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CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors.

October 9, 2014 - 7:53am

CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors.

Proc Natl Acad Sci U S A. 2014 Oct 7;

Authors: Sugathan A, Biagioli M, Golzio C, Erdin S, Blumenthal I, Manavalan P, Ragavendran A, Brand H, Lucente D, Miles J, Sheridan SD, Stortchevoi A, Kellis M, Haggarty SJ, Katsanis N, Gusella JF, Talkowski ME

Abstract
Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing). Suppressing CHD8 to levels comparable with the loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8-binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (P < 10(-8)) and CHD8-bound genes (P = 0.0043), which align with previously identified coexpression modules during fetal development. We also find an intriguing enrichment of cancer-related gene sets among CHD8-bound genes (P < 10(-10)). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene-expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis.

PMID: 25294932 [PubMed - as supplied by publisher]

Childhood acne in a boy with XYY syndrome.

October 9, 2014 - 7:53am
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Childhood acne in a boy with XYY syndrome.

BMJ Case Rep. 2014;2014

Authors: Kasparis C, Loffeld A

Abstract
A 3-year-old boy was referred to the dermatology department with a 12-month history of facial erythema associated with a papular-pustular facial eruption consistent with childhood acne. He had been diagnosed with XYY syndrome identified during genetic analysis for cardiac anomalies at birth. XYY syndrome is an aneuploidy of the sex chromosomes which affects 1 in 1000 male births. It is often asymptomatic and identified incidentally following genetic analysis for other conditions. The syndrome can be associated with an increased risk of learning difficulties and delayed language skills. Early diagnosis could alert physicians to the possibility of subtle developmental and learning abnormalities and result in prompt management. Our case highlights the fact that the presence of childhood acne could aid in the early detection of XYY syndrome.

PMID: 24395875 [PubMed - indexed for MEDLINE]

Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum.

October 8, 2014 - 7:42am

Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum.

Transl Psychiatry. 2014;4:e460

Authors: James SJ, Shpyleva S, Melnyk S, Pavliv O, Pogribny IP

Abstract
Epigenetic mechanisms regulate programmed gene expression during prenatal neurogenesis and serve as a mediator between genetics and environment in postnatal life. The recent discovery of 5-hydroxymethylcytosine (5-hmC), with highest concentration in the brain, has added a new dimension to epigenetic regulation of neurogenesis and the development of complex behavior disorders. Here, we take a candidate gene approach to define the role 5-hmC in Engrailed-2 (EN-2) gene expression in the autism cerebellum. The EN-2 homeobox transcription factor, previously implicated in autism, is essential for normal cerebellar patterning and development. We previously reported EN-2 overexpression associated with promoter DNA hypermethylation in the autism cerebellum but because traditional DNA methylation methodology cannot distinguish 5-methylcytosine (5-mC) from 5-hmC, we now extend our investigation by quantifying global and gene-specific 5-mC and 5-hmC. Globally, 5-hmC was significantly increased in the autism cerebellum and accompanied by increases in the expression of de novo methyltransferases DNMT3A and DNMT3B, ten-eleven translocase genes TET1 and TET3, and in 8-oxo-deoxyguanosine (8-oxo-dG) content, a marker of oxidative DNA damage. Within the EN-2 promoter, there was a significant positive correlation between 5-hmC content and EN-2 gene expression. Based on reports of reduced MeCP2 affinity for 5-hmC, MeCP2 binding studies in the EN-2 promoter revealed a significant decrease in repressive MeCP2 binding that may contribute to the aberrant overexpression of EN-2. Because normal cerebellar development depends on perinatal EN-2 downregulation, the sustained postnatal overexpression suggests that a critical window of cerebellar development may have been missed in some individuals with autism with downstream developmental consequences. Epigenetic regulation of the programmed on-off switches in gene expression that occur at birth and during early brain development warrants further investigation.

PMID: 25290267 [PubMed - as supplied by publisher]

Autism spectrum disorder severity reflects the average contribution of de novo and familial influences.

October 8, 2014 - 7:42am

Autism spectrum disorder severity reflects the average contribution of de novo and familial influences.

