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Glutamate receptor, metabotropic 7 (GRM7) gene variations and susceptibility to autism: A case-control study.

June 18, 2016 - 6:28am

Glutamate receptor, metabotropic 7 (GRM7) gene variations and susceptibility to autism: A case-control study.

Autism Res. 2016 Jun 17;

Authors: Noroozi R, Taheri M, Movafagh A, Mirfakhraie R, Solgi G, Sayad A, Mazdeh M, Darvish H

Abstract
Autism spectrum disorder (ASD) as a synaptopathy is revealed to be pertained to aberrant glutamatergic neurotransmission. Glutamate receptor, metabotropic 7 (GRM7), a receptor coding gene of this pathway, is a new candidate gene for autism. The aim of this study was to examine if there is a relationship between genetic variants rs779867 and rs6782011 of GRM7 with ASD. The present research was designed as a population-based, case-control study including 518 ASD patients versus 472 control individuals. The results showed that the frequency of rs779867 G/G genotype was significantly higher in ASD patients compared to healthy controls (P = 0.0001). Also, the G allele of this SNP was found to be significantly more frequent in the patients than control group (P = 0.0001). Haplotype analysis exhibited significant association of two estimated block of rs6782011/rs779867 in ASD patients versus control group. We found higher significant frequency of GT haplotype and lower frequencies of AT and AC haplotypes in the patients group compared to healthy controls (P = 0.001, P = 0.006, and P = 0.05, respectively). Our study indicated that the rs779867 polymorphism is associated with ASD; thus, results of this study provide supportive evidence of association of the GRM7 gene with ASD. Autism Res 2016. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 27312574 [PubMed - as supplied by publisher]

Biological Psychiatry and Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Adopt Neuroscience-Based Nomenclature.

June 18, 2016 - 6:28am

Biological Psychiatry and Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Adopt Neuroscience-Based Nomenclature.

Biol Psychiatry. 2016 Jul 1;80(1):2-3

Authors: Krystal JH, Abi-Dargham A, Barch DM, Bullmore ET, Carter CS, Geschwind DH, Harrison PJ, Nestler EJ, Stein MB

PMID: 27312230 [PubMed - in process]

Delayed diagnosis in a house of correction: Smith-Magenis syndrome due to a de novo nonsense RAI1 variant.

June 18, 2016 - 6:28am

Delayed diagnosis in a house of correction: Smith-Magenis syndrome due to a de novo nonsense RAI1 variant.

Am J Med Genet A. 2016 Jun 17;

Authors: Yeetong P, Vilboux T, Ciccone C, Boulier K, Schnur RE, Gahl WA, Huizing M, Laje G, Smith AC

Abstract
We report a 25-year-old female confirmed to have Smith-Magenis syndrome (SMS) due to a de novo RAI1 variant. Her past history is significant for developmental and intellectual delay, early and escalating maladaptive behaviors, and features consistent with significant sleep disturbance, the etiology of which was not confirmed for over two decades. The diagnosis of SMS was initially suspected in 1998 (at age 12 years), but that was 5 years before the initial report of RAI1 variants as causative of the SMS phenotype; cytogenetic fluorescence in situ hybridization studies failed to confirm an interstitial deletion of 17p11.2. Re-evaluation for suspected SMS was pursued with RAI1 sequencing analysis in response to urgent parental concerns of escalating behaviors and aggression with subsequent incarceration of the subject for assault of a health professional. Genetic analysis revealed a de novo RAI1 (NM_030665.3) nonsense variant, c.5536C>T; p.Q1846X. This case illustrates the importance of confirming the SMS diagnosis, which is associated with cognitive and functional impairment, as well as significant psychiatric co-morbidities and behavioral problems. The diagnosis was particularly relevant to the legal discussion and determination of her competence to stand trial. As other similar cases may exist, this report will help to increase awareness of the possibility of a very late diagnosis of SMS, with the need for re-evaluation of individuals suspected to have SMS who were initially evaluated prior to the identification of the RAI1 gene. © 2016 Wiley Periodicals, Inc.

PMID: 27311559 [PubMed - as supplied by publisher]

Social behavior in a genetic model of dopamine dysfunction at different neurodevelopmental time points.

June 18, 2016 - 6:28am
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Social behavior in a genetic model of dopamine dysfunction at different neurodevelopmental time points.

