ASD symptoms in children with ADHD : familial and genetic underpinnings

In this chapter the studies presented in this thesis are summarized and discussed. In addition, clinical implications and suggestions for future research are provided. Introduction ADHD is a common psychiatric disorder characterized by inattention, impulsivity, and hyperactivity. Impairments in social functioning are an important and common associated feature in children with ADHD. Despite this, there is a paucity of knowledge about the etiology of social problems in children with ADHD, and about the relation of these problems with other disorders that are characterized by problems in social functioning, especially ASD. In their apparent lack of social understanding (Cantwell, 1996), children with ADHD seem to be similar to children with ASD, which suggests a certain degree of symptom overlap between ADHD and ASD. This thesis presents studies into the nature and genetic causes of the occurrence of ASD symptoms in children with ADHD, which is introduced by a chapter on the social problems of children with ADHD. Study results ADHD and social functioning Most children with ADHD do show an interest in connecting with other people, but they often fail to properly attune their behavior to other people and the social context. As a consequence, children with ADHD frequently have conflicts, suffer from unpopularity, and have little or no close friends. Specific socially inadequate behaviors displayed by children with ADHD that are associated with peer rejection are negative, aggressive behaviors (including being bossy, argumentative, explosive and violating rules), as well as typical ADHD behaviors (e.g., loud, fidgety, inattentive, and intrusive behavior). Multiple studies have focussed on comorbid disorders, especially oppositional defiant disorder and conduct disorder, as sources for social problems in children with ADHD. Although comorbid disorders are important predictors of severe problems in social functioning, it also seems evident that ADHD as such brings along important limitations in acquiring and performing social skills. All three ADHD core dimensions impair the adjustment of behavior to a continuously changing (social) environment. Therefore, problems in social interaction may at least in some children be a direct consequence of the core dimensions of ADHD. Indeed, many children with ADHD have appropriate knowledge of adequate social behavior, but difficulties to apply this in real world settings (Barkley, 1997).

Anti-tumor properties of methoxylated analogues of resveratrol in malignant MCF-7 but not in non-tumorigenic MCF-10A mammary epithelial cell lines

Resveratrol is a plant-derived polyphenol that is known for its anti-inflammatory and anti-tumorigenic properties in in vitro and in vivo models. Recent studies show that some resveratrol analogues might be more potent anti-tumor agents, which may partly be attributed to their ability to activate the aryl hydrocarbon receptor (AHR). Here, the anti-tumorigenic properties of resveratrol and structural analogues oxyresveratrol, pinostilbene, pterostilbene and tetramethoxystilbene (TMS) were studied in vitro, using in the malignant human MCF-7 breast cancer cell line and non-tumorigenic breast epithelial cell line MCF-10A. Cell viability and migration assays showed that methoxylated analogues of resveratrol are more potent anti-tumorigenic compounds than resveratrol and its hydroxylated analogue oxyresveratrol, with 2,3’,4,5’-tetramethoxy-trans-stilbene (TMS) being the most potent compound. TMS decreased MCF-7 tumor cell viability with 50% at 3.6 μM and inhibited migration with 37.5 ± 14.8% at 3 μM. In addition, TMS activated the AHR more potently (EC50 in a reporter gene assay 2.0 μM) and induced AHR-mediated induction of cytochrome P450 1A1 (CYP1A1) activity (EC50 value of 0.7 μM) more than resveratrol and the other analogues tested. Cell cycle analysis showed that TMS induced a shift in cell cycle status from the G1 to the G2/M phase causing a cell cycle arrest in the MCF-7 cells, while no effect of TMS was observed in the non-tumorigenic MCF-10A mammary epithelial cell line. Gene expression analysis showed that 3 μM TMS increased gene expression of CYP1A1 (289-fold), CYP1B1 (5-fold) and Nqo1 (2-fold), and decreased gene expression of IL-8 (3-fold) in MCF-7 cells. In MCF-10A cells, 10 μM TMS also increased gene expression of CYP1A1 (5-fold) and CYP1B1 (2-fold), but decreased gene expression of Nqo1 (1.4-fold) in contrast to MCF-7 cells. TMS displays more potent anti-tumorigenic properties and activates the AHR more effectively than resveratrol. In addition, this is the first study to show that TMS, but not resveratrol, selectively inhibits the cell cycle of breast tumor cells and not the non-tumorigenic cells. Our study provides more insight in the anti-tumor properties of the methoxylated analogues of resveratrol in breast cells in vitro

