Hee Jeong Yoo

Family-based association study of 5-HTTLPR and the 5-HT2A receptor gene polymorphisms with autism spectrum disorder in Korean trios.

The potential role of the serotoninergic system in the development of autistic disorder has long been suggested based on the observation of hyperserotoninemia in autistic subjects and the results of drug treatment studies. Promoter region polymorphisms (5-HTTLPR) of the serotonin transporter gene (SLC6A4) and the 5-HT2A receptor gene (HTR2A) have been studied as potential candidate genes in autism spectrum disorder (ASD). The objective of this family-based linkage/association study is to evaluate the relationship between ASD and 5-HTTLPR as well as that between some SNPs of HTR2A and ASD in Korean trios by using the transmission disequilibrium test (TDT). Genotyping was performed for 5-HTTLPR and two single nucleotide polymorphisms (SNPs) (-1438G/A and 102T/C) of HTR2A. The TDT, linkage disequilibrium (LD) analysis and haplotype analysis were performed. This study comprised 126 complete trios of ASD patients and both parents. With regard to the transmission of 5-HTTLPR, the long allelic variant was preferentially transmitted in the ASD subjects. Based on the TDT results, there was no significant difference in the transmission of the two SNPs of HTR2A. However, in the results of the haplotype analysis, the AT haplotype demonstrated significant evidence of association with autism. The global chi(2) test for haplotype transmission revealed a significant association between HTR2A and autism. Although we identified a significant association between ASD and 5-HTTLPR as well as between ASD and HTR2A, it cannot exclude the chance finding because of the low level of statistical significance and relatively small power. We believe that further studies are required to examine the relationship between serotonin-related genes and the behavioral phenotypes of ASD in the Korean population.

Association between phthalates and externalizing behaviors and cortical thickness in children with attention deficit hyperactivity disorder.

BACKGROUNDnPrevious studies have implicated the relationship between environmental phthalate exposure and attention deficit hyperactivity disorder (ADHD) symptoms of childhood, but no studies have been conducted in children who have a confirmed diagnosis of ADHD obtained through meticulous diagnostic testing. We aimed to determine whether phthalate metabolites in urine would be higher in children with ADHD than in those without ADHD and would correlate with symptom severity and cortical thickness in ADHD children.nnnMETHODnA cross-sectional examination of urine phthalate metabolite concentrations was performed; scores for ADHD symptoms, externalizing problems, and continuous performance tests were obtained from 180 children with ADHD, and brain-imaging data were obtained from 115 participants. For the control group, children without ADHD (N = 438) were recruited. Correlations between phthalate metabolite concentrations and clinical measures and brain cortical thickness were investigated.nnnRESULTSnConcentrations of phthalate metabolites, particularly the di(2-ethylhexyl) phthalate (DEHP) metabolite, were significantly higher in boys with ADHD than in boys without ADHD. Concentrations of the di-n-butyl phthalate (DBP) metabolite were significantly higher in the combined or hyperactive-impulsive subtypes compared to the inattentive subtype, and the metabolite was positively correlated with the severity of externalizing symptoms. Concentrations of the DEHP metabolite were negatively correlated with cortical thickness in the right middle and superior temporal gyri.nnnCONCLUSIONSnThe results of this study suggest an association between phthalate concentrations and both the diagnosis and symptom severity of ADHD. Imaging findings suggest a negative impact of phthalates on regional cortical maturation in children with ADHD.

Association between urine cotinine levels, continuous performance test variables, and attention deficit hyperactivity disorder and learning disability symptoms in school-aged children

BACKGROUNDnWe examined the cross-sectional relationship between environmental tobacco smoke exposure, continuous performance test (CPT) measures, and attention deficit hyperactivity disorder (ADHD) or learning disability symptoms in school-aged children.nnnMETHODnIn total, 989 children (526 boys, mean age 9.1 ± 0.7 years), recruited from five South Korean cities participated in this study. We used urine cotinine as a biomarker for environmental tobacco smoke exposure, and obtained the childrens scores on a CPT. Parents completed the Korean versions of the ADHD rating scale-IV (ADHD-RS) and learning disability evaluation scale (LDES). Using generalized linear mixed model (GLMM), we assessed the associations between urine cotinine concentrations, neuropsychological variables, and symptoms of ADHD and learning disabilities. Additionally, we conducted structural equation models to explore the effects pathways.nnnRESULTSnAfter adjusting for a range of relevant covariates, GLMM showed urinary cotinine levels were significantly and positively associated with CPT scores on omission errors, commission errors, response time, and response time variability, and with parent- and teacher-rated ADHD-RS scores. In addition, urine cotinine levels were negatively associated with LDES scores on spelling and mathematical calculations. The structural equation model revealed that CPT variables mediated the association between urine cotinine levels and parental reports of symptoms of ADHD and learning disabilities.nnnCONCLUSIONSnOur data indicate that environmental exposure to tobacco smoke is associated with ADHD and learning disabilities in children, and that impairments in attention and inhibitory control probably mediate the effect.