Genes Brain Behav. 2015 Sep;14(7):503-15

Authors: Kabitzke PA, Simpson EH, Kandel ER, Balsam PD

Abstract
Impairments in social behavior characterize many neurodevelopmental psychiatric disorders. In fact, the temporal emergence and trajectory of these deficits can define the disorder, specify their treatment and signal their prognosis. The sophistication of mouse models with neurobiological endophenotypes of many aspects of psychiatric diseases has increased in recent years, with the necessity to evaluate social behavior in these models. We adapted an assay for the multimodal characterization of social behavior at different development time points (juvenile, adolescent and adult) in control mice in different social contexts (specifically, different sex pairings). Although social context did not affect social behavior in juvenile mice, it did have an effect on the quantity and type of social interaction as well as ultrasonic vocalizations in both adolescence and adulthood. We compared social development in control mice to a transgenic mouse model of the increase in postsynaptic striatal D2R activity observed in patients with schizophrenia (D2R-OE mice). Genotypic differences in social interactions emerged in adolescence and appeared to become more pronounced in adulthood. That vocalizations emitted from dyads with a D2R-OE subject were negatively correlated with active social behavior while vocalizations from control dyads were positively correlated with both active and passive social behavior also suggest social deficits. These data show that striatal dopamine dysfunction plays an important role in the development of social behavior and mouse models such as the one studied here provide an opportunity for screening potential therapeutics at different developmental time points.

PMID: 26176662 [PubMed - indexed for MEDLINE]

Overlap of autism spectrum disorder and glucose transporter 1 deficiency syndrome associated with a heterozygous deletion at the 1p34.2 region.

June 18, 2016 - 6:28am
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Overlap of autism spectrum disorder and glucose transporter 1 deficiency syndrome associated with a heterozygous deletion at the 1p34.2 region.

J Neurol Sci. 2015 Sep 15;356(1-2):212-4

Authors: Lee MS, Kim YJ, Kim EJ, Lee MJ

PMID: 26117362 [PubMed - indexed for MEDLINE]

Cognitive and Neurobehavioral Profile in Boys With Duchenne Muscular Dystrophy.

June 18, 2016 - 6:28am
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Cognitive and Neurobehavioral Profile in Boys With Duchenne Muscular Dystrophy.

J Child Neurol. 2015 Oct;30(11):1472-82

Authors: Banihani R, Smile S, Yoon G, Dupuis A, Mosleh M, Snider A, McAdam L

Abstract
Duchenne muscular dystrophy is a progressive neuromuscular condition that has a high rate of cognitive and learning disabilities as well as neurobehavioral disorders, some of which have been associated with disruption of dystrophin isoforms. Retrospective cohort of 59 boys investigated the cognitive and neurobehavioral profile of boys with Duchenne muscular dystrophy. Full-scale IQ of < 70 was seen in 27%; learning disability in 44%, intellectual disability in 19%; attention-deficit/hyperactivity disorder in 32%; autism spectrum disorders in 15%; and anxiety in 27%. Mutations affecting Dp260 isoform and 5'untranslated region of Dp140 were observed in 60% with learning disability, 50% intellectual disability, 77% with autism spectrum disorders, and 94% with anxiety. No statistically significant correlation was noted between comorbidities and dystrophin isoforms; however, there is a trend of cumulative loss of dystrophin isoforms with declining full-scale IQ. Enhanced psychology testing to include both cognitive and neurobehavioral disorders is recommended for all individuals with Duchenne muscular dystrophy.

PMID: 25660133 [PubMed - indexed for MEDLINE]

The Altered Promoter Methylation Of Oxytocin Receptor Gene In Autism.

June 17, 2016 - 6:23am

The Altered Promoter Methylation Of Oxytocin Receptor Gene In Autism.

J Neurogenet. 2016 Jun 16;:1-15

Authors: Elagoz Yuksel M, Yuceturk B, Karatas OF, Ozen M, Dogangun B

Abstract
Autism spectrum disorders (ASDs) are one of the life long existing disorders. Abnormal methylation status of gene promoters of oxytonergic system has been implicated as among the etiologic factors of ASDs. We, therefore, investigated the methylation frequency of oxytocin receptor gene (OXTR) promoter from peripheral blood samples of children with autistic features. Our sample includes 66 children in total (22-94 months); 27 children with ASDs according to the DSM-IV-TR and the Childhood Autism Rating Scale and 39 children who don't have any autistic like symptoms as the healthy control group. We investigated the DNA methylation status of OXTR promoter by methylation specific enzymatic digestion of genomic DNA and polymerase chain reaction. A significant relationship has been found between ASDs and healthy controls for the reduction of methylation frequency of the regions MT1 and MT3 of OXTR. We could not find any association in the methylation frequency of MT2 and MT4 regions of OXTR. Although our findings indicate high frequency of OXTR promoter hypomethylation in ASDs, there is need for independent replication of the results in a bigger sample set. We expect that future studies with the inclusion of larger, more homogeneous samples will attempt to disentangle the causes of ASDs.

