pubmed: autism and genetics

Subscribe to pubmed: autism and genetics feed pubmed: autism and genetics
NCBI: db=pubmed; Term=autism AND genetics
Updated: 2 hours 46 min ago

Sexual dimorphic effect in the genetic association of monoamine oxidase A (MAOA) markers with autism spectrum disorder.

December 17, 2014 - 8:00am
Related Articles

Sexual dimorphic effect in the genetic association of monoamine oxidase A (MAOA) markers with autism spectrum disorder.

Prog Neuropsychopharmacol Biol Psychiatry. 2014 Apr 3;50:11-20

Authors: Verma D, Chakraborti B, Karmakar A, Bandyopadhyay T, Singh AS, Sinha S, Chatterjee A, Ghosh S, Mohanakumar KP, Mukhopadhyay K, Rajamma U

Abstract
Autism spectrum disorders are heritable and behaviorally-defined neurodevelopmental disorders having skewed sex ratio. Serotonin as modulator of behavior and implication of serotonergic dysfunction in ASD etiology corroborates that serotonergic system genes are potential candidates for autism susceptibility. In the current study X-chromosomal gene, MAOA responsible for degradation of serotonin is investigated for possible association with ASD using population-based approach. Study covers analysis of 8 markers in 421 subjects including cases and ethnically-matched controls from West Bengal. MAOA marker, rs6323 and various haplotypes formed between the markers show significant association with the disorder. Stratification on the basis of sex reveals significant genetic effect of rs6323 with low activity T allele posing higher risk in males, but not in females. Haplotypic association results also show differential effect both in males and females. Contrasting linkage disequilibrium pattern between pair of markers involving rs6323 in male cases and controls further supports the sex-bias in genetic association. Bioinformatic analysis shows presence of Y-encoded SRY transcription factor binding sites in the neighborhood of rs1137070. C allele of rs1137070 causes deletion of GATA-2 binding site and GATA-2 is known to interact with SRY. This is the first study highlighting male-specific effect of rs6323 marker and its haplotypes in ASD etiology and it suggests sexual dimorphic effect of MAOA in this disorder. Overall results of this study identify MAOA as a possible ASD susceptibility locus and the differential genetic effect in males and females might contribute to the sex ratio differences and molecular pathology of the disorder.

PMID: 24291416 [PubMed - indexed for MEDLINE]

Neuron-specific chromatin remodeling: a missing link in epigenetic mechanisms underlying synaptic plasticity, memory, and intellectual disability disorders.

December 17, 2014 - 8:00am
Related Articles

Neuron-specific chromatin remodeling: a missing link in epigenetic mechanisms underlying synaptic plasticity, memory, and intellectual disability disorders.

Neuropharmacology. 2014 May;80:18-27

Authors: Vogel-Ciernia A, Wood MA

Abstract
Long-term memory formation requires the coordinated regulation of gene expression. Until recently nucleosome remodeling, one of the major epigenetic mechanisms for controlling gene expression, had been largely unexplored in the field of neuroscience. Nucleosome remodeling is carried out by chromatin remodeling complexes (CRCs) that interact with DNA and histones to physically alter chromatin structure and ultimately regulate gene expression. Human exome sequencing and gene wide association studies have linked mutations in CRC subunits to intellectual disability disorders, autism spectrum disorder and schizophrenia. However, how mutations in CRC subunits were related to human cognitive disorders was unknown. There appears to be both developmental and adult specific roles for the neuron specific CRC nBAF (neuronal Brg1/hBrm Associated Factor). nBAF regulates gene expression required for dendritic arborization during development, and in the adult, contributes to long-term potentiation, a form of synaptic plasticity, and long-term memory. We propose that the nBAF complex is a novel epigenetic mechanism for regulating transcription required for long-lasting forms of synaptic plasticity and memory processes and that impaired nBAF function may result in human cognitive disorders.

PMID: 24140580 [PubMed - indexed for MEDLINE]

[Oxidative stress, rRNA genes, and antioxidant enzymes in pathogenesis of schizophrenia and autism: modeling and clinical advices].

December 17, 2014 - 8:00am
Related Articles

[Oxidative stress, rRNA genes, and antioxidant enzymes in pathogenesis of schizophrenia and autism: modeling and clinical advices].