Associations between maternal stress during pregnancy and offspring internalizing and externalizing problems in childhood.

BackgroundMaternal psychological health during pregnancy has been associated with offspring psychopathology. However, it is uncertain whether these associations are mediated by the postpartum depression and related child-rearing factors. Therefore, we examined the associations between prenatal and postnatal factors and internalizing and externalizing behavioral problems in childhood, focusing on maternal psychological health in school-aged children in Korea.FindingsThe current study included 1,003 children (580 boys, 423 girls, mean age 9.05u2009±u20090.70xa0years, age range 8–11 years) recruited from schools in five Korean cities. Children’s internalizing and externalizing problems were assessed by the Child Behavior Checklist (CBCL). The parents of the children completed structured questionnaires on perinatal factors. Among 1,003 children, 44 had internalizing problems (IP) and 30 had externalizing problems (EP). When comparing children with IP (nu2009=u200944) and without IP (nu2009=u2009959), severe maternal stress during pregnancy (OR3.36, 95% CI 1.80-6.25) and postpartum depression (OR3.19, 95% CI 1.36-7.53) showed a significant association with the IP. When comparing children with EP (nu2009=u200930) and without EP (nu2009=u2009973), low family income (OR2.19, 95% CI 1.05-4.56), unwanted pregnancy (OR2.76, 95% CI 1.28-5.95) and severe maternal stress during pregnancy (OR2.69, 95% CI 1.29-5.61) with the EP. Only maternal stress during pregnancy was significantly associated with the IP after controlling for postpartum depression and with the EP after controlling for family income and unwanted pregnancy.ConclusionThis study suggests the importance of maternal psychological health during perinatal period on children’s mental health. Further prospective studies in a larger sample are required to confirm our findings.

Nocturnal Enuresis Is Associated with Attention Deficit Hyperactivity Disorder and Conduct Problems

Objective There are no published prevalence estimates of elimination disorders and their association with disruptive-behavior disorders among children in the Asian region using standardized diagnostic interviews. This study was conducted to determine the prevalence of elimination disorders and its association with disruptive-behavior disorders in a representative sample of children in Seoul, Korea. Methods The diagnosis of enuresis and encopresis was derived from parent-reported data for enuresis and encopresis, collected using the Diagnostic Interview Schedule for Children, from a representative sample of 6- to 12-year-old children (n=1,645) who participated in the 2005 Seoul Child and Adolescent Mental Health Survey. Prevalence data for attention deficit and disruptive-behavior disorders were collected from the same sample. Results The overall 12-month prevalence of nocturnal enuresis and encopresis was 1.8% and 0.6%, respectively. Enuresis and encopresis prevalence in boys was significantly greater than that in girls. Enuresis and encopresis was most common at 7 to 9 years of age. Enuresis was significantly associated with ADHD (OR 2.6, 95% CI 1.0-6.9) and conduct disorder (CD; OR 4.7, 95% CI 1.0-22.4). Conclusion Enuresis is significantly associated with ADHD and CD, so these conditions must be assessed together during the evaluation of children with enuresis.

Genome-Wide Association Scan of Korean Autism Spectrum Disorders with Language Delay: A Preliminary Study

Objective Communication problems are a prevalent symptom of autism spectrum disorders (ASDs), which have a genetic background. Although several genome-wide studies on ASD have suggested a number of candidate genes, few studies have reported the association or linkage of specific endophenotypes to ASDs. Methods Forty-two Korean ASD patients who showed a language delay were enrolled in this study with their parents. We performed a genome-wide scan by using the Affymetrix SNP Array 5.0 platform to identify candidate genes responsible for language delay in ASDs. Results We detected candidate single-nucleotide polymorphisms (SNPs) in chromosome 11, rs11212733 (p-value=9.76×10-6) and rs7125479 (p-value=1.48×10-4), as a marker of language delay in ASD using the transmission disequilibrium test and multifactor dimensionality reduction test. Conclusion Although our results suggest that several SNPs are associated with language delay in ASD, rs11212733 we were not able to observe any significant results after correction of multiple comparisons. This may imply that more samples may be required to identify genes associated with language delay in ASD.