PMID: 27309964 [PubMed - as supplied by publisher]

Evaluation of polygenic risks for narcolepsy and essential hypersomnia.

June 17, 2016 - 6:23am

Evaluation of polygenic risks for narcolepsy and essential hypersomnia.

J Hum Genet. 2016 Jun 16;

Authors: Yamasaki M, Miyagawa T, Toyoda H, Khor SS, Liu X, Kuwabara H, Kano Y, Shimada T, Sugiyama T, Nishida H, Sugaya N, Tochigi M, Otowa T, Okazaki Y, Kaiya H, Kawamura Y, Miyashita A, Kuwano R, Kasai K, Tanii H, Sasaki T, Honda Y, Honda M, Tokunaga K

Abstract
In humans, narcolepsy is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Essential hypersomnia (EHS) is another type of sleep disorder that is characterized by excessive daytime sleepiness without cataplexy. A human leukocyte antigen (HLA) class II allele, HLA-DQB1*06:02, is a major genetic factor for narcolepsy. Almost all narcoleptic patients are carriers of this HLA allele, while 30-50% of EHS patients and 12% of all healthy individuals in Japan carry this allele. The pathogenesis of narcolepsy and EHS is thought to be partially shared. To evaluate the contribution of common single-nucleotide polymorphisms (SNPs) to narcolepsy onset and to assess the common genetic background of narcolepsy and EHS, we conducted a polygenic analysis that included 393 narcoleptic patients, 38 EHS patients with HLA-DQB1*06:02, 119 EHS patients without HLA-DQB1*06:02 and 1582 healthy individuals. We also included 376 individuals with panic disorder and 213 individuals with autism to confirm whether the results were biased. Polygenic risks in narcolepsy were estimated to explain 58.1% (PHLA-DQB1*06:02=2.30 × 10(-48), Pwhole genome without HLA-DQB1*06:02=6.73 × 10(-2)) including HLA-DQB1*06:02 effects and 1.3% (Pwhole genome without HLA-DQB1*06:02=2.43 × 10(-2)) excluding HLA-DQB1*06:02 effects. The results also indicated that small-effect SNPs contributed to the development of narcolepsy. Reported susceptibility SNPs for narcolepsy in the Japanese population, CPT1B (carnitine palmitoyltransferase 1B), TRA@ (T-cell receptor alpha) and P2RY11 (purinergic receptor P2Y, G-protein coupled, 11), were found to explain 0.8% of narcolepsy onset (Pwhole genome without HLA-DQB1*06:02=9.74 × 10(-2)). EHS patients with HLA-DQB1*06:02 were estimated to have higher shared genetic background to narcoleptic patients than EHS patients without HLA-DQB1*06:02 even when the effects of HLA-DQB1*06:02 were excluded (EHS with HLA-DQB1*06:02: 40.4%, PHLA-DQB1*06:02=7.02 × 10(-)(14), Pwhole genome without HLA-DQB1*06:02=1.34 × 10(-)(1), EHS without HLA-DQB1*06:02: 0.4%, Pwhole genome without HLA-DQB1*06:02=3.06 × 10(-)(1)). Meanwhile, the polygenic risks for narcolepsy could not explain the onset of panic disorder and autism, suggesting that our results were reasonable.Journal of Human Genetics advance online publication, 16 June 2016; doi:10.1038/jhg.2016.65.

PMID: 27305985 [PubMed - as supplied by publisher]

Autism spectrum disorder prevalence and associations with air concentrations of lead, mercury, and arsenic.

June 16, 2016 - 6:22am

Autism spectrum disorder prevalence and associations with air concentrations of lead, mercury, and arsenic.