Zh Obshch Biol. 2013 Sep-Oct;74(5):340-53

Authors: Porokhovnik LN, Pasekov VP, Egolina NA, Tsvetkova TG, Kosiakova NV, Gorbachevskaia NL, Sukhotina NK, Kozlovskaia GV, Sorokin AB, Korovina NIu, Liapunova NA

Abstract
Ribosomal genes (RG), or genes for rRNA, are represented by multiple tandem repeats in eukaryotic genomes, and just a part of them is transcriptionally active. The quantity of active copies is a stable genome feature which determines the cell's capability for rapid synthesis of proteins, necessary to cope with stress conditions. Low number of active RG copies leads to reduced stress resistance and elevated risk of multifactorial disorders (MFD). Oxidative stress (OS) in the brain cells is believed to be involved in the pathogenesis of infantile autism (IA) and schizophrenia, i.e., MFDs with a manifested genetic predisposition. With autism, OS markers are found almost in every research, whilst with schizophrenia, the OS data are contradictory. Earlier, in a sample of patients with schizophrenia, we have found significantly higher quantity of active RG copies than at the average in healthy population. Here we have estimated the number of active RG copies in a sample of patients with IA (n = 51) and revealed significantly lower mean value than in healthy population. A novel mathematical model of the dynamic pattern of OS has been proposed. The model is realized as an ordinary differential equation system, supposing induction of antioxidant protection enzymes being mediated by reactive oxygen species (ROS), with the subsequent decrease of ROS content in a cell. The rate of synthesis of antioxidant protection enzymes is limited by the ribosome synthesis rate which depends on the number of active RG copies. Analysis of the model showed that the system always approaches a single stable equilibrium point along a damped oscillation trajectory, which in some degree resembles the dynamics of 'predator-prey' interaction in Lotka-Volterra model. The stationary ROS level inversely depends on the number of active RG copies. Our study explains the inconsistency of clinical data of OS in schizophrenia and suggests a novel criterion for discriminative cytogenetic diagnostics of schizophrenia and IA, as well as allows to assume that antioxidant therapy should be effective only for children with low number of active RG copies.

PMID: 25438566 [PubMed - indexed for MEDLINE]

Beta-propeller protein-associated neurodegeneration (BPAN), a rare form of NBIA: novel mutations and neuropsychiatric phenotype in three adult patients.

December 15, 2014 - 3:19pm
Related Articles

Beta-propeller protein-associated neurodegeneration (BPAN), a rare form of NBIA: novel mutations and neuropsychiatric phenotype in three adult patients.

Parkinsonism Relat Disord. 2014 Mar;20(3):332-6

Authors: Verhoeven WM, Egger JI, Koolen DA, Yntema H, Olgiati S, Breedveld GJ, Bonifati V, van de Warrenburg BP

Abstract
Neurodegeneration with brain iron accumulation (NBIA) comprises a group of rare neuropsychiatric syndromes characterized by iron accumulation in the basal ganglia. The pantothenate kinase-associated neurodegeneration (PKAN) was the first NBIA form to be genetically identified almost 15 years ago. Nowadays, eight types can be genetically distinguished. More recently, a novel NBIA was delineated and termed Static Encephalopathy of childhood with Neurodegeneration in Adulthood (SENDA), characterized by early intellectual disability followed by delayed progressive motor and cognitive deterioration with an onset in the second to third decade. Very recently, mutations in the WD repeat-containing protein 45 (WDR45) gene located on Xp11.23 were shown to be the causal factor. The protein encoded by WDR45 propels protein interaction important for autophagy. This form was therefore retermed Beta-propeller Protein Associated Neurodegeneration (BPAN). Here, the first three Dutch patients with genetically proven BPAN are comprehensively described with respect to course and neurological as well as neuropsychiatric phenotypes. All three showed a characteristic delayed progression of neurological symptoms with parkinsonism and prominent dystonia. Treatment with levodopa/carbidopa had limited effects only. Neuropsychiatric symptoms within the autistic and affective spectrum were present in the early phase of the disease. The specific course and prognosis should implicate restrained psychopharmacological interventions. The clinical picture and imaging hallmarks are often highly suggestive and should lead to suspect this specific disorder. However, the identification of a WDR45 mutation is needed for a definite diagnosis of BPAN.

PMID: 24368176 [PubMed - indexed for MEDLINE]

Reviewing the ketamine model for schizophrenia.

December 15, 2014 - 3:19pm
Related Articles

Reviewing the ketamine model for schizophrenia.