Proc Natl Acad Sci U S A. 2014 Oct 6;

Authors: Robinson EB, Samocha KE, Kosmicki JA, McGrath L, Neale BM, Perlis RH, Daly MJ

Abstract
Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions-phenotypically and genetically-although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.

PMID: 25288738 [PubMed - as supplied by publisher]

DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores.

October 8, 2014 - 7:42am

DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores.

Hum Genet. 2014 Oct 7;

Authors: Davis JM, Searles VB, Anderson N, Keeney J, Raznahan A, Horwood LJ, Fergusson DM, Kennedy MA, Giedd J, Sikela JM

Abstract
DUF1220 protein domains exhibit the greatest human lineage-specific copy number expansion of any protein-coding sequence in the genome, and variation in DUF1220 copy number has been linked to both brain size in humans and brain evolution among primates. Given these findings, we examined associations between DUF1220 subtypes CON1 and CON2 and cognitive aptitude. We identified a linear association between CON2 copy number and cognitive function in two independent populations of European descent. In North American males, an increase in CON2 copy number corresponded with an increase in WISC IQ (R (2) = 0.13, p = 0.02), which may be driven by males aged 6-11 (R (2) = 0.42, p = 0.003). We utilized ddPCR in a subset as a confirmatory measurement. This group had 26-33 copies of CON2 with a mean of 29, and each copy increase of CON2 was associated with a 3.3-point increase in WISC IQ (R (2) = 0.22, p = 0.045). In individuals from New Zealand, an increase in CON2 copy number was associated with an increase in math aptitude ability (R (2) = 0.10 p = 0.018). These were not confounded by brain size. To our knowledge, this is the first study to report a replicated association between copy number of a gene coding sequence and cognitive aptitude. Remarkably, dosage variations involving DUF1220 sequences have now been linked to human brain expansion, autism severity and cognitive aptitude, suggesting that such processes may be genetically and mechanistically inter-related. The findings presented here warrant expanded investigations in larger, well-characterized cohorts.

PMID: 25287832 [PubMed - as supplied by publisher]

Fragile X Syndrome: A Review of Associated Medical Problems.

October 8, 2014 - 7:42am

Fragile X Syndrome: A Review of Associated Medical Problems.

Pediatrics. 2014 Oct 6;

Authors: Kidd SA, Lachiewicz A, Barbouth D, Blitz RK, Delahunty C, McBrien D, Visootsak J, Berry-Kravis E

Abstract
Fragile X syndrome (FXS) is the most common known genetic cause of inherited intellectual disability and the most common known single-gene cause of autism spectrum disorder. It has been reported that a spectrum of medical problems are commonly experienced by people with FXS, such as otitis media, seizures, and gastrointestinal problems. Previous studies examining the prevalence of medical problems related to FXS have been challenging to interpret because of their marked differences in population, setting, and sampling. Through this comprehensive review, we update the literature by reviewing studies that have reported on prominent medical problems associated with FXS. We then compare prevalence results from those studies with results from a large cross-sectional database consisting of data collected by fragile X clinics that specialize in the care of children with FXS and are part of the Fragile X Clinical and Research Consortium. It is vital for pediatricians and other clinicians to be familiar with the medical problems related to FXS so that affected patients may receive proper diagnosis and treatment; improved care may lead to better quality of life for these patients and their families.

PMID: 25287458 [PubMed - as supplied by publisher]

An unusual clinical severity of 16p11.2 deletion syndrome caused by unmasked recessive mutation of CLN3.

October 8, 2014 - 7:42am
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An unusual clinical severity of 16p11.2 deletion syndrome caused by unmasked recessive mutation of CLN3.

Eur J Hum Genet. 2014 Mar;22(3):369-73

Authors: Pebrel-Richard C, Debost-Legrand A, Eymard-Pierre E, Greze V, Kemeny S, Gay-Bellile M, Gouas L, Tchirkov A, Vago P, Goumy C, Francannet C