Environ Monit Assess. 2016 Jul;188(7):407

Authors: Dickerson AS, Rahbar MH, Bakian AV, Bilder DA, Harrington RA, Pettygrove S, Kirby RS, Durkin MS, Han I, Moyé LA, Pearson DA, Wingate MS, Zahorodny WM

Abstract
Lead, mercury, and arsenic are neurotoxicants with known effects on neurodevelopment. Autism spectrum disorder (ASD) is a neurodevelopmental disorder apparent by early childhood. Using data on 4486 children with ASD residing in 2489 census tracts in five sites of the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring (ADDM) Network, we used multi-level negative binomial models to investigate if ambient lead, mercury, and arsenic concentrations, as measured by the US Environmental Protection Agency National-Scale Air Toxics Assessment (EPA-NATA), were associated with ASD prevalence. In unadjusted analyses, ambient metal concentrations were negatively associated with ASD prevalence. After adjusting for confounding factors, tracts with air concentrations of lead in the highest quartile had significantly higher ASD prevalence than tracts with lead concentrations in the lowest quartile (prevalence ratio (PR) = 1.36; 95 '% CI: 1.18, 1.57). In addition, tracts with mercury concentrations above the 75th percentile (>1.7 ng/m(3)) and arsenic concentrations below the 75th percentile (≤0.13 ng/m(3)) had a significantly higher ASD prevalence (adjusted RR = 1.20; 95 % CI: 1.03, 1.40) compared to tracts with arsenic, lead, and mercury concentrations below the 75th percentile. Our results suggest a possible association between ambient lead concentrations and ASD prevalence and demonstrate that exposure to multiple metals may have synergistic effects on ASD prevalence.

PMID: 27301968 [PubMed - in process]

Mouse pups lacking collapsin response mediator protein 4 manifest impaired olfactory function and hyperactivity in the olfactory bulb.

June 16, 2016 - 6:22am
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Mouse pups lacking collapsin response mediator protein 4 manifest impaired olfactory function and hyperactivity in the olfactory bulb.

Eur J Neurosci. 2015 Sep;42(6):2335-45

Authors: Tsutiya A, Nishihara M, Goshima Y, Ohtani-Kaneko R

Abstract
Members of the collapsin response mediator protein (CRMP) family are reported to be involved in the pathogenesis of various neuronal disorders, including schizophrenia and autism. One of them, CRMP4, is reported to participate in aspects of neuronal development, such as axonal guidance and dendritic development. However, no physiological or behavioral phenotypes in Crmp4 knockout (Crmp4-KO) mice have been identified, making it difficult to elucidate the in vivo roles of CRMP4. Focusing on the olfaction process because of the previous study showing strong expression of Crmp4 mRNA in the olfactory bulb (OB) during the early postnatal period, it was aimed to test the hypothesis that Crmp4-KO pups would exhibit abnormal olfaction. Based on measurements of their ultrasonic vocalizations, impaired olfactory ability in Crmp4-KO pups was found. In addition, c-Fos expression, a marker of neuron activity, revealed hyperactivity in the OB of Crmp4-KO pups compared with wild-types following exposure to an odorant. Moreover, the mRNA and protein expression levels of glutamate receptor 1 (GluR1) and 2 (GluR2) were exaggerated in Crmp4-KO pups relative to other excitatory and inhibitory receptors and transporters, raising the possibility that enhanced expression of these excitatory receptors contributes to the hyperactivity phenotype and impairs olfactory ability. This study provides evidence for an animal model for elucidating the roles of CRMP4 in the development of higher brain functions as well as for elucidating the developmental regulatory mechanisms controlling the activity of the neural circuitry.

PMID: 26118640 [PubMed - indexed for MEDLINE]

Duplications of SLC1A3: Associated with ADHD and autism.

June 15, 2016 - 6:20am

Duplications of SLC1A3: Associated with ADHD and autism.

Eur J Med Genet. 2016 Jun 10;

Authors: van Amen-Hellebrekers CJ, Jansen S, Pfundt R, Schuurs-Hoeijmakers JH, Koolen DA, Marcelis CL, de Leeuw N, de Vries BB

Abstract
We report four patients with a similar gain in 5p13.2 encompassing a single gene: SLC1A3. Behavioural problems resembling ADHD and/or autism-like features are observed which is in line with the glial glutamate transporter role of SLC1A3. We consider an association between SLC1A3 and the behavioural problems which can also be considered a contributing factor to behavioural problems in larger duplications overlapping the 5p13 microduplication syndrome region.

