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Horizons of psychiatric genetics and epigenetics: where are we and where are we heading?

March 18, 2015 - 6:02am

Horizons of psychiatric genetics and epigenetics: where are we and where are we heading?

Iran J Psychiatry Behav Sci. 2014;8(3):1-10

Authors: Mostafavi Abdolmaleky H

Abstract
Today multinational studies using genome-wide association scan (GWAS) for >1000,000 polymorphisms on >100,000 cases with major psychiatric diseases versus controls, combined with next-generation sequencing have found ~100 genetic polymorphisms associated with schizophrenia (SCZ), bipolar disorder (BD), autism, attention deficit and hyperactivity disorder (ADHD), etc. However, the effect size of each genetic mutation has been generally low (<1%), and altogether could portray a tiny fraction of these mental diseases. Furthermore, none of these polymorphisms was specific to disease phenotypes indicating that they are simply genetic risk factors rather than causal mutations. The lack of identification of the major gene(s) in huge genetic studies increased the tendency for reexamining the roles of environmental factors in psychiatric and other complex diseases. However, this time at cellular/molecular levels mediated by epigenetic mechanisms that are heritable, but reversible while interacting with the environment. Now, gene-specific or whole-genome epigenetic analyses have introduced hundreds of aberrant epigenetic marks in the blood or brain of individuals with psychiatric diseases that include aberrations in DNA methylation, histone modifications and microRNA expression. Interestingly, most of the current psychiatric drugs such as valproate, lithium, antidepressants, antipsychotics and even electroconvulsive therapy (ECT) modulate epigenetic codes. The existing data indicate that, the impacts of environment/nurture, including the uterine milieu and early-life events might be more significant than genetic/nature in most psychiatric diseases. The lack of significant results in large-scale genetic studies led to revise the bolded roles of genetics and now we are at the turning point of genomics for reconsidering environmental factors that through epigenetic mechanisms may impact the brain development/functions causing disease phenotypes.

PMID: 25780369 [PubMed]

Weak association of glyoxalase 1 (GLO1) variants with autism spectrum disorder.

March 18, 2015 - 6:02am
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Weak association of glyoxalase 1 (GLO1) variants with autism spectrum disorder.

Eur Child Adolesc Psychiatry. 2015 Jan;24(1):75-82

Authors: Kovač J, Podkrajšek KT, Lukšič MM, Battelino T

Abstract
The prevalence of the autism spectrum disorder (ASD) was recently estimated to 1 in 88 children by the CDC MMWR. In up to 25 % of the cases, the genetic cause can be identified. Past studies identified increased level of advanced glycation end products (AGE) in the brain samples of ASD patients. The methylglyoxal (MG) is one of the main precursors for AGE formation. Humans developed effective mechanism of the MG metabolism involving two enzymes glyoxalase 1 (GLO1) and hydroxyacylglutathione hydrolase (HAGH). Our aim was to analyse genetic variants of GLO1 and HAGH in population of 143 paediatric participants with ASD. We detected 7 genetic variants in GLO1 and 16 variants in HAGH using high-resolution melting (HRM) analysis. A novel association between variant rs1049346 and ASD [OR (allele C)] = 1.5; 95 % CI = 1.1-2.2 and p < 0.05) was identified, and weak association between ASD and variant rs2736654 [OR (allele A)] = 2.2; 95 % CI = 0.99-4.9; p = 0.045) was confirmed. Additionally, a novel genetic variant (GLO1 c.484G > A, p.Ala161Thr) with predicted potentially damaging effect on the activity of the glyoxalase 1 that may contribute to the aetiology of ASD was identified in one participant with ASD. No association between genetic variants of the HAGH gene and ASD was found. Increased level of MG and, consequently, AGEs can induce oxidative stress, mitochondrial dysfunction and inflammation all of which have been implicated to act in the aetiology of the ASD. Our results indicate potential importance of MG metabolism in ASD. However, these results must be interpreted with caution until a causative relation is demonstrated.

PMID: 24671236 [PubMed - indexed for MEDLINE]

Developmental neuropsychological assessment of 4- to 5-year-old children born following Preimplantation Genetic Diagnosis (PGD): A pilot study.

March 17, 2015 - 8:11am

Developmental neuropsychological assessment of 4- to 5-year-old children born following Preimplantation Genetic Diagnosis (PGD): A pilot study.