Abstract
With the introduction of array comparative genomic hybridization (aCGH) techniques in the diagnostic setting of patients with developmental delay and congenital malformations, many new microdeletion syndromes have been recognized. One of these recently recognized microdeletion syndromes is the 16p11.2 deletion syndrome, associated with variable clinical outcomes including developmental delay, autism spectrum disorder, epilepsy, and obesity, but also apparently normal phenotype. We report on a 16-year-old patient with developmental delay, exhibiting retinis pigmentosa with progressive visual failure from the age of 9 years, ataxia, and peripheral neuropathy. Chromosomal microarray analysis identified a 1.7-Mb 16p11.2 deletion encompassing the 593-kb common deletion (∼29.5 to ∼30.1 Mb; Hg18) and the 220-kb distal deletion (∼28.74 to ∼28.95 Mb; Hg18) that partially included the CLN3 gene. As the patient's clinical findings were different from usual 16p11.2 microdeletion phenotypes and showed some features reminiscent of juvenile neuronal ceroid-lipofuscinosis (JNCL, Batten disease, OMIM 204200), we suspected and confirmed a mutation of the remaining CLN3 allele. This case further illustrates that unmasking of hemizygous recessive mutations by chromosomal deletion represents one explanation for the phenotypic variability observed in chromosomal deletion disorders.

PMID: 23860047 [PubMed - indexed for MEDLINE]

Prostaglandin E2 alters Wnt-dependent migration and proliferation in neuroectodermal stem cells: implications for autism spectrum disorders.

October 7, 2014 - 7:21am
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Prostaglandin E2 alters Wnt-dependent migration and proliferation in neuroectodermal stem cells: implications for autism spectrum disorders.

Cell Commun Signal. 2014;12:19

Authors: Wong CT, Ahmad E, Li H, Crawford DA

Abstract
Prostaglandin E2 (PGE2) is a natural lipid-derived molecule that is involved in important physiological functions. Abnormal PGE2 signalling has been associated with pathologies of the nervous system. Previous studies provide evidence for the interaction of PGE2 and canonical Wnt signalling pathways in non-neuronal cells. Since the Wnt pathway is crucial in the development and organization of the brain, the main goal of this study is to determine whether collaboration between these pathways exists in neuronal cell types. We report that PGE2 interacts with canonical Wnt signalling through PKA and PI-3K in neuroectodermal (NE-4C) stem cells. We used time-lapse microscopy to determine that PGE2 increases the final distance from origin, path length travelled, and the average speed of migration in Wnt-activated cells. Furthermore, PGE2 alters distinct cellular phenotypes that are characteristic of Wnt-induced NE-4C cells, which corresponds to the modified splitting behaviour of the cells. We also found that in Wnt-induced cells the level of β-catenin protein was increased and the expression levels of Wnt-target genes (Ctnnb1, Ptgs2, Ccnd1, Mmp9) was significantly upregulated in response to PGE2 treatment. This confirms that PGE2 activated the canonical Wnt signalling pathway. Furthermore, the upregulated genes have been previously associated with ASD. Our findings show, for the first time, evidence for cross-talk between PGE2 and Wnt signalling in neuronal cells, where PKA and PI-3K might act as mediators between the two pathways. Given the importance of PGE2 and Wnt signalling in prenatal development of the nervous system, our study provides insight into how interaction between these two pathways may influence neurodevelopment.

PMID: 24656144 [PubMed - indexed for MEDLINE]

Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism.

October 7, 2014 - 7:21am
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Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism.

FASEB J. 2014 Jun;28(6):2398-413

Authors: Patrick RP, Ames BN

Abstract
Serotonin and vitamin D have been proposed to play a role in autism; however, no causal mechanism has been established. Here, we present evidence that vitamin D hormone (calcitriol) activates the transcription of the serotonin-synthesizing gene tryptophan hydroxylase 2 (TPH2) in the brain at a vitamin D response element (VDRE) and represses the transcription of TPH1 in tissues outside the blood-brain barrier at a distinct VDRE. The proposed mechanism explains 4 major characteristics associated with autism: the low concentrations of serotonin in the brain and its elevated concentrations in tissues outside the blood-brain barrier; the low concentrations of the vitamin D hormone precursor 25-hydroxyvitamin D [25(OH)D3]; the high male prevalence of autism; and the presence of maternal antibodies against fetal brain tissue. Two peptide hormones, oxytocin and vasopressin, are also associated with autism and genes encoding the oxytocin-neurophysin I preproprotein, the oxytocin receptor, and the arginine vasopressin receptor contain VDREs for activation. Supplementation with vitamin D and tryptophan is a practical and affordable solution to help prevent autism and possibly ameliorate some symptoms of the disorder.