PMID: 27296938 [PubMed - as supplied by publisher]

KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome.

June 15, 2016 - 6:20am
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KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome.

Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):751-6

Authors: Tang X, Kim J, Zhou L, Wengert E, Zhang L, Wu Z, Carromeu C, Muotri AR, Marchetto MC, Gage FH, Chen G

Abstract
Rett syndrome is a severe form of autism spectrum disorder, mainly caused by mutations of a single gene methyl CpG binding protein 2 (MeCP2) on the X chromosome. Patients with Rett syndrome exhibit a period of normal development followed by regression of brain function and the emergence of autistic behaviors. However, the mechanism behind the delayed onset of symptoms is largely unknown. Here we demonstrate that neuron-specific K(+)-Cl(-) cotransporter2 (KCC2) is a critical downstream gene target of MeCP2. We found that human neurons differentiated from induced pluripotent stem cells from patients with Rett syndrome showed a significant deficit in KCC2 expression and consequently a delayed GABA functional switch from excitation to inhibition. Interestingly, overexpression of KCC2 in MeCP2-deficient neurons rescued GABA functional deficits, suggesting an important role of KCC2 in Rett syndrome. We further identified that RE1-silencing transcriptional factor, REST, a neuronal gene repressor, mediates the MeCP2 regulation of KCC2. Because KCC2 is a slow onset molecule with expression level reaching maximum later in development, the functional deficit of KCC2 may offer an explanation for the delayed onset of Rett symptoms. Our studies suggest that restoring KCC2 function in Rett neurons may lead to a potential treatment for Rett syndrome.

PMID: 26733678 [PubMed - indexed for MEDLINE]

Increased Cortical Inhibition in Autism-Linked Neuroligin-3R451C Mice Is Due in Part to Loss of Endocannabinoid Signaling.

June 15, 2016 - 6:20am
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Increased Cortical Inhibition in Autism-Linked Neuroligin-3R451C Mice Is Due in Part to Loss of Endocannabinoid Signaling.

PLoS One. 2015;10(10):e0140638

Authors: Speed HE, Masiulis I, Gibson JR, Powell CM

Abstract
A single, maternally inherited, X-linked point mutation leading to an arginine to cysteine substitution at amino acid 451 (R451C) of Neuroligin 3 (NLGN3R451C) is a likely cause of autism in two brothers. Knockin mice expressing the Nlgn3R451C mutation in place of wild-type Nlgn3 demonstrate increased inhibitory synaptic strength in somatosensory cortex, resulting in an excitatory/inhibitory (E/I) imbalance that is potentially relevant for autism-associated behavioral deficits characteristic of these mice. We have replicated the increase in evoked inhibitory postsynaptic currents (eIPSCs) onto layer II/III cortical pyramidal neurons. We also find that increased frequency of spontaneous mIPSCs in Nlgn3R451C mice occurs in the absence of action potential-driven transmission. This suggests the E/I imbalance is due to changes at the synapse level, as opposed to the network level. Next, we use paired whole-cell recordings in an attempt to identify specific interneuron subtypes affected by the Nlgn3R451C mutation. Curiously, we observe no change in the amplitude of cell-to-cell, unitary IPSCs (uIPSCs) from parvalbumin-positive (PV) or somatostatin-positive (SOM) interneurons onto pyramidal neurons. We also observe no change in the number or density of PV and SOM interneurons in LII/III of somatosensory cortex. This effectively rules out a role for these particular interneurons in the increased inhibitory synaptic transmission, pointing to perhaps alternative interneuron subtypes. Lastly, impaired endocannabinoid signaling has been implicated in hippocampal synaptic dysfunction in Nlgn3R451C mice, but has not been investigated at cortical synapses. We find that bath application of the CB1 antagonist, AM 251 in WT mice eliminates the Nlgn3R451C increase in eIPSC amplitude and mIPSC frequency, indicating that increased inhibitory transmission in mutant mice is due, at least in part, to a loss of endocannabinoid signaling through CB1 receptors likely acting at interneurons other than PV or SOM.

PMID: 26469287 [PubMed - indexed for MEDLINE]

Comparison of Fecal Microbiota in Children with Autism Spectrum Disorders and Neurotypical Siblings in the Simons Simplex Collection.

June 15, 2016 - 6:20am
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Comparison of Fecal Microbiota in Children with Autism Spectrum Disorders and Neurotypical Siblings in the Simons Simplex Collection.