J Psychopharmacol. 2014 Apr;28(4):287-302

Authors: Frohlich J, Van Horn JD

Abstract
The observation that antagonists of the N-methyl-D-aspartate receptor (NMDAR), such as phencyclidine (PCP) and ketamine, transiently induce symptoms of acute schizophrenia had led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. The glutamate hypothesis can explain negative and cognitive symptoms of schizophrenia better than the dopamine hypothesis, and has the potential to explain dopamine dysfunction itself. The pharmacological and psychomimetic effects of ketamine, which is safer for human subjects than phencyclidine, are herein reviewed. Ketamine binds to a variety of receptors, but principally acts at the NMDAR, and convergent genetic and molecular evidence point to NMDAR hypofunction in schizophrenia. Furthermore, NMDAR hypofunction can explain connectional and oscillatory abnormalities in schizophrenia in terms of both weakened excitation of inhibitory γ-aminobutyric acidergic (GABAergic) interneurons that synchronize cortical networks and disinhibition of principal cells. Individuals with prenatal NMDAR aberrations might experience the onset of schizophrenia towards the completion of synaptic pruning in adolescence, when network connectivity drops below a critical value. We conclude that ketamine challenge is useful for studying the positive, negative, and cognitive symptoms, dopaminergic and GABAergic dysfunction, age of onset, functional dysconnectivity, and abnormal cortical oscillations observed in acute schizophrenia.

PMID: 24257811 [PubMed - indexed for MEDLINE]

Correct developmental expression level of Rai1 in forebrain neurons is required for control of body weight, activity levels and learning and memory.

December 15, 2014 - 3:19pm
Related Articles

Correct developmental expression level of Rai1 in forebrain neurons is required for control of body weight, activity levels and learning and memory.

Hum Mol Genet. 2014 Apr 1;23(7):1771-82

Authors: Cao L, Molina J, Abad C, Carmona-Mora P, Cárdenas Oyarzo A, Young JI, Walz K

Abstract
Potocki-Lupski syndrome (PTLS) is a genomic disorder associated with an ∼3 Mb duplication in 17p11.2. Clinical features include leanness, intellectual disability, autistic features and developmental deficits. RAI1 gene dosage is associated with the PTLS phenotypes. To understand where and when Rai1 overexpression is detrimental, we generated a mouse that over-expresses Rai1 conditionally in forebrain neurons (I-Rai1). Phenotypic characterization of I-Rai1 mice showed significant underweight, hyperactivity and impaired learning and memory ability compared with wild-type littermates. Doxycycline administration can turn off the transgene expression allowing the restoration of Rai1 normal expression levels. When the transgene was turned off from conception to 3 months of age, no phenotypic differences were observed between I-Rai1 and their wild-type littermates. Surprisingly, we found that turning off the transgene expression before the onset of the phenotypes (1-3 months) or after the onset of the phenotypes (3-5 months) cannot prevent nor reverse the phenotypic outcomes. Our results indicate that Rai1 dosage in forebrain neurons is critical during the development and is related to body weight regulation, activity levels and learning and memory.

PMID: 24218365 [PubMed - indexed for MEDLINE]

Stimulation of 5-HT2C receptors improves cognitive deficits induced by human tryptophan hydroxylase 2 loss of function mutation.

December 15, 2014 - 3:19pm
Related Articles

Stimulation of 5-HT2C receptors improves cognitive deficits induced by human tryptophan hydroxylase 2 loss of function mutation.

Neuropsychopharmacology. 2014 Apr;39(5):1125-34

Authors: Del'Guidice T, Lemay F, Lemasson M, Levasseur-Moreau J, Manta S, Etievant A, Escoffier G, Doré FY, Roman FS, Beaulieu JM

Abstract
Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. However, little is known about the impact of Tph2 gene variants on cognition. Mice expressing a human TPH2 variant (Tph2-KI) were used to investigate cognitive consequences of TPH2 loss of function and pharmacological treatments. We applied a recently developed behavioral assay, the automated H-maze, to study cognitive functions in Tph2-KI mice. This assay involves the consecutive discovery of three different rules: a delayed alternation task, a non-alternation task, and a delayed reversal task. Possible contribution of locomotion, reward, and sensory perception were also investigated. The expression of loss-of-function mutant Tph2 in mice was associated with impairments in reversal learning and cognitive flexibility, accompanied by perseverative behaviors similar to those observed in human clinical studies. Pharmacological restoration of 5-HT synthesis with 5-hydroxytryptophan or treatment with the 5-HT(2C) receptor agonist CP809.101 reduced cognitive deficits in Tph2-KI mice and abolished perseveration. In contrast, treatment with the psychostimulant methylphenidate exacerbated cognitive deficits in mutant mice. Results from this study suggest a contribution of TPH2 in the regulation of cognition. Furthermore, identification of a role for a 5-HT(2) receptor agonist as a cognition-enhancing agent in mutant mice suggests a potential avenue to explore for the personalized treatment of cognitive symptoms in humans with reduced 5-HT synthesis and TPH2 polymorphisms.

