significant LD between 5‐HTTLPR and ADHD (χ2 = 4.9, P = 0.036). QTDT revealed positive association between 12 repeats of the intron 2 VNTR and attention (P = 0.031), but case‐control and TDT logistic regression analyses were negative. These markers have low heterozygosity in the Korean population, which would be expected to reduce the power of association. This result suggests that future studies should include more polymorphic markers and subjects to thoroughly investigate a potential association between SLC6A4 and ADHD in the Korean population. © 2005 Wiley‐Liss, Inc.

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