PLoS One. 2015;10(10):e0137725

Authors: Son JS, Zheng LJ, Rowehl LM, Tian X, Zhang Y, Zhu W, Litcher-Kelly L, Gadow KD, Gathungu G, Robertson CE, Ir D, Frank DN, Li E

Abstract
In order to assess potential associations between autism spectrum disorder (ASD) phenotype, functional GI disorders and fecal microbiota, we recruited simplex families, which had only a single ASD proband and neurotypical (NT) siblings, through the Simons Simplex Community at the Interactive Autism Network (SSC@IAN). Fecal samples and metadata related to functional GI disorders and diet were collected from ASD probands and NT siblings of ASD probands (age 7-14). Functional gastrointestinal disorders (FGID) were assessed using the parent-completed ROME III questionnaire for pediatric FGIDs, and problem behaviors were assessed using the Child Behavior Check List (CBCL). Targeted quantitative polymerase chain reaction (qPCR) assays were conducted on selected taxa implicated in ASD, including Sutterella spp., Bacteroidetes spp. and Prevotella spp. Illumina sequencing of the V1V2 and the V1V3 regions of the bacterial 16S rRNA genes from fecal DNA was performed to an average depth of 208,000 and 107,000 high-quality reads respectively. Twenty-five of 59 ASD children and 13 of 44 NT siblings met ROME III criteria for at least one FGID. Functional constipation was more prevalent in ASD (17 of 59) compared to NT siblings (6 of 44, P = 0.035). The mean CBCL scores in NT siblings with FGID, ASD children with FGID and ASD without FGID were comparably higher (58-62 vs. 44, P < 0.0001) when compared to NT children without FGID. There was no significant difference in macronutrient intake between ASD and NT siblings. There was no significant difference in ASD severity scores between ASD children with and without FGID. No significant difference in diversity or overall microbial composition was detected between ASD children with NT siblings. Exploratory analysis of the 16S rRNA sequencing data, however, identified several low abundance taxa binned at the genus level that were associated with ASD and/or first order ASD*FGID interactions (FDR <0.1).

PMID: 26427004 [PubMed - indexed for MEDLINE]

Genome-Wide Association Study for Autism Spectrum Disorder in Taiwanese Han Population.

June 15, 2016 - 6:20am
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Genome-Wide Association Study for Autism Spectrum Disorder in Taiwanese Han Population.

PLoS One. 2015;10(9):e0138695

Authors: Kuo PH, Chuang LC, Su MH, Chen CH, Chen CH, Wu JY, Yen CJ, Wu YY, Liu SK, Chou MC, Chou WJ, Chiu YN, Tsai WC, Gau SS

Abstract
BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic components. Several recent genome-wide association (GWA) studies in Caucasian samples have reported a number of gene regions and loci correlated with the risk of ASD--albeit with very little consensus across studies.
METHODS: A two-stage GWA study was employed to identify common genetic variants for ASD in the Taiwanese Han population. The discovery stage included 315 patients with ASD and 1,115 healthy controls, using the Affymetrix SNP array 6.0 platform for genotyping. Several gene regions were then selected for fine-mapping and top markers were examined in extended samples. Single marker, haplotype, gene-based, and pathway analyses were conducted for associations.
RESULTS: Seven SNPs had p-values ranging from 3.4~9.9*10-6, but none reached the genome-wide significant level. Five of them were mapped to three known genes (OR2M4, STYK1, and MNT) with significant empirical gene-based p-values in OR2M4 (p = 3.4*10(-5)) and MNT (p = 0.0008). Results of the fine-mapping study showed single-marker associations in the GLIS1 (rs12082358 and rs12080993) and NAALADL2 (rs3914502 and rs2222447) genes, and gene-based associations for the OR2M3-OR2T5 (olfactory receptor genes, p = 0.02), and GLIPR1/KRR1 gene regions (p = 0.015). Pathway analyses revealed important pathways for ASD, such as olfactory and G protein-coupled receptors signaling pathways.
CONCLUSIONS: We reported Taiwanese Han specific susceptibility genes and variants for ASD. However, further replication in other Asian populations is warranted to validate our findings. Investigation in the biological functions of our reported genetic variants might also allow for better understanding on the underlying pathogenesis of autism.

PMID: 26398136 [PubMed - indexed for MEDLINE]

PBAP: a pipeline for file processing and quality control of pedigree data with dense genetic markers.