PMID: 24558199 [PubMed - indexed for MEDLINE]

The neurobiology of autism spectrum disorders.

October 7, 2014 - 7:21am
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The neurobiology of autism spectrum disorders.

Eur Psychiatry. 2014 Jan;29(1):11-9

Authors: Parellada M, Penzol MJ, Pina L, Moreno C, González-Vioque E, Zalsman G, Arango C

Abstract
Data is progressively and robustly accumulating regarding the biological basis of autism. Autism spectrum disorders (ASD) are currently considered a group of neurodevelopmental disorders with onset very early in life and a complex, heterogeneous, multifactorial aetiology. A comprehensive search of the last five years of the Medline database was conducted in order to summarize recent evidence on the neurobiological bases of autism. The main findings on genetic influence, neuropathology, neurostructure and brain networks are summarized. In addition, findings from peripheral samples of subjects with autism and animal models, which show immune, oxidative, mitochondrial dysregulations, are reported. Then, other biomarkers from very different systems associated with autism are reported. Finally, an attempt is made to try and integrate the available evidence, which points to a oligogenetic, multifactorial aetiology that converges in an aberrant micro-organization of the cortex, with abnormal functioning of the synapses and abnormalities in very general physiological pathways (such as inflammatory, immune and redox systems).

PMID: 24275633 [PubMed - indexed for MEDLINE]

Alpha-lipoic acid effects on brain glial functions accompanying double-stranded RNA antiviral and inflammatory signaling.

October 7, 2014 - 7:21am
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Alpha-lipoic acid effects on brain glial functions accompanying double-stranded RNA antiviral and inflammatory signaling.

Neurochem Int. 2014 Jan;64:55-63

Authors: Scumpia PO, Kelly-Scumpia K, Stevens BR

Abstract
Double-stranded RNAs (dsRNA) serve as viral ligands that trigger innate immunity in astrocytes and microglial, as mediated through Toll-like receptor 3 (TLR3) and dsRNA-dependent protein kinase (PKR). Beneficial transient TLR3 and PKR anti-viral signaling can become deleterious when events devolve into inflammation and cytotoxicity. Viral products in the brain cause glial cell dysfunction, and are a putative etiologic factor in neuropsychiatric disorders, notably schizophrenia, bipolar disorder, Parkinson's, and autism spectrum. Alpha-lipoic acid (LA) has been proposed as a possible therapeutic neuroprotectant. The objective of this study was to test our hypothesis that LA can control untoward antiviral mechanisms associated with neural dysfunction. Utilizing rat brain glial cultures (91% astrocytes:9% microglia) treated with PKR- and TLR3-ligand/viral mimetic dsRNA, polyinosinic-polycytidylic acid (polyI:C), we report in vitro glial antiviral signaling and LA reduction of the effects of this signaling. LA blunted the dsRNA-stimulated expression of IFNα/β-inducible genes Mx1, PKR, and TLR3. And in polyI:C treated cells, LA promoted gene expression of rate-limiting steps that benefit healthy neural redox status in glutamateric systems. To this end, LA decreased dsRNA-induced inflammatory signaling by downregulating IL-1β, IL-6, TNFα, iNOS, and CAT2 transcripts. In the presence of polyI:C, LA prevented cultured glial cytotoxicity which was correlated with increased expression of factors known to cooperatively control glutamate/cystine/glutathione redox cycling, namely glutamate uptake transporter GLAST/EAAT1, γ-glutamyl cysteine ligase catalytic and regulatory subunits, and IL-10. Glutamate exporting transporter subunits 4F2hc and xCT were downregulated by LA in dsRNA-stimulated glia. l-Glutamate net uptake was inhibited by dsRNA, and this was relieved by LA. Glutathione synthetase mRNA levels were unchanged by dsRNA or LA. This study demonstrates the protective effects of LA in astroglial/microglial cultures, and suggests the potential for LA efficacy in virus-induced CNS pathologies, with the caveat that antiviral benefits are concomitantly blunted. It is concluded that LA averts key aspects of TLR3- and PKR-provoked glial dysfunction, and provides rationale for exploring LA in whole animal and human clinical studies to blunt or avert neuropsychiatric disorders.