Child Neuropsychol. 2015 Mar 16;:1-14

Authors: Sacks GC, Altarescu G, Guedalia J, Varshaver I, Gilboa T, Levy-Lahad E, Eldar-Geva T

Abstract
The purpose of this pilot study was to evaluate developmental neuropsychological profiles of 4- to 5-year-old children born after Preimplantation Genetic Diagnosis (PGD). Twenty-seven participants received a neurological examination and a battery of neuropsychological assessments including Wechsler Preschool & Primary Scale of Intelligence - Third Edition (WPPSI-III; cognitive development), Preschool Language Scale, Fourth Edition (PLS-4; language development), Wide Range Assessment of Visual Motor Abilities (visual motor abilities), Childhood Autism Rating Scales II (a screening test for autistic spectrum disorders), and the Miles ABC Test (ocular dominance). Parental questionnaires included the Behavior Rating Inventory of Executive Function Preschool Version (BRIEF-P; executive function), Child Behavior Checklist (CBCL) and the Carey Temperament Scales Behavioral Style Questionnaire (socioemotional development and temperament), and the Vineland Adaptive Behavior Scales, Interview Edition, Second Edition (general adaptive behavior). Subjects' tests results were compared to each test's norms. Children born after PGD demonstrated scores within the normal or above-normal ranges for all developmental outcomes (mean ± SD): WPPSI-III-VIQ 107.4 ± 14.4 (p = .013), PLS-4-Total 113.2 ± 12.4, p < .001), CBCL-Total 41.1 ± 8.6 (p < .001), BRIEF-P-Global Executive Composite 44.8 ± 9.5 (p = .009). Twelve (44%) of the PGD children had a significant difference between their VIQ and PIQ scores (compared to 27% in the general population). One subject was found to show possible signs of autistic spectrum disorder, although a family history of autism was noted. In conclusion, in this pilot study, children assessed at age 4-5 years and conceived after PGD displayed developmental neuropsychological outcomes within normal limits as compared to their chronologic peers. A larger study is needed to evaluate and follow the neuropsychological development of children born after PGD.

PMID: 25774437 [PubMed - as supplied by publisher]

Rare autism-associated variants implicate syntaxin 1 (STX1 R26Q) phosphorylation and the dopamine transporter (hDAT R51W) in dopamine neurotransmission and behaviors.

March 17, 2015 - 8:11am

Rare autism-associated variants implicate syntaxin 1 (STX1 R26Q) phosphorylation and the dopamine transporter (hDAT R51W) in dopamine neurotransmission and behaviors.

EBioMedicine. 2015 Feb;2(2):135-146

Authors: Cartier E, Hamilton PJ, Belovich AN, Shekar A, Campbell NG, Saunders C, Andreassen TF, Gether U, Veenstra-Vanderweele J, Sutcliffe JS, Ulery-Reynolds PG, Erreger K, Matthies HJ, Galli A

Abstract
BACKGROUND: Syntaxin 1 (STX1) is a presynaptic plasma membrane protein that coordinates synaptic vesicle fusion. STX1 also regulates the function of neurotransmitter transporters, including the dopamine (DA) transporter (DAT). The DAT is a membrane protein that controls DA homeostasis through the high-affinity re-uptake of synaptically released DA.
METHODS: We adopt newly developed animal models and state-of-the-art biophysical techniques to determine the contribution of the identified gene variants to impairments in DA neurotransmission observed in autism spectrum disorder (ASD).
OUTCOMES: Here, we characterize two independent autism-associated variants in the genes that encode STX1 and the DAT. We demonstrate that each variant dramatically alters DAT function. We identify molecular mechanisms that converge to inhibit reverse transport of DA and DA-associated behaviors. These mechanisms involve decreased phosphorylation of STX1 at Ser14 mediated by casein kinase 2 as well as a reduction in STX1/DAT interaction. These findings point to STX1/DAT interactions and STX1 phosphorylation as key regulators of DA homeostasis.
INTERPRETATION: We determine the molecular identity and the impact of these variants with the intent of defining DA dysfunction and associated behaviors as possible complications of ASD.

PMID: 25774383 [PubMed - as supplied by publisher]

Potocki-Lupski syndrome in conjunction with bilateral clubfoot.

March 15, 2015 - 6:21am

Potocki-Lupski syndrome in conjunction with bilateral clubfoot.