June 15, 2016 - 6:20am
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PBAP: a pipeline for file processing and quality control of pedigree data with dense genetic markers.

Bioinformatics. 2015 Dec 1;31(23):3790-8

Authors: Nato AQ, Chapman NH, Sohi HK, Nguyen HD, Brkanac Z, Wijsman EM

Abstract
MOTIVATION: Huge genetic datasets with dense marker panels are now common. With the availability of sequence data and recognition of importance of rare variants, smaller studies based on pedigrees are again also common. Pedigree-based samples often start with a dense marker panel, a subset of which may be used for linkage analysis to reduce computational burden and to limit linkage disequilibrium between single-nucleotide polymorphisms (SNPs). Programs attempting to select markers for linkage panels exist but lack flexibility.
RESULTS: We developed a pedigree-based analysis pipeline (PBAP) suite of programs geared towards SNPs and sequence data. PBAP performs quality control, marker selection and file preparation. PBAP sets up files for MORGAN, which can handle analyses for small and large pedigrees, typically human, and results can be used with other programs and for downstream analyses. We evaluate and illustrate its features with two real datasets.
AVAILABILITY AND IMPLEMENTATION: PBAP scripts may be downloaded from http://faculty.washington.edu/wijsman/software.shtml.
CONTACT: wijsman@uw.edu.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 26231429 [PubMed - indexed for MEDLINE]

Behavioral characteristics associated with 19p13.2 microdeletions.

June 15, 2016 - 6:20am
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Behavioral characteristics associated with 19p13.2 microdeletions.

Am J Med Genet A. 2015 Oct;167A(10):2334-43

Authors: Welham A, Barth B, Moss J, Penhallow J, Sheth K, Wilde L, Wynn S, Oliver C

Abstract
A small number of recent papers have described individuals with intellectual disabilities and microdeletions in chromosome band 19p13.2. However, little is known about the behavioral characteristics of individuals with microdeletions in this area. The current study examines behavioral characteristics of a series of 10 participants ranging in age from 2 to 20 years with 19p13.2 microdeletions. Parents/caregivers completed a series of established behavioral measures which have aided the elucidation of the behavioral phenotypes of a number of genetic neurodevelopmental syndromes. All but the youngest two participants (aged 2 and 3 years) were verbal, ambulant, and classified as "partly able" or "able" with regard to self-help skills. Six of eight participants for whom a screening measure for autism spectrum disorders (ASD) could be deployed met criteria for an ASD. Six of the 10 participants had displayed self-injurious behavior in the month prior to assessment, eight had displayed destruction/disruption of property, and eight had shown physically aggressive behaviors. Repetitive behaviors were prevalent in the sample (with all participants displaying at least one repetitive behavior to a clinically relevant level), as were problems with sleep. Low mood was not prevalent in this group, and nor were overactivity or impulsivity. Full determination of a behavioral phenotype for this group would require a larger sample size, distinguishing between genetic subtypes. However, the current data suggest that ASD characteristics, repetitive, and challenging behaviors (such as aggression and self-injury) might be associated with 19p13.2 microdeletions, providing a basis for future investigation.

PMID: 26189583 [PubMed - indexed for MEDLINE]

VoICE: A semi-automated pipeline for standardizing vocal analysis across models.

June 15, 2016 - 6:20am
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VoICE: A semi-automated pipeline for standardizing vocal analysis across models.

Sci Rep. 2015;5:10237

Authors: Burkett ZD, Day NF, Peñagarikano O, Geschwind DH, White SA

Abstract
The study of vocal communication in animal models provides key insight to the neurogenetic basis for speech and communication disorders. Current methods for vocal analysis suffer from a lack of standardization, creating ambiguity in cross-laboratory and cross-species comparisons. Here, we present VoICE (Vocal Inventory Clustering Engine), an approach to grouping vocal elements by creating a high dimensionality dataset through scoring spectral similarity between all vocalizations within a recording session. This dataset is then subjected to hierarchical clustering, generating a dendrogram that is pruned into meaningful vocalization "types" by an automated algorithm. When applied to birdsong, a key model for vocal learning, VoICE captures the known deterioration in acoustic properties that follows deafening, including altered sequencing. In a mammalian neurodevelopmental model, we uncover a reduced vocal repertoire of mice lacking the autism susceptibility gene, Cntnap2. VoICE will be useful to the scientific community as it can standardize vocalization analyses across species and laboratories.