PMID: 24269587 [PubMed - indexed for MEDLINE]

PTEN knockdown alters dendritic spine/protrusion morphology, not density.

October 7, 2014 - 7:21am
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PTEN knockdown alters dendritic spine/protrusion morphology, not density.

J Comp Neurol. 2014 Apr 1;522(5):1171-90

Authors: Haws ME, Jaramillo TC, Espinosa F, Widman AJ, Stuber GD, Sparta DR, Tye KM, Russo SJ, Parada LF, Stavarache M, Kaplitt M, Bonci A, Powell CM

Abstract
Mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) are implicated in neuropsychiatric disorders including autism. Previous studies report that PTEN knockdown in neurons in vivo leads to increased spine density and synaptic activity. To better characterize synaptic changes in neurons lacking PTEN, we examined the effects of shRNA knockdown of PTEN in basolateral amygdala neurons on synaptic spine density and morphology by using fluorescent dye confocal imaging. Contrary to previous studies in the dentate gyrus, we find that knockdown of PTEN in basolateral amygdala leads to a significant decrease in total spine density in distal dendrites. Curiously, this decreased spine density is associated with increased miniature excitatory postsynaptic current frequency and amplitude, suggesting an increase in number and function of mature spines. These seemingly contradictory findings were reconciled by spine morphology analysis demonstrating increased mushroom spine density and size with correspondingly decreased thin protrusion density at more distal segments. The same analysis of PTEN conditional deletion in the dentate gyrus demonstrated that loss of PTEN does not significantly alter total density of dendritic protrusions in the dentate gyrus, but does decrease thin protrusion density and increases density of more mature mushroom spines. These findings suggest that, contrary to previous reports, PTEN knockdown may not induce de novo spinogenesis, but instead may increase synaptic activity by inducing morphological and functional maturation of spines. Furthermore, behavioral analysis of basolateral amygdala PTEN knockdown suggests that these changes limited only to the basolateral amygdala complex may not be sufficient to induce increased anxiety-related behaviors.

PMID: 24264880 [PubMed - indexed for MEDLINE]

The role of β3 integrin gene variants in Autism Spectrum Disorders - Diagnosis and symptomatology.

October 5, 2014 - 6:13am

The role of β3 integrin gene variants in Autism Spectrum Disorders - Diagnosis and symptomatology.

Gene. 2014 Sep 30;

Authors: Schuch JB, Muller D, Endres RG, Bosa CA, Longo D, Schuler-Faccini L, Ranzan J, Becker MM, Dos Santos Riesgo R, Roman T

Abstract
Autism Spectrum Disorders (ASDs) represent a group of very complex early-onset neurodevelopmental diseases. In this study, we analyzed 5 SNPs (rs2317385, rs5918, rs15908, rs12603582, rs3809865) at the β3 integrin locus (ITGB3), which has been suggested as a possible susceptibility gene, both as single markers and as part of haplotypes in 209 ASD children and their biological parents. We tested for association with the following: a) DSM-IV ASD diagnosis; b) clinical symptoms common in ASD patients (repetitive behaviors, echolalia, seizures and epilepsy, mood instability, aggression, psychomotor agitation, sleep disorders); and c) dimensional scores obtained with the Autism Screening Questionnaire and the Childhood Autism Rating Scale. These hypotheses were investigated using family-based tests, logistic regression models and analysis of covariance. The family-based tests showed an association with the H5 haplotype (composed by GTCGA alleles, the order of SNPs as above), which was transmitted less often than expected by chance (P=0.006; Pcorr=0.036). The analyses of the clinical symptoms showed a trend for an association with rs12603582 (P=0.008; Pcorr=0.064) and positive results for the haplotype composed of rs15908 and rs12603582 (Pglcorr=0.048; Pindcorr=0.015), both in symptoms of echolalia. Other nominal associations with different variants were found and involved epilepsy/seizures, aggression symptoms and higher ASQ scores. Although our positive results are not definitive, they suggest small effect associations of the ITGB3 gene with both ASD diagnosis and symptoms of echolalia. Other studies are nonetheless needed to fully understand the involvement of this locus on the etiology of ASDs and its different clinical aspects.