Protective effect of breastfeeding with regard to children’s behavioral and cognitive problems

BackgroundBreastfeeding has been associated with a lower risk for behavioral problems in childhood. However, it is uncertain whether these associations are mediated by the mother’s or child’s IQ. We examined the association between breastfeeding and attention-deficit hyperactivity disorder (ADHD) and other behavioral problems in childhood and assessed the role of the child’s IQ and the mother’s IQ in generating this association.FindingsThe current study included 874 children (8-11 years) recruited from schools in five Korean cities. Mothers were asked about nursing, and the prevalence of attention-deficit hyperactivity disorder (ADHD) and behavioral problems were compared between children who were breastfed and those who were not breastfed. After adjusting for age, gender, area of residence, and yearly family income, a lack of breastfeeding was associated with increased internalizing, externalizing, and overall behavioral problems as well as the diagnosis of ADHD. These associations weakened but mostly remained significant after adjusting for child’s IQ and maternal IQ. In addition, a lack of breastfeeding was associated with low child’s IQ and this association weakened, but remained significant even after adjusting for maternal IQ and the diagnosis of ADHD.ConclusionsThis study suggests that there is a protective effect of breastfeeding on childhood behavioral outcomes with a partial mediation of this effect by the child’s IQ, and there is a positive effect of breastfeeding on childhood intelligence with a partial mediation of this effect by the child’s attention problem.

Difference in mitochondrial DNA copy number in peripheral blood cells between probands with autism spectrum disorders and their unaffected siblings

Abstract Objectives: Several reports suggest that mitochondrial dysfunction is involved in the pathophysiology of autism spectrum disorders (ASD). Therefore, mitochondrial DNA (mtDNA) copy number, a common biomarker for mitochondrial dysfunction, might be associated with ASD phenotypes. Methods: Relative mtDNA copy number in the peripheral blood cells of 100 Korean ASD patients and their unaffected sib-pairs was measured by quantitative polymerase chain reaction (qPCR). Results: ASD patients had significantly higher relative mtDNA copy numbers than their unaffected sibs (Pu2009=u2009.042). In addition, there were statistically significant correlations between mtDNA copy number and clinical phenotypes for language and communication in ASD. Conclusions: Our findings suggest that mitochondrial dysfunction and elevated mtDNA copy number may be a biological subtype of ASD that is related to the phenotype for communication.

Di-(2-Ethylhexyl) Phthalate Exposure Is Negatively Correlated with Trait Anxiety in Girls but not with Trait Anxiety in Boys or Anxiety-Like Behavior in Male Mice

The authors aimed to study the effects of postnatal exposure to phthalate on anxiety-like behavior in mice and anxiety proneness in children. Male Imprinting Control Region (ICR) mice aged 4 weeks were administered 20 to 540 mg/kg of di-(2-ethylhexyl) phthalate (DEHP) or vehicle and assessed in the Open Field Test. A group of 277 children aged 8-11 years (150 males) was recruited from South Korea. A cross-sectional examination of urinary DEHP and dibutylphthalate metabolite concentrations was conducted, and the children were scored on the Trait Anxiety Inventory for Children (TAIC). DEHP metabolite concentrations in the urine were significantly and negatively correlated with TAIC scores in the female population but not in the male population. There were no significant group differences in the percentage of distance moved or time spent in the central area in male mice treated with DEHP or vehicle. Our results suggest a sex-dependent effect of DEHP on anxiety proneness in childhood.

Replicative genetic association study between functional polymorphisms in AVPR1A and social behavior scales of autism spectrum disorder in the Korean population

BackgroundArginine vasopressin has been shown to affect social and emotional behaviors, which is mediated by the arginine vasopressin receptor (AVPR1A). Genetic polymorphisms in the AVPR1A promoter region have been identified to be associated with susceptibility to social deficits in autism spectrum disorder (ASD). We hypothesize that alleles of polymorphisms in the promoter region of AVPR1A may differentially interact with certain transcriptional factors, which in turn affect quantitative traits, such as sociality, in children with autism.MethodsWe performed an association study between ASD and polymorphisms in the AVPR1A promoter region in the Korean population using a family-based association test (FBAT). We evaluated the correlation between genotypes and the quantitative traits that are related to sociality in children with autism. We also performed a promoter assay in T98G cells and evaluated the binding affinities of transcription factors to alleles of rs7294536.ResultsThe polymorphisms—RS1, RS3, rs7294536, and rs10877969—were analyzed. Under the dominant model, RS1–310, the shorter allele, was preferentially transmitted. The FBAT showed that the rs7294536 A allele was also preferentially transmitted in an additive and dominant model under the bi-allelic mode. When quantitative traits were used in the FBAT, rs7294536 and rs10877969 were statistically significant in all genotype models and modes. Luciferase and electrophoretic mobility-shift assays suggest that the rs7294536 A/G allele results in a Nf-κB binding site that exhibits differential binding affinities depending on the allele.ConclusionThese results demonstrate that polymorphisms in the AVPR1A promoter region might be involved in pathophysiology of ASD and in functional regulation of the expression of AVPR1A.