J Pediatr Orthop B. 2015 Mar 12;

Authors: Dhanaraj D, Chu A, Pappas JG, Moran E, Lehman WB

Abstract
Potocki-Lupski syndrome (PTLS) is a rare chromosomal microduplication syndrome resulting in multiple congenital abnormalities including developmental delays, autistic features, and certain structural anomalies, with cardiovascular being the most common. The phenotype of this contiguous gene duplication syndrome is quite variable and may include musculoskeletal abnormalities. Given the infrequency and novelty of this disorder, full phenotypic characterization of PTLS has not yet been fully elucidated. We present a case of severe bilateral clubfoot in a patient with PTLS. Diagnosis was made by array-based comparative genomic hybridization and confirmed by fluorescence in-situ hybridization. Because clubfoot was also present in an apparently unaffected brother, the presence of PTLS may have acted as a modifier of the phenotype. This report highlights the complex interaction of chromosomal and familial factors that contribute to musculoskeletal birth defects.

PMID: 25768679 [PubMed - as supplied by publisher]

Hippocampal neuroligin-2 links early-life stress with impaired social recognition and increased aggression in adult mice.

March 15, 2015 - 6:21am

Hippocampal neuroligin-2 links early-life stress with impaired social recognition and increased aggression in adult mice.

Psychoneuroendocrinology. 2015 Feb 26;55:128-143

Authors: Kohl C, Wang XD, Grosse J, Fournier C, Harbich D, Westerholz S, Li JT, Bacq A, Sippel C, Hausch F, Sandi C, Schmidt MV

Abstract
Early-life stress is a key risk factor for the development of neuropsychiatric disorders later in life. Neuronal cell adhesion molecules have been strongly implicated in the pathophysiology of psychiatric disorders and in modulating social behaviors associated with these diseases. Neuroligin-2 is a synaptic cell adhesion molecule, located at the postsynaptic membrane of inhibitory GABAergic synapses, and is involved in synaptic stabilization and maturation. Alterations in neuroligin-2 expression have previously been associated with changes in social behavior linked to psychiatric disorders, including schizophrenia and autism. In this study, we show that early-life stress, induced by limited nesting and bedding material, leads to impaired social recognition and increased aggression in adult mice, accompanied by increased expression levels of hippocampal neuroligin-2. Viral overexpression of hippocampal neuroligin-2 in adulthood mimics early-life stress-induced alterations in social behavior and social cognition. Moreover, viral knockdown of neuroligin-2 in the adult hippocampus attenuates the early-life stress-induced behavioral changes. Our results highlight the importance of neuroligin-2 in mediating early-life stress effects on social behavior and social cognition and its promising role as a novel therapeutic target for neuropsychiatric disorders.

PMID: 25765754 [PubMed - as supplied by publisher]

Replicated linear association between DUF1220 copy number and severity of social impairment in autism.

March 12, 2015 - 6:50am

Replicated linear association between DUF1220 copy number and severity of social impairment in autism.

Hum Genet. 2015 Mar 11;

Authors: Davis JM, Searles Quick VB, Sikela JM

Abstract
Sequences encoding DUF1220 protein domains exhibit an exceptional human-specific increase in copy number and have been associated with several phenotypes related to brain size. Autism is a highly heritable and heterogeneous condition characterized behaviorally by social and communicative impairments, and increased repetitive and stereotyped behavior. Given the accelerated brain growth pattern observed in many individuals with autism, and the association between DUF1220 subtype CON1 copy number and brain size, we previously investigated associations between CON1 copy number and autism-related symptoms. We determined that CON1 copy number increase is associated with increasing severity of all three behavioral features of autism. The present study sought to replicate these findings in an independent population (N = 166). Our results demonstrate a replication of the linear relationship between CON1 copy number and the severity of social impairment in individuals with autism as measured by Autism Diagnostic Interview-Revised Social Diagnostic Score, such that with each additional copy of CON1 Social Diagnostic Score increased 0.24 points (SE = 0.11, p = 0.036). We also identified an analogous trend between CON1 copy number and Communicative Diagnostic Score, but did not replicate the relationship between CON1 copy number and Repetitive Behavior Diagnostic Score. Interestingly, these associations appear to be most pronounced in multiplex children. These results, representing the first replication of a gene dosage relationship with the severity of a primary symptom of autism, lend further support to the possibility that the same protein domain family implicated in the evolutionary expansion of the human brain may also be involved in autism severity.

PMID: 25758905 [PubMed - as supplied by publisher]

Exposure to air pollution from traffic and neurodevelopmental disorders in Swedish twins.