PMID: 25280596 [PubMed - as supplied by publisher]

Neurocognitive abilities in the general population and composite genetic risk scores for attention-deficit hyperactivity disorder.

October 4, 2014 - 6:00am

Neurocognitive abilities in the general population and composite genetic risk scores for attention-deficit hyperactivity disorder.

J Child Psychol Psychiatry. 2014 Oct 3;

Authors: Martin J, Hamshere ML, Stergiakouli E, O'Donovan MC, Thapar A

Abstract
BACKGROUND: The genetic architecture of ADHD is complex, with rare and common variants involved. Common genetic variants (as indexed by a composite risk score) associated with clinical ADHD significantly predict ADHD and autistic-like behavioural traits in children from the general population, suggesting that ADHD lies at the extreme of normal trait variation. ADHD and other neurodevelopmental disorders share neurocognitive difficulties in several domains (e.g. impaired cognitive ability and executive functions). We hypothesised that ADHD composite genetic risk scores derived from clinical ADHD cases would also contribute to variation in neurocognitive abilities in the general population.
METHODS: Children (N = 6,832) from a UK population cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC), underwent neurocognitive testing. Parent-reported measures of their children's ADHD and autistic-like traits were used to construct a behavioural latent variable of 'neurodevelopmental traits'. Composite genetic risk scores for ADHD were calculated for ALSPAC children based on findings from an independent ADHD case-control genome-wide association study. Structural equation modelling was used to assess associations between ADHD composite genetic risk scores and IQ, working memory, inhibitory control and facial emotion recognition, as well as the latent 'neurodevelopmental trait' measure.
RESULTS: The results confirmed that neurocognitive and neurodevelopmental traits are correlated in children in the general population. Composite genetic risk scores for ADHD were independently associated with lower IQ (β = -.05, p < .001) and working memory performance (β = -.034, p = .013), even after accounting for the relationship with latent neurodevelopmental behavioural trait scores. No associations were found between composite genetic risk scores and inhibitory control or emotion recognition (p > .05).
CONCLUSIONS: These findings suggest that common genetic variants relevant to clinically diagnosed ADHD have pleiotropic effects on neurocognitive traits as well as behavioural dimensions in the general population. This further suggests that the well-recognised association between cognition and neurodevelopmental behavioural traits is underpinned at a biological level.

PMID: 25280069 [PubMed - as supplied by publisher]

Autism spectrum disorders and coexisting disorders in a nationwide Swedish twin study.

October 4, 2014 - 6:00am

Autism spectrum disorders and coexisting disorders in a nationwide Swedish twin study.

J Child Psychol Psychiatry. 2014 Oct 3;

Authors: Lundström S, Reichenberg A, Melke J, Råstam M, Kerekes N, Lichtenstein P, Gillberg C, Anckarsäter H

Abstract
BACKGROUND: Evidence from twin and molecular genetic studies is accumulating that Autism Spectrum Disorder (ASD) shares substantial etiological factors with other disorders. This is mirrored in clinical practice where ASD without coexisting disorders is rare. The present study aims to examine the range of coexisting disorders in ASD in a genetically informative cohort.
METHODS: Parents of all Swedish 9-year-old twins born between 1992 and 2001 (n = 19,130) underwent a telephone interview designed to screen for child psychiatric disorders, including ASD. To ensure full coverage of child psychiatric disorders, data were also retrieved from population-based health registers. We investigated the coexistence of eight psychiatric disorders known to coexist with ASDs in probands and their co-twins.
RESULTS: Half of the individuals with ASDs (50.3%) had four or more coexisting disorders and only 4% did not have any concomitant disorder. The 'healthy co-twin' in ASD discordant monozygotic twin pairs was very often (79% of boys and 50% of girls) affected by at least one non-ASD disorder. The corresponding figures for ASD discordant dizygotic twin pairs were significantly lower (46% of males and 30% of females).
CONCLUSIONS: Detailed phenotypic descriptions including symptoms of problems associated with a wide range of child psychiatric disorders may aid in unraveling the genetic architecture of ASD and should guide the development of intervention strategies addressing each problem type specifically.

PMID: 25279993 [PubMed - as supplied by publisher]

Evidence for ASD Recurrence Rates and Reproductive Stoppage From Large UK ASD Research Family Databases.

