http://www.molecularautism.com The latest research articles published by Molecular Autism 2011-12-12T00:00:00Z Background: Duplications of chromosome 15q11-q13 account for ~3% of autism cases. Chromosome 15q11-q13 contains imprinted genes necessary for normal mammalian neurodevelopment controlled by a differentially methylated imprinting center (PWS-IC). Maternal duplications of 15q11-q13 (dup15q) occur as both interstitial duplications (int dup(15)) and isodicentric chromosome 15 (idic15). Over-expression of the maternally expressed gene UBE3A is predicted to be the primary cause of the autistic features associated with dup15q. Previous analysis of two post-mortem dup15q frontal cortical samples showed heterogeneity between the two cases, with one showing levels of GABAA receptor genes, UBE3A, and SNRPN in a manner not predicted by copy number or parental imprint. Methods: Postmortem human brain tissue (BA19, extrastriate visual cortex) was obtained from 8 dup15q, 10 idiopathic autism and 21 typical control samples. Quantitative PCR was used to confirm duplication status. Quantitative reverse transcriptase PCR and Western blot analyses were performed to measure 15q11-q13 transcript and protein levels, respectively. Methylation-sensitive high resolution melt curve analysis was performed on brain genomic DNA to identify the maternal:paternal ratio of methylation at PWS-IC. Results: Dup15q brain samples showed a higher level of PWS-IC methylation than control or autism samples, indicating that the duplication of 15q was maternal in origin. UBE3A transcript and protein levels were significantly higher in dup15q than control and autism, as expected, although levels were variable and lower than expected based on copy number in some samples. In contrast, this increase in copy number did not result in consistently increased GABRB3 transcript or protein levels for dup15q samples. Furthermore, SNRPN was expected to be unchanged in expression in dup15q because it is expressed from the single unmethylated paternal allele, yet SNRPN levels were significantly reduced in dup15q samples compared to controls. PWS-IC methylation positively correlated with UBE3A and GABRB3, but negatively correlated with SNRPN levels. Idiopathic autism samples exhibited significantly lower GABRB3 and significantly more variable SNRPN levels compared to controls. Conclusions: While these results show that increased UBE3A/UBE3A is a consistent feature of dup15q syndrome, they also suggest that gene expression within 15q11-q13 is not based entirely on copy number but can be influenced by epigenetic mechanisms in brain. http://www.molecularautism.com/content/2/1/19 Haley Scoles Nora Urraca Samuel Chadwick Lawrence Reiter Janine LaSalle Molecular Autism 2011, null:19 2011-12-12T00:00:00Z doi:10.1186/2040-2392-2-19 /content/figures/2040-2392-2-19-toc.gif Molecular Autism 2040-2392 ${item.volume} 19 2011-12-12T00:00:00Z PDF Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic component. The skewed prevalence toward males and evidence suggestive of linkage to the X chromosome in some studies suggest the presence of X-linked susceptibility genes in people with ASD. Methods: We analyzed genome-wide association study (GWAS) data on the X chromosome in three independent autism GWAS data sets: two family data sets and one case-control data set. We performed meta- and joint analyses on the combined family and case-control data sets. In addition to the meta- and joint analyses, we performed replication analysis by using the two family data sets as a discovery data set and the case-control data set as a validation data set. Results: One SNP, rs17321050, in the transducin β-like 1X-linked (TBL1X) gene [OMIM:300196] showed chromosome-wide significance in the meta-analysis (P value = 4.86 × 10-6) and joint analysis (P value = 4.53 × 10-6) in males. The SNP was also close to the replication threshold of 0.0025 in the discovery data set (P = 5.89 × 10-3) and passed the replication threshold in the validation data set (P = 2.56 × 10-4). Two other SNPs in the same gene in linkage disequilibrium with rs17321050 also showed significance close to the chromosome-wide threshold in the meta-analysis. Conclusions: TBL1X is in the Wnt signaling pathway, which has previously been implicated as having a role in autism. Deletions in the Xp22.2 to Xp22.3 region containing TBL1X and surrounding genes are associated with several genetic syndromes that include intellectual disability and autistic features. Our results, based on meta-analysis, joint analysis and replication analysis, suggest that TBL1X may play a role in ASD risk. http://www.molecularautism.com/content/2/1/18 Ren-Hua Chung Deqiong Ma Kai Wang Dale Hedges James Jaworski John Gilbert Michael Cuccaro Harry Wright Ruth Abramson Ioanna Konidari Patrice Whitehead Gerard Schellenberg Hakon Hakonarson Jonathan Haines Margaret Pericak-Vance Eden Martin Molecular Autism 2011, null:18 2011-11-04T00:00:00Z doi:10.1186/2040-2392-2-18 Novel candidate gene for autism TBL1X, which is part of the Wnt signaling pathway, is identified as a candidate gene for autism spectrum disorder (ASD), in the largest chromosome-wide study of the X chromosome in association with ASD. /content/figures/2040-2392-2-18-toc.gif Molecular Autism 2040-2392 ${item.volume} 18 2011-11-04T00:00:00Z XML Background: The inheritance pattern in most cases of autism is complex. The risk of autism is increased in siblings of children with autism and previous studies have indicated that the level of risk can be further identified by the accumulation of multiple susceptibility single nucleotide polymorphisms (SNPs) allowing for the identification of a higher-risk subgroup among siblings. As a result of the sex difference in the prevalence of autism, we explored the potential for identifying sex-specific autism susceptibility SNPs in siblings of children with autism and the ability to develop a sex-specific risk assessment genetic scoring system. Methods: SNPs were chosen from genes known to be associated with autism. These markers were evaluated using an exploratory sample of 480 families from the Autism Genetic Resource Exchange (AGRE) repository. A reproducibility index (RI) was proposed and calculated in all children with autism and in males and females separately. Differing genetic scoring models were then constructed to develop a sex-specific genetic score model designed to identify individuals with a higher risk of autism. The ability of the genetic scores to identify high-risk children was then evaluated and replicated in an independent sample of 351 affected and 90 unaffected siblings from families with at least 1 child with autism. Results: We identified three risk SNPs that had a high RI in males, two SNPs with a high RI in females, and three SNPs with a high RI in both sexes. Using these results, genetic scoring models for males and females were developed which demonstrated a significant association with autism (P = 2.2 × 10-6 and 1.9 × 10-5, respectively). Conclusions: Our results demonstrate that individual susceptibility associated SNPs for autism may have important differential sex effects. We also show that a sex-specific risk score based on the presence of multiple susceptibility associated SNPs allow for the identification of subgroups of siblings of children with autism who have a significantly higher risk of autism. http://www.molecularautism.com/content/2/1/17 Jerome Carayol Gerard Schellenberg Beth Dombroski Emmanuelle Genin Francis Rousseau Geraldine Dawson Molecular Autism 2011, null:17 2011-10-21T00:00:00Z doi:10.1186/2040-2392-2-17 /content/figures/2040-2392-2-17-toc.gif Molecular Autism 2040-2392 ${item.volume} 17 2011-10-21T00:00:00Z XML Background: The neurobiological basis of autism remains poorly understood. The diagnosis of autism is based solely on behavioural characteristics because there are currently no reliable biological markers. To test whether the anterior pituitary hormones and cortisol could be useful as biological markers for autism, we assessed the basal serum levels of these hormones in subjects with autism and normal controls.FindingsUsing a suspension array system, we determined the serum levels of six anterior pituitary hormones, including adrenocorticotropic hormone and growth hormone, in 32 drug-naive subjects (aged 6 to 18 years, all boys) with autism, and 34 healthy controls matched for age