March 12, 2015 - 6:50am
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Exposure to air pollution from traffic and neurodevelopmental disorders in Swedish twins.

Twin Res Hum Genet. 2014 Dec;17(6):553-62

Authors: Gong T, Almqvist C, Bölte S, Lichtenstein P, Anckarsäter H, Lind T, Lundholm C, Pershagen G

Abstract
BACKGROUND: Recent studies have reported associations between air pollution exposure and neurodevelopmental disorders in children, but the role of pre- and postnatal exposure has not been elucidated.
AIM: We aimed to explore the risk for autism spectrum disorders (ASD) and attention-deficit hyperactivity disorder (ADHD) among children in relation to pre- and postnatal exposure to air pollution from road traffic.
METHODS: Parents of 3,426 twins born in Stockholm during 1992-2000 were interviewed, when their children were 9 or 12 years old, for symptoms of neurodevelopmental disorders. Residence time-weighted concentrations of particulate matter with a diameter <10 μm (PM10) and nitrogen oxides (NOx) from road traffic were estimated at participants' addresses during pregnancy, the first year, and the ninth year of life using dispersion modeling, controlling for seasonal variation. Multivariate regression models were used to examine the association between air pollution exposure and neurodevelopmental outcomes, adjusting for potential confounding factors.
RESULTS: No clear or consistent associations were found between air pollution exposure during any of the three time windows and any of the neurodevelopmental outcomes. For example, a 5-95% difference in exposure to NOx during pregnancy was associated with odds ratios (ORs) of 0.92 (95% confidence interval (CI): 0.44-1.96) and 0.90 (95% CI: 0.58-1.40) for ASD and ADHD respectively. A corresponding range in exposure to PM10 during pregnancy was related to ORs of 1.01 (95% CI: 0.52-1.96) and 1.00 (95% CI: 0.68-1.47) for ASD and ADHD.
CONCLUSIONS: Our data do not provide support for an association between pre- or postnatal exposure to air pollution from road traffic and neurodevelopmental disorders in children.

PMID: 25229653 [PubMed - indexed for MEDLINE]

The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment.

March 11, 2015 - 8:33am

The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment.

Nat Commun. 2015;6:6404

Authors: Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, Liu W, Klei L, Lei J, Yin J, Reilly SK, Tebbenkamp AT, Bichsel C, Pletikos M, Sestan N, Roeder K, State MW, Devlin B, Noonan JP

Abstract
Recent studies implicate chromatin modifiers in autism spectrum disorder (ASD) through the identification of recurrent de novo loss of function mutations in affected individuals. ASD risk genes are co-expressed in human midfetal cortex, suggesting that ASD risk genes converge in specific regulatory networks during neurodevelopment. To elucidate such networks, we identify genes targeted by CHD8, a chromodomain helicase strongly associated with ASD, in human midfetal brain, human neural stem cells (hNSCs) and embryonic mouse cortex. CHD8 targets are strongly enriched for other ASD risk genes in both human and mouse neurodevelopment, and converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in dysregulation of ASD risk genes directly targeted by CHD8. Integration of CHD8-binding data into ASD risk models improves detection of risk genes. These results suggest loss of CHD8 contributes to ASD by perturbing an ancient gene regulatory network during human brain development.

PMID: 25752243 [PubMed - in process]

Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors.

March 7, 2015 - 7:55am

Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors.

Front Synaptic Neurosci. 2015;7:3

Authors: Born G, Grayton HM, Langhorst H, Dudanova I, Rohlmann A, Woodward BW, Collier DA, Fernandes C, Missler M