PMID: 24196946 [PubMed - indexed for MEDLINE]

22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan-McDermid syndrome.

December 15, 2014 - 3:19pm
Related Articles

22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan-McDermid syndrome.

Genet Med. 2014 Apr;16(4):318-28

Authors: Sarasua SM, Dwivedi A, Boccuto L, Chen CF, Sharp JL, Rollins JD, Collins JS, Rogers RC, Phelan K, DuPont BR

Abstract
PURPOSE: Phelan-McDermid syndrome is a developmental disability syndrome with varying deletions of 22q13 and varying clinical severity. We tested the hypothesis that, in addition to loss of the telomeric gene SHANK3, specific genomic regions within 22q13 are associated with important clinical features.
METHODS: We used a customized oligo array comparative genomic hybridization of 22q12.3-terminus to obtain deletion breakpoints in a cohort of 70 patients with terminal 22q13 deletions. We used association and receiver operating characteristic statistical methods in a novel manner and also incorporated protein interaction networks to identify 22q13 genomic locations and genes associated with clinical features.
RESULTS: Specific genomic regions and candidate genes within 22q13.2q13.32 were associated with severity of speech/language delay, neonatal hypotonia, delayed age at walking, hair-pulling behaviors, male genital anomalies, dysplastic toenails, large/fleshy hands, macrocephaly, short and tall stature, facial asymmetry, and atypical reflexes. We also found regions suggestive of a negative association with autism spectrum disorders.
CONCLUSION: This work advances the field of research beyond the observation of a correlation between deletion size and phenotype and identifies candidate 22q13 loci, and in some cases specific genes, associated with singular clinical features observed in Phelan-McDermid syndrome. Our statistical approach may be useful in genotype-phenotype analyses for other microdeletion or microduplication syndromes.

PMID: 24136618 [PubMed - indexed for MEDLINE]

Autoantibodies against neuronal progenitors in sera from children with autism.

December 15, 2014 - 3:19pm
Related Articles

Autoantibodies against neuronal progenitors in sera from children with autism.

Brain Dev. 2014 Apr;36(4):322-9

Authors: Mazur-Kolecka B, Cohen IL, Gonzalez M, Jenkins EC, Kaczmarski W, Brown WT, Flory M, Frackowiak J

Abstract
The pathological role of autoantibodies in development of CNS disorders is a new idea with growing interest among neuroscientists. The involvement of autoimmune response in the pathogenesis of autism spectrum disorders (ASD) has been suggested by the presence of multiple brain-specific autoantibodies in children with ASD and in their mothers. The possibility of the effect of autoimmunity on neurogenesis and postnatal brain plasticity has not been determined. The presence of autoantibodies against human neuronal progenitor cells (NPCs) stimulated for neuronal differentiation in culture was tested in sera from children with autism (n=20) and age-matched controls (n=18) by immunoblotting and immunocytochemistry. Immunoreactivity against multiple NPCs proteins of molecular sizes of approximately 55 kDa, 105 kDa, 150 kDa, and 210 kDa in sera from individuals with autism had a higher incidence and was stronger than in control sera which immunoreacted mainly with a 150 kDa protein. The sera from children with autism immunoreacted the strongest with NPCs expressing neuronal markers Tuj1 and doublecortin, but not astrocyte marker GFAP. The epitopes recognized by antibodies from sera were not human-specific because they detected also NPCs in situ in murine hippocampus. The autoimmune reactions against NPCs suggest an impaired tolerance to neural antigens in autism. These autoantibodies may be symptomatic for autism and furthermore, their presence suggests that autoimmunity may affect postnatal neuronal plasticity particularly after impairment of blood-brain barrier. Future studies will determine the diagnostic value of the presence of autoantibodies in autism and the therapeutic value of prevention of autoimmunity in autism.

PMID: 23838310 [PubMed - indexed for MEDLINE]

Co-morbidity of autism and SLI: kinds, kin and complexity.