and gender. We also determined cortisol levels in these subjects by enzyme-linked immunosorbent assay. Serum levels of adrenocorticotropic hormone, growth hormone and cortisol were significantly higher in subjects with autism than in controls. In addition, there was a significantly positive correlation between cortisol and adrenocorticotropic hormone levels in autism. Conclusion: Our results suggest that increased basal serum levels of adrenocorticotropic hormone accompanied by increased cortisol and growth hormone may be useful biological markers for autism. http://www.molecularautism.com/content/2/1/16 Keiko Iwata Hideo Matsuzaki Taishi Miyachi Chie Shimmura Shiro Suda Kenji Tsuchiya Kaori Matsumoto Katsuaki Suzuki Yasuhide Iwata Kazuhiko Nakamura Masatsugu Tsujii Toshirou Sugiyama Kohji Sato Norio Mori Molecular Autism 2011, null:16 2011-10-19T00:00:00Z doi:10.1186/2040-2392-2-16 /content/figures/2040-2392-2-16-toc.gif Molecular Autism 2040-2392 ${item.volume} 16 2011-10-19T00:00:00Z XML Background: The brain develops in concert and in coordination with the developing facial tissues, with each influencing the development of the other and sharing genetic signaling pathways. Autism spectrum disorders (ASDs) result from alterations in the embryological brain, suggesting that the development of the faces of children with ASD may result in subtle facial differences compared to typically developing children. In this study, we tested two hypotheses. First, we asked whether children with ASD display a subtle but distinct facial phenotype compared to typically developing children. Second, we sought to determine whether there are subgroups of facial phenotypes within the population of children with ASD that denote biologically discrete subgroups. Methods: The 3dMD cranial System was used to acquire three-dimensional stereophotogrammetric images for our study sample of 8- to 12-year-old boys diagnosed with essential ASD (n = 65) and typically developing boys (n = 41) following approved Institutional Review Board protocols. Three-dimensional coordinates were recorded for 17 facial anthropometric landmarks using the 3dMD Patient software. Statistical comparisons of facial phenotypes were completed using Euclidean Distance Matrix Analysis and Principal Coordinates Analysis. Data representing clinical and behavioral traits were statistically compared among groups by using χ2 tests, Fisher's exact tests, Kolmogorov-Smirnov tests and Student's t-tests where appropriate. Results: First, we found that there are significant differences in facial morphology in boys with ASD compared to typically developing boys. Second, we also found two subgroups of boys with ASD with facial morphology that differed from the majority of the boys with ASD and the typically developing boys. Furthermore, membership in each of these distinct subgroups was correlated with particular clinical and behavioral traits. Conclusions: Boys with ASD display a facial phenotype distinct from that of typically developing boys, which may reflect alterations in the prenatal development of the brain. Subgroups of boys with ASD defined by distinct facial morphologies correlated with clinical and behavioral traits, suggesting potentially different etiologies and genetic differences compared to the larger group of boys with ASD. Further investigations into genes involved in neurodevelopment and craniofacial development of these subgroups will help to elucidate the causes and significance of these subtle facial differences. http://www.molecularautism.com/content/2/1/15 Kristina Aldridge Ian George Kimberly Cole Jordan Austin T Nicole Takahashi Ye Duan Judith Miles Molecular Autism 2011, null:15 2011-10-14T00:00:00Z doi:10.1186/2040-2392-2-15 The face of autism A distinctive facial phenotype in boys with autism, which differs from that of typically developing boys, may reflect alterations in embryologic brain development in children with autism spectrum disorders. /content/figures/2040-2392-2-15-toc.gif Molecular Autism 2040-2392 ${item.volume} 15 2011-10-14T00:00:00Z XML Background: Axon-guidance proteins play a crucial role in brain development. As the dysfunction of axon-guidance signaling is thought to