Abstract
Human genetics has identified rare copy number variations and deleterious mutations for all neurexin genes (NRXN1-3) in patients with neurodevelopmental diseases, and electrophysiological recordings in animal brains have shown that Nrxns are important for synaptic transmission. While several mouse models for Nrxn1α inactivation have previously been studied for behavioral changes, very little information is available for other variants. Here, we validate that mice lacking Nrxn2α exhibit behavioral abnormalities, characterized by social interaction deficits and increased anxiety-like behavior, which partially overlap, partially differ from Nrxn1α mutant behaviors. Using patch-clamp recordings in Nrxn2α knockout brains, we observe reduced spontaneous transmitter release at excitatory synapses in the neocortex. We also analyse at this cellular level a novel NRXN2 mouse model that carries a combined deletion of Nrxn2α and Nrxn2β. Electrophysiological analysis of this Nrxn2-mutant mouse shows surprisingly similar defects of excitatory release to Nrxn2α, indicating that the β-variant of Nrxn2 has no strong function in basic transmission at these synapses. Inhibitory transmission as well as synapse densities and ultrastructure remain unchanged in the neocortex of both models. Furthermore, at Nrxn2α and Nrxn2-mutant excitatory synapses we find an altered facilitation and N-methyl-D-aspartate receptor (NMDAR) function because NMDAR-dependent decay time and NMDAR-mediated responses are reduced. As Nrxn can indirectly be linked to NMDAR via neuroligin and PSD-95, the trans-synaptic nature of this complex may help to explain occurrence of presynaptic and postsynaptic effects. Since excitatory/inhibitory imbalances and impairment of NMDAR function are alledged to have a role in autism and schizophrenia, our results support the idea of a related pathomechanism in these disorders.

PMID: 25745399 [PubMed]

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

March 7, 2015 - 7:55am
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DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores.

Hum Genet. 2015 Jan;134(1):67-75

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 - indexed for MEDLINE]

Impairment of translation in neurons as a putative causative factor for autism.

March 7, 2015 - 7:55am
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Impairment of translation in neurons as a putative causative factor for autism.

Biol Direct. 2014;9:16

Authors: Poliakov E, Koonin EV, Rogozin IB

Abstract
BACKGROUND: A dramatic increase in the prevalence of autism and Autistic Spectrum Disorders (ASD) has been observed over the last two decades in USA, Europe and Asia. Given the accumulating data on the possible role of translation in the etiology of ASD, we analyzed potential effects of rare synonymous substitutions associated with ASD on mRNA stability, splicing enhancers and silencers, and codon usage.
PRESENTATION OF THE HYPOTHESIS: We hypothesize that subtle impairment of translation, resulting in dosage imbalance of neuron-specific proteins, contributes to the etiology of ASD synergistically with environmental neurotoxins.
TESTING THE HYPOTHESIS: A statistically significant shift from optimal to suboptimal codons caused by rare synonymous substitutions associated with ASD was detected whereas no effect on other analyzed characteristics of transcripts was identified. This result suggests that the impact of rare codons on the translation of genes involved in neuron development, even if slight in magnitude, could contribute to the pathogenesis of ASD in the presence of an aggressive chemical background. This hypothesis could be tested by further analysis of ASD-associated mutations, direct biochemical characterization of their effects, and assessment of in vivo effects on animal models.
IMPLICATIONS OF THE HYPOTHESIS: It seems likely that the synergistic action of environmental hazards with genetic variations that in themselves have limited or no deleterious effects but are potentiated by the environmental factors is a general principle that underlies the alarming increase in the ASD prevalence.
REVIEWERS: This article was reviewed by Andrey Rzhetsky, Neil R. Smalheiser, and Shamil R. Sunyaev.

PMID: 25011470 [PubMed - indexed for MEDLINE]

Towards a molecular characterization of autism spectrum disorders: an exome sequencing and systems approach.

March 7, 2015 - 7:55am
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Towards a molecular characterization of autism spectrum disorders: an exome sequencing and systems approach.

Transl Psychiatry. 2014;4:e394

Authors: An JY, Cristino AS, Zhao Q, Edson J, Williams SM, Ravine D, Wray J, Marshall VM, Hunt A, Whitehouse AJ, Claudianos C

Abstract
The hypothetical 'AXAS' gene network model that profiles functional patterns of heterogeneous DNA variants overrepresented in autism spectrum disorder (ASD), X-linked intellectual disability, attention deficit and hyperactivity disorder and schizophrenia was used in this current study to analyze whole exome sequencing data from an Australian ASD cohort. An optimized DNA variant filtering pipeline was used to identify loss-of-function DNA variations. Inherited variants from parents with a broader autism phenotype and de novo variants were found to be significantly associated with ASD. Gene ontology analysis revealed that putative rare causal variants cluster in key neurobiological processes and are overrepresented in functions involving neuronal development, signal transduction and synapse development including the neurexin trans-synaptic complex. We also show how a complex gene network model can be used to fine map combinations of inherited and de novo variations in families with ASD that converge in the L1CAM pathway. Our results provide an important step forward in the molecular characterization of ASD with potential for developing a tool to analyze the pathogenesis of individual affected families.