December 15, 2014 - 3:19pm
Related Articles

Co-morbidity of autism and SLI: kinds, kin and complexity.

Int J Lang Commun Disord. 2011 Mar-Apr;46(2):127-37

Authors: Tomblin B

Abstract
There has been a long-standing interest in the relationship between specific language impairment (SLI) and autism spectrum disorder (ASD). In the last decade Tager-Flusberg and colleagues have proposed that this relationship consists of a partial overlap between the two. Therefore, among children with ASD there exists a subgroup who have SLI and ASD which has been called 'ALI'. Tager-Flusberg's laboratory has presented several papers showing similar language profiles and brain structure abnormalities in both SLI and ALI. Others (Bishop, Whitehouse, Botting, Williams) have been less convinced that these ALI children have both ASD and SLI. Although they generally agree that the two groups are grossly similar, careful inspection of the data shows that there are differences. I will argue that many of the problems in this debate stem from a view of SLI that represents a particular kind of language learner and therefore a particular and unique profile can be assumed. I argue for recognizing that SLI is not likely to be a unique kind of language learner. Many of the features reported to be characteristic of SLI are also found in other forms of neurodevelopmental disorders. Other features are the outgrowth of studying clinically identified children with SLI and thus the profile appears to reflect biases and practices in the clinical service system. As a result it may be more reasonable to conclude that there is a large group of children with ASD who have poor language skills. The question then remains why are there so many children with ASD who also have poor language? There are several factors that collectively are strong candidates for answers to this question.

PMID: 21401812 [PubMed - indexed for MEDLINE]

A Novel Non-Developmental Role of the SAX-7/L1CAM Cell Adhesion Molecule in Synaptic Regulation in Caenorhabditis elegans.

December 10, 2014 - 7:18am
Related Articles

A Novel Non-Developmental Role of the SAX-7/L1CAM Cell Adhesion Molecule in Synaptic Regulation in Caenorhabditis elegans.

Genetics. 2014 Dec 8;

Authors: Opperman K, Moseley-Alldredge M, Yochem J, Bell L, Kanayinkal T, Chen L

Abstract
The L1CAM family of cell adhesion molecules is a conserved set of single-pass transmembrane proteins that play diverse roles required for proper nervous system development and function. Mutations in L1CAMs can cause the neurological L1 syndrome and are associated with autism and neuropsychiatric disorders. L1CAM expression in the mature nervous system suggests additional functions besides the well-characterized developmental roles. In this study, we demonstrate that the gene encoding the Caenorhabditis elegans L1CAM, sax-7, genetically interacts with gtl-2, as well as with unc-13 and rab-3, genes that function in neurotransmission. These sax-7 genetic interactions result in synthetic phenotypes that are consistent with abnormal synaptic function. Using an inducible sax-7 expression system and pharmacological reagents that interfere with cholinergic transmission, we uncovered a previously uncharacterized non-developmental role for sax-7 that impinges on synaptic function.

PMID: 25488979 [PubMed - as supplied by publisher]

Preeclampsia, Placental Insufficiency, and Autism Spectrum Disorder or Developmental Delay.

December 9, 2014 - 6:59am

Preeclampsia, Placental Insufficiency, and Autism Spectrum Disorder or Developmental Delay.

JAMA Pediatr. 2014 Dec 8;

Authors: Walker CK, Krakowiak P, Baker A, Hansen RL, Ozonoff S, Hertz-Picciotto I