Dual-spindle formation in zygotes keeps parental genomes apart in early mammalian embryos

At the beginning of mammalian life, the genetic material from each parent meets when the fertilized egg divides. It was previously thought that a single microtubule spindle is responsible for spatially combining the two genomes and then segregating them to create the two-cell embryo. We used light-sheet microscopy to show that two bipolar spindles form in the zygote and then independently congress the maternal and paternal genomes. These two spindles aligned their poles before anaphase but kept the parental genomes apart during the first cleavage. This spindle assembly mechanism provides a potential rationale for erroneous divisions into more than two blastomeric nuclei observed in mammalian zygotes and reveals the mechanism behind the observation that parental genomes occupy separate nuclear compartments in the two-cell embryo

Anti-tumor properties of methoxylated analogues of resveratrol in malignant MCF-7 but not in non-tumorigenic MCF-10A mammary epithelial cell lines

Resveratrol is a plant-derived polyphenol that is known for its anti-inflammatory and anti-tumorigenic properties in in vitro and in vivo models. Recent studies show that some resveratrol analogues might be more potent anti-tumor agents, which may partly be attributed to their ability to activate the aryl hydrocarbon receptor (AHR). Here, the anti-tumorigenic properties of resveratrol and structural analogues oxyresveratrol, pinostilbene, pterostilbene and tetramethoxystilbene (TMS) were studied in vitro, using in the malignant human MCF-7 breast cancer cell line and non-tumorigenic breast epithelial cell line MCF-10A. Cell viability and migration assays showed that methoxylated analogues of resveratrol are more potent anti-tumorigenic compounds than resveratrol and its hydroxylated analogue oxyresveratrol, with 2,3’,4,5’-tetramethoxy-trans-stilbene (TMS) being the most potent compound. TMS decreased MCF-7 tumor cell viability with 50% at 3.6 μM and inhibited migration with 37.5 ± 14.8% at 3 μM. In addition, TMS activated the AHR more potently (EC50 in a reporter gene assay 2.0 μM) and induced AHR-mediated induction of cytochrome P450 1A1 (CYP1A1) activity (EC50 value of 0.7 μM) more than resveratrol and the other analogues tested. Cell cycle analysis showed that TMS induced a shift in cell cycle status from the G1 to the G2/M phase causing a cell cycle arrest in the MCF-7 cells, while no effect of TMS was observed in the non-tumorigenic MCF-10A mammary epithelial cell line. Gene expression analysis showed that 3 μM TMS increased gene expression of CYP1A1 (289-fold), CYP1B1 (5-fold) and Nqo1 (2-fold), and decreased gene expression of IL-8 (3-fold) in MCF-7 cells. In MCF-10A cells, 10 μM TMS also increased gene expression of CYP1A1 (5-fold) and CYP1B1 (2-fold), but decreased gene expression of Nqo1 (1.4-fold) in contrast to MCF-7 cells. TMS displays more potent anti-tumorigenic properties and activates the AHR more effectively than resveratrol. In addition, this is the first study to show that TMS, but not resveratrol, selectively inhibits the cell cycle of breast tumor cells and not the non-tumorigenic cells. Our study provides more insight in the anti-tumor properties of the methoxylated analogues of resveratrol in breast cells in vitro

Quantitative Linkage for Autism Spectrum Disorders Symptoms in Attention-Deficit/Hyperactivity Disorder:Significant Locus on Chromosome 7q11