PMID: 24893065 [PubMed - indexed for MEDLINE]

Association of CDH11 with non-syndromic ASD.

March 7, 2015 - 7:55am
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Association of CDH11 with non-syndromic ASD.

Am J Med Genet B Neuropsychiatr Genet. 2014 Jul;165B(5):391-8

Authors: Crepel A, De Wolf V, Brison N, Ceulemans B, Walleghem D, Peuteman G, Lambrechts D, Steyaert J, Noens I, Devriendt K, Peeters H

Abstract
We report a sporadic patient with Autism Spectrum Disorder (ASD), mild intellectual disability and attention deficit hyperactivity disorder (ADHD) with a de novo partial deletion of CADHERIN 11 (CDH11). The deletion is associated with one of the breakpoints of a de novo complex chromosomal rearrangement 46,XY,t(3;16;5)(q29;q22;q15)inv4(p14;q21)ins(4;5)(q21;q14.3q15). Cadherins are cell adhesion molecules involved in synaptic plasticity. Since genetic evidence points towards a role for cadherins in ASD, we studied the possible contribution of CDH11 to ASD. A case-control association study for 14 SNP variants in 519 ASD cases and 1,192 controls showed significant overrepresentation of rs7187376C/C genotypes in the patient group [P = 0.0049 (Chi-square = 7.90 1 df) and O.R. 3.88 C.I. = 1.403-10.733]. There was no association for C/T versus T/T [P = 0.6772 (Chi-square = 0.17 1 df)] nor was there association at the allelic level [P = 0.4373 (Chi-square = 0.6 1 df)]. In addition to the association of common variants in CDH11 with ASD, we studied the possible contribution of rare variants by sequencing CDH11 in 247 patients, and found three novel variants in the coding region of CDH1, of which two variants were unlikely to be causal. Targeted CNV screening in these 247 patients did not reveal copy number variation in CDH11. In conclusion, the data provide evidence for the involvement of CDH11 in ASD which is consistent with the association of other cadherins with ASD and neuropsychiatric diseases.

PMID: 24839052 [PubMed - indexed for MEDLINE]

Grand-paternal age and the development of autism-like symptoms in mice progeny.

March 7, 2015 - 7:55am
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Grand-paternal age and the development of autism-like symptoms in mice progeny.

Transl Psychiatry. 2014;4:e386

Authors: Sampino S, Juszczak GR, Zacchini F, Swiergiel AH, Modlinski JA, Loi P, Ptak GE

Abstract
Advanced paternal age (APA) contributes to the risk of autism spectrum disorders (ASDs) in children. In this study, we used a mouse model to investigate the effects of APA on behavioral features related to autistic syndromes (that is, social deficits, communication impairments and stereotypic/repetitive behaviors). We also examined whether such effects are transmitted across generations. To do this, males aged 15 months (APA) and 4 months (control) were bred with 4-month-old females, and the resulting offspring (F1) and their progeny (F2; conceived by 4-month-old parents) were tested for the presence and severity of ASD-like behaviors. Our results indicate that APA resulted in offspring that displayed distinctive symptoms of ASD. We found that both F1 conceived from old fathers and F2 derived from old grandfathers displayed increased ultrasound vocalization (USV) activity, decreased sociability, increased grooming activity and increased anxiety-like responses. Moreover, such abnormalities were partially transmitted to the second generation of mice, having APA grandfathers. In conclusion, our study suggests that the risk of ASD could develop over generations, consistent with heritable mutations and/or epigenetic alterations associated with APA.

PMID: 24780920 [PubMed - indexed for MEDLINE]

Etiologies underlying sex differences in Autism Spectrum Disorders.

March 7, 2015 - 7:55am
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Etiologies underlying sex differences in Autism Spectrum Disorders.

Front Neuroendocrinol. 2014 Aug;35(3):255-71

Authors: Schaafsma SM, Pfaff DW

Abstract
The male predominance of Autism Spectrum Disorders (ASD) is one of the best-known, and at the same time, one of the least understood characteristics of these disorders. In this paper we review genetic, epigenetic, hormonal, and environmental mechanisms underlying this male preponderance. Sex-specific effects of Y-linked genes (including SRY expression leading to testicular development), balanced and skewed X-inactivation, genes that escape X-inactivation, parent-of-origin allelic imprinting, and the hypothetical heterochromatin sink are reviewed. These mechanisms likely contribute to etiology, instead of being simply causative to ASD. Environments, both internal and external, also play important roles in ASD's etiology. Early exposure to androgenic hormones and early maternal immune activation comprise environmental factors affecting sex-specific susceptibility to ASD. The gene-environment interactions underlying ASD, suggested here, implicate early prenatal stress as being especially detrimental to boys with a vulnerable genotype.