October 3, 2014 - 8:52am

Evidence for ASD Recurrence Rates and Reproductive Stoppage From Large UK ASD Research Family Databases.

Autism Res. 2014 Oct 1;

Authors: Wood CL, Warnell F, Johnson M, Hames A, Pearce MS, McConachie H, Parr JR

Abstract
Following a diagnosis of a developmental disorder such as autism spectrum disorder (ASD) in early childhood, parents may decide to have fewer children than previously planned. The tendency for families to halt reproduction after receiving a diagnosis for one child is known as reproductive stoppage. Stoppage may lead to an underestimate of recurrence risk estimates of parents having more than one child with ASD. Using two large UK ASD family databases, we investigated recurrence rates for ASD and evidence for reproductive stoppage for both ASD and undiagnosed ASD/broader autism phenotype in a subgroup of families. Reproductive stoppage was tested for using the Mann-Whitney U-test to disprove the null hypothesis that affected and nonaffected children were distributed randomly by birth order. Dahlberg's later-sib method was used to estimate recurrence risk and take stoppage into account. Data were available from 299 families (660 children) including 327 with ASD. Ten percent of the complete families had more than one child with an ASD. Using Dahlberg's later-sib method, the recurrence risk for ASD was 24.7% overall and 50.0% in families with two or more older siblings with ASD. Children with ASD were born significantly later in families than those without ASD in all sibship combinations. This study shows strong evidence that ASD is associated with reproductive stoppage. These data have important implications for family planning and genetic counseling. Autism Res 2014, ●●: ●●-●●. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 25273900 [PubMed - as supplied by publisher]

MIRA: mutual information-based reporter algorithm for metabolic networks.

October 3, 2014 - 8:52am
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MIRA: mutual information-based reporter algorithm for metabolic networks.

Bioinformatics. 2014 Jun 15;30(12):i175-84

Authors: Cicek AE, Roeder K, Ozsoyoglu G

Abstract
MOTIVATION: Discovering the transcriptional regulatory architecture of the metabolism has been an important topic to understand the implications of transcriptional fluctuations on metabolism. The reporter algorithm (RA) was proposed to determine the hot spots in metabolic networks, around which transcriptional regulation is focused owing to a disease or a genetic perturbation. Using a z-score-based scoring scheme, RA calculates the average statistical change in the expression levels of genes that are neighbors to a target metabolite in the metabolic network. The RA approach has been used in numerous studies to analyze cellular responses to the downstream genetic changes. In this article, we propose a mutual information-based multivariate reporter algorithm (MIRA) with the goal of eliminating the following problems in detecting reporter metabolites: (i) conventional statistical methods suffer from small sample sizes, (ii) as z-score ranges from minus to plus infinity, calculating average scores can lead to canceling out opposite effects and (iii) analyzing genes one by one, then aggregating results can lead to information loss. MIRA is a multivariate and combinatorial algorithm that calculates the aggregate transcriptional response around a metabolite using mutual information. We show that MIRA's results are biologically sound, empirically significant and more reliable than RA.
RESULTS: We apply MIRA to gene expression analysis of six knockout strains of Escherichia coli and show that MIRA captures the underlying metabolic dynamics of the switch from aerobic to anaerobic respiration. We also apply MIRA to an Autism Spectrum Disorder gene expression dataset. Results indicate that MIRA reports metabolites that highly overlap with recently found metabolic biomarkers in the autism literature. Overall, MIRA is a promising algorithm for detecting metabolic drug targets and understanding the relation between gene expression and metabolic activity.
AVAILABILITY AND IMPLEMENTATION: The code is implemented in C# language using .NET framework. Project is available upon request.

PMID: 24931981 [PubMed - indexed for MEDLINE]

Activating KIR molecules and their cognate ligands prevail in children with a diagnosis of ASD and in their mothers.

October 3, 2014 - 8:52am
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Activating KIR molecules and their cognate ligands prevail in children with a diagnosis of ASD and in their mothers.