We studied 261 ADHD probands and 354 of their siblings to assess quantitative trait loci associated with autism spectrum disorder symptoms (as measured by the Children's Social Behavior Questionnaire (CSBQ)) using a genome-wide linkage approach, followed by locus-wide association analysis. A genome-wide significant locus for the CSBQ subscale addressing social interaction was found on chromosome 7q11, with suggestive signals supporting this locus on three other CSBQ subscales. We identified two other suggestive loci for the CSBQ total scale and individual subscales on chromosomes 4q35 and 7p12. Fine-mapping the significantly linked locus resulted in interesting candidate genes, although their association was not significant after permutation testing

Identifying Loci for the Overlap Between ADHD and ASD Using a Genome-wide QTL Linkage Approach

Background: Recent studies in the general population and clinical samples have shown that Pervasive Developmental Disorder (PDD) and Attention-Deficit/Hyperactivity Disorder (ADHD) overlap, both in symptoms and in underlying genetic influences.Objectives: In this study, the genetic basis for PDD symptoms in children with ADHD was addressed using a Quantitative Trait Locus linkage approach.Methods: Genome wide linkage analyses were performed in the Dutch participants of the International Multi-Center ADHD Genetics (IMAGE) study comprising 365 DSM-IV combined type ADHD probands and 439 of their siblings who were part of 365 families. The total and subscale scores of the Children’s Social Behavior Questionnaire (CSBQ; a measure of subtle PDD symptoms) with heritabilities >0.2 were used as quantitative traits. A total of 5407 autosomal single-nucleotide polymorphisms (SNPs) were used to run multipoint regression-based linkage analyses using MERLIN-regress software.Results: Suggestive linkage signals (LOD? 2.0) were found on chromosomes 2q, 3p, 7p, 7q, and 8p. The signal on chromosome 7q11.2 overlapped for three CSBQ scales, namely the total score (LOD 2.08), and the scales addressing withdrawn behavior (LOD 3.07) and understanding of social information (LOD 2.01), respectively. The regions on chromosome 7q11 and 8p21 that we identified have previously been found for autism, and the chromosome 7p13 finding overlaps with a linkage study for ADHD.Conclusions: Defining an ADHD subtype with PDD symptoms appears to be a valuable approach for detecting susceptibility loci for the overlap between ADHD and PD

Identifying loci for the overlap between attention-deficit/hyperactivity disorder and autism spectrum disorder using a genome-wide QTL linkage approach

OBJECTIVE: The genetic basis for autism spectrum disorder (ASD) symptoms in children with attention-deficit/hyperactivity disorder (ADHD) was addressed using a genome-wide linkage approach. METHOD: Participants of the International Multi-Center ADHD Genetics study comprising 1,143 probands with ADHD and 1,453 siblings were analyzed. The total and subscale scores of the Social Communication Questionnaire (SCQ) were used as quantitative traits for multipoint regression-based linkage analyses on 5,407 autosomal single-nucleotide polymorphisms applying MERLIN-regress software, both without and with inclusion of ADHD symptom scores as covariates. RESULTS: The analyses without ADHD symptom scores as covariates resulted in three suggestive linkage signals, i.e., on chromosomes 15q24, 16p13, and 18p11. Inclusion of ADHD symptom scores as covariates resulted in additional suggestive loci on chromosomes 7q36 and 12q24, whereas the LOD score of the locus on chromosome 15q decreased below the threshold for suggestive linkage. The loci on 7q, 16p, and 18p were found for the SCQ restricted and repetitive subscale, that on 15q was found for the SCQ communication subscale, and that on 12q for the SCQ total score. CONCLUSIONS: Our findings suggest that QTLs identified in this study are ASD specific, although the 15q QTL potentially has pleiotropic effects for ADHD and ASD. This study confirms that genetic factors influence ASD traits along a continuum of severity, as loci potentially underlying ASD symptoms in children with ADHD were identified even though subjects with autism had been excluded from the IMAGE sample, and supports the hypothesis that differential genetic factors underlie the three ASD dimensions