PMID: 24705124 [PubMed - indexed for MEDLINE]

Sex differences in attention Deficit Hyperactivity Disorder: candidate genetic and endocrine mechanisms.

March 7, 2015 - 7:55am
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Sex differences in attention Deficit Hyperactivity Disorder: candidate genetic and endocrine mechanisms.

Front Neuroendocrinol. 2014 Aug;35(3):331-46

Authors: Davies W

Abstract
Attention Deficit Hyperactivity Disorder (ADHD) is a developmental condition characterised by severe inattention, pathological impulsivity and hyperactivity; it is relatively common affecting up to 6% of children, and is associated with a risk of long-term adverse educational and social consequences. Males are considerably more likely to be diagnosed with ADHD than females; the course of the disorder and its associated co-morbidities also appear to be sensitive to sex. Here, I discuss fundamental biological (genetic and endocrine) mechanisms that have been shown to, or could theoretically, contribute towards these sexually dimorphic phenomena. Greater understanding of how and why the sexes differ with respect to ADHD vulnerability should allow us to identify and characterise novel protective and risk factors for the disorder, and should ultimately facilitate improved diagnosis, prognosis and treatment.

PMID: 24680800 [PubMed - indexed for MEDLINE]

The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines.

March 7, 2015 - 7:55am
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The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines.

Transl Psychiatry. 2014;4:e374

Authors: Pathania M, Davenport EC, Muir J, Sheehan DF, López-Doménech G, Kittler JT

Abstract
Copy number variation (CNV) at the 15q11.2 region has been identified as a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the individual roles for genes at this locus in nervous system development, function and connectivity remain poorly understood. Haploinsufficiency of one gene in this region, Cyfip1, may provide a model for 15q11.2 CNV-associated neuropsychiatric phenotypes. Here we show that altering CYFIP1 expression levels in neurons both in vitro and in vivo influences dendritic complexity, spine morphology, spine actin dynamics and synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor lateral diffusion. CYFIP1 is highly enriched at synapses and its overexpression in vitro leads to increased dendritic complexity. Neurons derived from Cyfip1 heterozygous animals on the other hand, possess reduced dendritic complexity, increased mobile F-actin and enhanced GluA2-containing AMPA receptor mobility at synapses. Interestingly, Cyfip1 overexpression or haploinsufficiency increased immature spine number, whereas activity-dependent changes in spine volume were occluded in Cyfip1 haploinsufficient neurons. In vivo, Cyfip1 heterozygous animals exhibited deficits in dendritic complexity as well as an altered ratio of immature-to-mature spines in hippocampal CA1 neurons. In summary, we provide evidence that dysregulation of CYFIP1 expression levels leads to pathological changes in CNS maturation and neuronal connectivity, both of which may contribute to the development of the neurological symptoms seen in ASD and SCZ.

PMID: 24667445 [PubMed - indexed for MEDLINE]

Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study.

March 7, 2015 - 7:55am
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Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study.

Transl Psychiatry. 2014;4:e373

Authors: Maltezos S, Horder J, Coghlan S, Skirrow C, O'Gorman R, Lavender TJ, Mendez MA, Mehta M, Daly E, Xenitidis K, Paliokosta E, Spain D, Pitts M, Asherson P, Lythgoe DJ, Barker GJ, Murphy DG

Abstract
There is increasing evidence that abnormalities in glutamate signalling may contribute to the pathophysiology of attention-deficit hyperactivity disorder (ADHD). Proton magnetic resonance spectroscopy ([1H]MRS) can be used to measure glutamate, and also its metabolite glutamine, in vivo. However, few studies have investigated glutamate in the brain of adults with ADHD naive to stimulant medication. Therefore, we used [1H]MRS to measure the combined signal of glutamate and glutamine (Glu+Gln; abbreviated as Glx) along with other neurometabolites such as creatine (Cr), N-acetylaspartate (NAA) and choline. Data were acquired from three brain regions, including two implicated in ADHD-the basal ganglia (caudate/striatum) and the dorsolateral prefrontal cortex (DLPFC)-and one 'control' region-the medial parietal cortex. We compared 40 adults with ADHD, of whom 24 were naive for ADHD medication, whereas 16 were currently on stimulants, against 20 age, sex and IQ-matched healthy controls. We found that compared with controls, adult ADHD participants had a significantly lower concentration of Glx, Cr and NAA in the basal ganglia and Cr in the DLPFC, after correction for multiple comparisons. There were no differences between stimulant-treated and treatment-naive ADHD participants. In people with untreated ADHD, lower basal ganglia Glx was significantly associated with more severe symptoms of inattention. There were no significant differences in the parietal 'control' region. We suggest that subcortical glutamate and glutamine have a modulatory role in ADHD adults; and that differences in glutamate-glutamine levels are not explained by use of stimulant medication.