Abstract
Importance: Increasing evidence suggests that autism spectrum disorder (ASD) and many forms of developmental delay (DD) originate during fetal development. Preeclampsia may trigger aberrant neurodevelopment through placental, maternal, and fetal physiologic mechanisms.
Objective: To determine whether preeclampsia is associated with ASD and/or DD.
Design, Setting, and Participants: The Childhood Autism Risks from Genetics and the Environment (CHARGE) study is a population-based, case-control investigation of ASD and/or DD origins. Children from 20 California counties aged 24 to 60 months at the time of recruitment and living in catchment areas with a biological parent fluent in English or Spanish were enrolled from January 29, 2003, through April 7, 2011. Children with ASD (n = 517) and DD (n = 194) were recruited through the California Department of Developmental Services, the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, and referrals. Controls with typical development (TD) (n = 350) were randomly selected from birth records and frequency matched on age, sex, and broad geographic region. Physicians diagnosing preeclampsia were masked to neurodevelopmental outcome, and those assessing neurodevelopmental function were masked to preeclampsia status.
Exposures: Preeclampsia and placental insufficiency were self-reported and abstracted from medical records.
Main Outcomes and Measures: The Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised were used to confirm ASD, whereas children with DD and TD were confirmed by Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales and were free of autistic symptoms. Hypotheses were formulated before data collection.
Results: Children with ASD were twice as likely to have been exposed in utero to preeclampsia as controls with TD after adjustment for maternal educational level, parity, and prepregnancy obesity (adjusted odds ratio, 2.36; 95% CI, 1.18-4.68); risk increased with greater preeclampsia severity (test for trend, P = .02). Placental insufficiency appeared responsible for the increase in DD risk associated with severe preeclampsia (adjusted odds ratio, 5.49; 95% CI, 2.06-14.64).
Conclusions and Relevance: Preeclampsia, particularly severe disease, is associated with ASD and DD. Faulty placentation manifests in the mother as preeclampsia with vascular damage, enhanced systemic inflammation, and insulin resistance; in the placenta as oxygen and nutrient transfer restriction and oxidative stress; and in the fetus as growth restriction and progressive hypoxemia. All are potential mechanisms for neurodevelopmental compromise.

PMID: 25485869 [PubMed - as supplied by publisher]

Leveraging genetics and genomics to define the causes of mental illness.

December 9, 2014 - 6:59am
Related Articles

Leveraging genetics and genomics to define the causes of mental illness.

Biol Psychiatry. 2015 Jan 1;77(1):3-5

Authors: State MW, Geschwind DH

PMID: 25483342 [PubMed - in process]

Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eosinophilic Esophagitis.

December 6, 2014 - 6:07am

Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eosinophilic Esophagitis.

Front Genet. 2014;5:401

Authors: Namjou B, Marsolo K, Caroll RJ, Denny JC, Ritchie MD, Verma SS, Lingren T, Porollo A, Cobb BL, Perry C, Kottyan LC, Rothenberg ME, Thompson SD, Holm IA, Kohane IS, Harley JB

Abstract
Objective: We report the first pediatric specific Phenome-Wide Association Study (PheWAS) using electronic medical records (EMRs). Given the early success of PheWAS in adult populations, we investigated the feasibility of this approach in pediatric cohorts in which associations between a previously known genetic variant and a wide range of clinical or physiological traits were evaluated. Although computationally intensive, this approach has potential to reveal disease mechanistic relationships between a variant and a network of phenotypes. Method: Data on 5049 samples of European ancestry were obtained from the EMRs of two large academic centers in five different genotyped cohorts. Recently, these samples have undergone whole genome imputation. After standard quality controls, removing missing data and outliers based on principal components analyses (PCA), 4268 samples were used for the PheWAS study. We scanned for associations between 2476 single-nucleotide polymorphisms (SNP) with available genotyping data from previously published GWAS studies and 539 EMR-derived phenotypes. The false discovery rate was calculated and, for any new PheWAS findings, a permutation approach (with up to 1,000,000 trials) was implemented. Results: This PheWAS found a variety of common variants (MAF > 10%) with prior GWAS associations in our pediatric cohorts including Juvenile Rheumatoid Arthritis (JRA), Asthma, Autism and Pervasive Developmental Disorder (PDD) and Type 1 Diabetes with a false discovery rate < 0.05 and power of study above 80%. In addition, several new PheWAS findings were identified including a cluster of association near the NDFIP1 gene for mental retardation (best SNP rs10057309, p = 4.33 × 10(-7), OR = 1.70, 95%CI = 1.38 - 2.09); association near PLCL1 gene for developmental delays and speech disorder [best SNP rs1595825, p = 1.13 × 10(-8), OR = 0.65(0.57 - 0.76)]; a cluster of associations in the IL5-IL13 region with Eosinophilic Esophagitis (EoE) [best at rs12653750, p = 3.03 × 10(-9), OR = 1.73 95%CI = (1.44 - 2.07)], previously implicated in asthma, allergy, and eosinophilia; and association of variants in GCKR and JAZF1 with allergic rhinitis in our pediatric cohorts [best SNP rs780093, p = 2.18 × 10(-5), OR = 1.39, 95%CI = (1.19 - 1.61)], previously demonstrated in metabolic disease and diabetes in adults. Conclusion: The PheWAS approach with re-mapping ICD-9 structured codes for our European-origin pediatric cohorts, as with the previous adult studies, finds many previously reported associations as well as presents the discovery of associations with potentially important clinical implications.