PMID: 26018425 [PubMed - indexed for MEDLINE]

Genetic Mapping in Mice Reveals the Involvement of Pcdh9 in Long-Term Social and Object Recognition and Sensorimotor Development.

June 15, 2016 - 6:20am
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Genetic Mapping in Mice Reveals the Involvement of Pcdh9 in Long-Term Social and Object Recognition and Sensorimotor Development.

Biol Psychiatry. 2015 Oct 1;78(7):485-95

Authors: Bruining H, Matsui A, Oguro-Ando A, Kahn RS, Van't Spijker HM, Akkermans G, Stiedl O, van Engeland H, Koopmans B, van Lith HA, Oppelaar H, Tieland L, Nonkes LJ, Yagi T, Kaneko R, Burbach JP, Yamamoto N, Kas MJ

Abstract
BACKGROUND: Quantitative genetic analysis of basic mouse behaviors is a powerful tool to identify novel genetic phenotypes contributing to neurobehavioral disorders. Here, we analyzed genetic contributions to single-trial, long-term social and nonsocial recognition and subsequently studied the functional impact of an identified candidate gene on behavioral development.
METHODS: Genetic mapping of single-trial social recognition was performed in chromosome substitution strains, a sophisticated tool for detecting quantitative trait loci (QTL) of complex traits. Follow-up occurred by generating and testing knockout (KO) mice of a selected QTL candidate gene. Functional characterization of these mice was performed through behavioral and neurological assessments across developmental stages and analyses of gene expression and brain morphology.
RESULTS: Chromosome substitution strain 14 mapping studies revealed an overlapping QTL related to long-term social and object recognition harboring Pcdh9, a cell-adhesion gene previously associated with autism spectrum disorder. Specific long-term social and object recognition deficits were confirmed in homozygous (KO) Pcdh9-deficient mice, while heterozygous mice only showed long-term social recognition impairment. The recognition deficits in KO mice were not associated with alterations in perception, multi-trial discrimination learning, sociability, behavioral flexibility, or fear memory. Rather, KO mice showed additional impairments in sensorimotor development reflected by early touch-evoked biting, rotarod performance, and sensory gating deficits. This profile emerged with structural changes in deep layers of sensory cortices, where Pcdh9 is selectively expressed.
CONCLUSIONS: This behavior-to-gene study implicates Pcdh9 in cognitive functions required for long-term social and nonsocial recognition. This role is supported by the involvement of Pcdh9 in sensory cortex development and sensorimotor phenotypes.

PMID: 25802080 [PubMed - indexed for MEDLINE]

Executive functioning in autism spectrum disorders: influence of task and sample characteristics and relation to symptom severity.

June 15, 2016 - 6:20am
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Executive functioning in autism spectrum disorders: influence of task and sample characteristics and relation to symptom severity.

Eur Child Adolesc Psychiatry. 2015 Nov;24(11):1399-417

Authors: Van Eylen L, Boets B, Steyaert J, Wagemans J, Noens I

Abstract
Impaired executive functioning (EF) has been proposed to underlie symptoms of autism spectrum disorders (ASD). However, insight in the EF profile of ASD individuals is hampered due to task impurity and inconsistent findings. To elucidate these inconsistencies, we investigated the influence of task and sample characteristics on EF in ASD, with an extended test battery designed to reduce task impurity. Additionally, we studied the relation between EF and ASD symptoms. EF (inhibition, cognitive flexibility, generativity, working memory and planning) was measured in open-ended versus structured assessment situations, while controlling for possible confounding EF and non-EF variables. The performance of 50 individuals with ASD was compared with that of 50 age, gender and IQ matched typically developing (TD) individuals. The effects of group (ASD versus TD), age (children versus adolescents) and gender were examined, as well as the correlation between age, IQ, ASD symptoms and EF. Individuals with ASD showed impairments in all EF domains, but deficits were more pronounced in open-ended compared to structured settings. Group differences did not depend on gender and only occasionally on participants' age. This suggests that inconsistencies between studies largely result from differences in task characteristics and less from differences in the investigated sample features. However, age and IQ strongly correlated with EF, indicating that group differences in these factors should be controlled for when studying EF. Finally, EF correlated with both social and non-social ASD symptoms, but further research is needed to clarify the nature of this relationship.

PMID: 25697266 [PubMed - indexed for MEDLINE]

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