PMID: 24643164 [PubMed - indexed for MEDLINE]

Environmental toxicants and autism spectrum disorders: a systematic review.

March 7, 2015 - 7:55am
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Environmental toxicants and autism spectrum disorders: a systematic review.

Transl Psychiatry. 2014;4:e360

Authors: Rossignol DA, Genuis SJ, Frye RE

Abstract
Although the involvement of genetic abnormalities in autism spectrum disorders (ASD) is well-accepted, recent studies point to an equal contribution by environmental factors, particularly environmental toxicants. However, these toxicant-related studies in ASD have not been systematically reviewed to date. Therefore, we compiled publications investigating potential associations between environmental toxicants and ASD and arranged these publications into the following three categories: (a) studies examining estimated toxicant exposures in the environment during the preconceptional, gestational and early childhood periods; (b) studies investigating biomarkers of toxicants; and (c) studies examining potential genetic susceptibilities to toxicants. A literature search of nine electronic scientific databases through November 2013 was performed. In the first category examining ASD risk and estimated toxicant exposures in the environment, the majority of studies (34/37; 92%) reported an association. Most of these studies were retrospective case-control, ecological or prospective cohort studies, although a few had weaker study designs (for example, case reports or series). Toxicants implicated in ASD included pesticides, phthalates, polychlorinated biphenyls (PCBs), solvents, toxic waste sites, air pollutants and heavy metals, with the strongest evidence found for air pollutants and pesticides. Gestational exposure to methylmercury (through fish exposure, one study) and childhood exposure to pollutants in water supplies (two studies) were not found to be associated with ASD risk. In the second category of studies investigating biomarkers of toxicants and ASD, a large number was dedicated to examining heavy metals. Such studies demonstrated mixed findings, with only 19 of 40 (47%) case-control studies reporting higher concentrations of heavy metals in blood, urine, hair, brain or teeth of children with ASD compared with controls. Other biomarker studies reported that solvent, phthalate and pesticide levels were associated with ASD, whereas PCB studies were mixed. Seven studies reported a relationship between autism severity and heavy metal biomarkers, suggesting evidence of a dose-effect relationship. Overall, the evidence linking biomarkers of toxicants with ASD (the second category) was weaker compared with the evidence associating estimated exposures to toxicants in the environment and ASD risk (the first category) because many of the biomarker studies contained small sample sizes and the relationships between biomarkers and ASD were inconsistent across studies. Regarding the third category of studies investigating potential genetic susceptibilities to toxicants, 10 unique studies examined polymorphisms in genes associated with increased susceptibilities to toxicants, with 8 studies reporting that such polymorphisms were more common in ASD individuals (or their mothers, 1 study) compared with controls (one study examined multiple polymorphisms). Genes implicated in these studies included paraoxonase (PON1, three of five studies), glutathione S-transferase (GSTM1 and GSTP1, three of four studies), δ-aminolevulinic acid dehydratase (one study), SLC11A3 (one study) and the metal regulatory transcription factor 1 (one of two studies). Notably, many of the reviewed studies had significant limitations, including lack of replication, limited sample sizes, retrospective design, recall and publication biases, inadequate matching of cases and controls, and the use of nonstandard tools to diagnose ASD. The findings of this review suggest that the etiology of ASD may involve, at least in a subset of children, complex interactions between genetic factors and certain environmental toxicants that may act synergistically or in parallel during critical periods of neurodevelopment, in a manner that increases the likelihood of developing ASD. Because of the limitations of many of the reviewed studies, additional high-quality epidemiological studies concerning environmental toxicants and ASD are warranted to confirm and clarify many of these findings.

PMID: 24518398 [PubMed - indexed for MEDLINE]

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