PMID: 25477900 [PubMed - as supplied by publisher]

Genetics studies indicate that neural induction and early neuronal maturation are disturbed in autism.

December 6, 2014 - 6:07am

Genetics studies indicate that neural induction and early neuronal maturation are disturbed in autism.

Front Cell Neurosci. 2014;8:397

Authors: Casanova EL, Casanova MF

Abstract
Postmortem neuropathological studies of autism consistently reveal distinctive types of malformations, including cortical dysplasias, heterotopias, and various neuronomorphometric abnormalities. In keeping with these observations, we review here that 88% of high-risk genes for autism influence neural induction and early maturation of the neuroblast. In addition, 80% of these same genes influence later stages of differentiation, including neurite and synapse development, suggesting that these gene products exhibit long-lasting developmental effects on cell development as well as elements of redundancy in processes of neural proliferation, growth, and maturation. We also address the putative genetic overlap of autism with conditions like epilepsy and schizophrenia, with implications to shared and divergent etiologies. This review imports the necessity of a frameshift in our understanding of the neurodevelopmental basis of autism to include all stages of neuronal maturation, ranging from neural induction to synaptogenesis.

PMID: 25477785 [PubMed - as supplied by publisher]

Novel Interactive Partners of Neuroligin 3: New Aspects for Pathogenesis of Autism.

December 4, 2014 - 8:48am

Novel Interactive Partners of Neuroligin 3: New Aspects for Pathogenesis of Autism.

J Mol Neurosci. 2014 Dec 3;

Authors: Shen C, Huo LR, Zhao XL, Wang PR, Zhong N

Abstract
Autism is a neurodevelopmental disorder with a strong genetic predisposition. Neurolign 3 (NLGN3) as a postsynaptic transmembrane protein, functions in both neuron synaptogenesis and glia-neuron communications. Previously, a gain of function mutation (R451C) in NLGN3 was identified in autistic patients, which illustrates the involvement of NLGN3 in autism pathogenesis. As proper synaptic targeting and functioning are controlled by intracellular protein interactions, in the current study, we tried to discover the intracellular regulation network in which NLGN3 might be involved by a yeast two-hybrid-based interactor identification. Fifty-one protein candidate partners were identified after screening a human fetal complementary DNA (cDNA) library with an intracellular fragment of NLGN3. The interactions of NLGN3 with a subset of candidates, including EEF1A1, FLNA, ITPRIP, CYP11A1, MT-CO2, GPR175, ACOT2, and QPRT, were further validated in human neuroblastoma cells or brain tissues. Furthermore, our study suggested that NLGN3 was functioning in cytosolic calcium balance and participating in calcium-regulated cellular processes. Our findings of novel NLGN3 binding partners provide evidences of involvement of NLGN3 in multiple biological pathways, especially calcium regulating and mitochondrial function, thus suggesting further significance. This new data not only leads to a better understanding of the physiological functions of NLGN3, but also provide new aspects for pathogenesis of autism.

PMID: 25464930 [PubMed - as supplied by publisher]

Autism spectrum disorders: from genes to neurobiology.

December 3, 2014 - 8:29am

Autism spectrum disorders: from genes to neurobiology.

Curr Opin Neurobiol. 2014 Nov 27;30C:92-99

Authors: Jeremy Willsey A, State MW

Abstract
Advances in genome-wide technology, coupled with the availability of large cohorts, are finally yielding a steady stream of autism spectrum disorder (ASD) genes carrying mutations of large effect. These findings represent important molecular clues, but at the same time present notable challenges to traditional strategies for moving from genes to neurobiology. A remarkable degree of genetic heterogeneity, the biological pleiotropy of ASD genes, and the tremendous complexity of the human brain are prompting the development of new strategies for translating genetic discoveries into therapeutic targets. Recent developments in systems biology approaches that 'contextualize' these genetic findings along spatial, temporal, and cellular axes of human brain development are beginning to bridge the gap between high-throughput gene discovery and testable pathophysiological hypotheses.

PMID: 25464374 [PubMed - as supplied by publisher]

21q21 deletion involving NCAM2: Report of 3 cases with neurodevelopmental disorders.

December 3, 2014 - 8:29am

21q21 deletion involving NCAM2: Report of 3 cases with neurodevelopmental disorders.