Brain Behav Immun. 2014 Feb;36:54-60

Authors: Guerini FR, Bolognesi E, Chiappedi M, Manca S, Ghezzo A, Agliardi C, Zanette M, Littera R, Carcassi C, Sotgiu S, Clerici M

Abstract
The activity of natural killer (NK) cells is modulated by the interaction between killer-cell immune globulin-like receptor (KIR) proteins and their cognate HLA ligands; activated NK cells produce inflammatory cytokines and mediate innate immune responses. Activating KIR/HLA complexes (aKIR/HLA) were recently suggested to prevail in children with autism spectrum disorders (ASD), a neurodevelopmental syndrome characterized by brain and behavioral abnormalities and associated with a degree of inflammation. We verified whether such findings could be confirmed by analyzing two sample cohorts of Sardinian and continental Italian ASD children and their mothers. Results showed that aKIR/HLA are increased whereas inhibitory KIR/HLA complexes are reduced in ASD children; notably this skewing was even more significant in their mothers. KIR and HLA molecules are expressed by placental cells and by the trophoblast and their interactions result in immune activation and influence fetal, as well as central nervous system development and plasticity. Data herein suggest that in utero KIR/HLA immune interactions favor immune activation in ASD; this may play a role in the pathogenesis of the disease.

PMID: 24120931 [PubMed - indexed for MEDLINE]

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes.

October 2, 2014 - 8:42am

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes.

Eur J Hum Genet. 2014 Oct 1;

Authors: Mullegama SV, Pugliesi L, Burns B, Shah Z, Tahir R, Gu Y, Nelson DL, Elsea SH

Abstract
Individuals with autism spectrum disorders (ASD) who have an identifiable single-gene neurodevelopmental disorder (NDD), such as fragile X syndrome (FXS, FMR1), Smith-Magenis syndrome (SMS, RAI1), or 2q23.1 deletion syndrome (del 2q23.1, MBD5) share phenotypic features, including a high prevalence of sleep disturbance. We describe the circadian deficits in del 2q23.1 through caregiver surveys in which we identify several frequent sleep anomalies, including night/early awakenings, coughing/snoring loudly, and difficulty falling asleep. We couple these findings with studies on the molecular analysis of the circadian deficits associated with haploinsufficiency of MBD5 in which circadian gene mRNA levels of NR1D2, PER1, PER2, and PER3 were altered in del 2q23.1 lymphoblastoid cell lines (LCLs), signifying that haploinsufficiency of MBD5 can result in dysregulation of circadian rhythm gene expression. These findings were further supported by expression microarrays of MBD5 siRNA knockdown cells that showed significantly altered expression of additional circadian rhythm signaling pathway genes. Based on the common sleep phenotypes observed in del 2q23.1, SMS, and FXS patients, we explored the possibility that MBD5, RAI1, and FMR1 function in overlapping circadian rhythm pathways. Bioinformatic analysis identified conserved putative E boxes in MBD5 and RAI1, and expression levels of NR1D2 and CRY2 were significantly reduced in patient LCLs. Circadian and mTOR signaling pathways, both associated with sleep disturbance, were altered in both MBD5 and RAI1 knockdown microarray data, overlapping with findings associated with FMR1. These data support phenotypic and molecular overlaps across these syndromes that may be exploited to provide therapeutic intervention for multiple disorders.European Journal of Human Genetics advance online publication, 1 October 2014; doi:10.1038/ejhg.2014.200.

PMID: 25271084 [PubMed - as supplied by publisher]

Mass spectrometry for the study of autism and neurodevelopmental disorders.

October 2, 2014 - 8:42am
Related Articles

Mass spectrometry for the study of autism and neurodevelopmental disorders.

Adv Exp Med Biol. 2014;806:525-44

Authors: Wetie AG, Dekroon RM, Mocanu M, Ryan JP, Darie CC, Woods AG

Abstract
Mass spectrometry (MS) has been increasingly used to study central nervous system disorders, including autism spectrum disorders (ASDs). The first studies of ASD using MS focused on the identification of external toxins, but current research is more directed at understanding endogenous protein changes that occur in ASD (ASD proteomics). This chapter focuses on how MS has been used to study ASDs, with particular focus on proteomic analysis. Other neurodevelopmental disorders have been investigated using this technique, including genetic syndromes associated with autism such as fragile X syndrome and Smith-Lemli-Opitz syndrome.

PMID: 24952201 [PubMed - indexed for MEDLINE]

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