Eur J Med Genet. 2014 Nov 20;

Authors: Petit F, Plessis G, Decamp M, Cuisset JM, Blyth M, Pendlebury M, Andrieux J

Abstract
Here we report three patients affected with neurodevelopmental disorders and harboring 21q21 deletions involving NCAM2 gene. NCAM (Neural Cell Adhesion Molecule) proteins are involved in axonal migration, synaptic formation and plasticity. Poor axonal growth and fasciculation is observed in animal models deficient for NCAM2. Moreover, this gene has been proposed as a candidate for autism, based on genome-wide association studies. In this report, we provide a comprehensive molecular and phenotypical characterisation of three deletion cases giving additional clues for the involvement of NCAM2 in neurodevelopment.

PMID: 25464110 [PubMed - as supplied by publisher]

Number of X-chromosome genes influences social behavior and vasopressin gene expression in mice.

December 3, 2014 - 8:29am

Number of X-chromosome genes influences social behavior and vasopressin gene expression in mice.

Psychoneuroendocrinology. 2014 Oct 23;51C:271-281

Authors: Cox KH, Quinnies KM, Eschendroeder A, Didrick PM, Eugster EA, Rissman EF

Abstract
Sex differences in behavior are widespread and often caused by hormonal differences between the sexes. In addition to hormones, the composition and numbers of the sex chromosomes also affect a variety of sex differences. In humans, X-chromosome genes are implicated in neurobehavioral disorders (i.e. fragile-X, autism). To investigate the role of X-chromosome genes in social behavior, we used a mouse model that has atypical sex chromosome configurations resembling Turner (45, XO) and Klinefelter syndromes (47, XXY). We examined a number of behaviors in juvenile mice. Mice with only one copy of most X-chromosome genes, regardless of gonadal sex, were less social in dyadic interaction and social preference tasks. In the elevated plus maze, mice with one X-chromosome spent less time in the distal ends of the open arms as compared to mice with two copies of X-chromosome genes. Using qRTPCR, we noted that amygdala from female mice with one X-chromosome had higher expression levels of vasopressin (Avp) as compared to mice in the other groups. Finally, in plasma from girls with Turner syndrome we detected reduced vasopressin (AVP) concentrations as compared to control patients. These novel findings link sex chromosome genes with social behavior via concentrations of AVP in brain, adding to our understanding of sex differences in neurobehavioral disorders.

PMID: 25462900 [PubMed - as supplied by publisher]

The link between oral contraceptive use and prevalence in autism spectrum disorder.

December 3, 2014 - 8:29am

The link between oral contraceptive use and prevalence in autism spectrum disorder.

Med Hypotheses. 2014 Oct 12;83(6):718-725

Authors: Strifert K

Abstract
Autism spectrum disorder (ASD) is a group of developmental disabilities that include full syndrome autism, Asperger's syndrome, and other pervasive developmental disorders. The identified prevalence of ASD has increased in a short time period across multiple studies causing some to conclude that it has reached epidemic proportions in the U.S. Many possible explanations for the rise in numbers of individuals diagnosed with ASD have been offered and yet, causes and contributing factors for ASD are inadequately understood. Current evidence suggests that both genetics and environment play a part in causing ASD. One possible risk factor for the increase in prevalence has been profoundly overlooked in the existing biomedical and epidemiologic literature. As the prevalence of ASD has risen in the last sixty years, so has the prevalence of the usage of the oral contraceptives and other modern hormonal delivery methods. In 1960 about one million American women were using oral contraceptives, today close to 11million women in the U.S. use oral contraceptives. Eighty-two percent of sexually active women in the U.S. have used oral contraceptives at some point during their reproductive years. Thus, the growth in use of progesterone/estrogen-based contraceptives in the United State has reached near-ubiquitous levels among women in the child-bearing age range. The suppression of ovulation produced by estrogen-progesterone is an indisputable abnormality. It is logical to consider the outcome of the ovum that would have been normally released from the ovary during ovulation. To date there is no comprehensive research into the potential neurodevelopmental effects of oral contraceptive use on progeny. The issue has been only sparsely considered in the biomedical literature. This article hypothesizes that the compounds, estrogen and progesterone, used in oral contraceptives modify the condition of the oocyte and give rise to a potent risk factor that helps explain the recent increase in the prevalence of ASD's. This hypothesis does not propose to delineate the cause of autism. Rather, it attempts to explain the recent dramatic increase in prevalence and point the way for further study that will lead to causal examination.

PMID: 25459142 [PubMed - as supplied by publisher]

Pages