underlie the microstructural abnormalities of the brain in people with autism, we examined the postmortem brains of people with autism to identify any changes in the expression of axon-guidance proteins. Results: The mRNA and protein expression of axon-guidance proteins, including ephrin (EFN)A4, eEFNB3, plexin (PLXN)A4, roundabout 2 (ROBO)2 and ROBO3, were examined in the anterior cingulate cortex and primary motor cortex of autistic brains (n = 8 and n = 7, respectively) and control brains (n = 13 and n = 8, respectively) using real-time reverse-transcriptase PCR (RT-PCR) and western blotting. Real-time RT-PCR revealed that the relative expression levels of EFNB3, PLXNA4A and ROBO2 were significantly lower in the autistic group than in the control group. The protein levels of these three genes were further analyzed by western blotting, which showed that the immunoreactive values for PLXNA4 and ROBO2, but not for EFNB3, were significantly reduced in the ACC of the autistic brains compared with control brains. Conclusions: In this study, we found decreased expression of axon-guidance proteins such as PLXNA4 and ROBO2 in the brains of people with autism, and suggest that dysfunctional axon-guidance protein expression may play an important role in the pathophysiology of autism. http://www.molecularautism.com/content/2/1/14 Shiro Suda Keiko Iwata Chie Shimmura Yosuke Kameno Ayyappan Anitha Ismail Thanseem Kazuhiko Nakamura Hideo Matsuzaki Kenji Tsuchiya Genichi Sugihara Yasuhide Iwata Katsuaki Suzuki Keita Koizumi Haruhiro Higashida Nori Takei Norio Mori Molecular Autism 2011, null:14 2011-08-22T00:00:00Z doi:10.1186/2040-2392-2-14 /content/figures/2040-2392-2-14-toc.gif Molecular Autism 2040-2392 ${item.volume} 14 2011-08-22T00:00:00Z XML Background: Immune anomalies have been documented in individuals with autism spectrum disorders (ASDs) and their family members. It is unknown whether the maternal immune profile during pregnancy is associated with the risk of bearing a child with ASD or other neurodevelopmental disorders. Methods: Using Luminex technology, levels of 17 cytokines and chemokines were measured in banked serum collected from women at 15 to 19 weeks of gestation who gave birth to a child ultimately diagnosed with (1) ASD (n = 84), (2) a developmental delay (DD) but not autism (n = 49) or (3) no known developmental disability (general population (GP); n = 159). ASD and DD risk associated with maternal cytokine and chemokine levels was estimated by using multivariable logistic regression analysis. Results: Elevated concentrations of IFN-γ, IL-4 and IL-5 in midgestation maternal serum were significantly associated with a 50% increased risk of ASD, regardless of ASD onset type and the presence of intellectual disability. By contrast, elevated concentrations of IL-2, IL-4 and IL-6 were significantly associated with an increased risk of DD without autism. Conclusion: The profile of elevated serum IFN-γ, IL-4 and IL-5 was more common in women who gave birth to a child subsequently diagnosed with ASD. An alternative profile of increased IL-2, IL-4 and IL-6 was more common for women who gave birth to a child subsequently diagnosed with DD without autism. Further investigation is needed to characterize the relationship between these divergent maternal immunological phenotypes and to evaluate their effect on neurodevelopment. http://www.molecularautism.com/content/2/1/13 Paula Goines Lisa Croen Daniel Braunschweig Cathleen Yoshida Judith Grether Robin Hansen Martin Kharrazi Paul Ashwood Judy Van de Water Molecular Autism 2011, null:13 2011-08-02T00:00:00Z doi:10.1186/2040-2392-2-13 /content/figures/2040-2392-2-13-toc.gif Molecular Autism 2040-2392 ${item.volume} 13 2011-08-02T00:00:00Z XML The development of robust, non-hypothesis based case/control studies has led to a large push forward towards identifying common genetic variants that contribute to complex traits. However, despite many attempts, the search for common disease-predisposing variants in childhood developmental disorders has largely failed. Recently, a role for rare causal variants and de novo mutations is emerging in the genetic architecture of some of these disorders, particularly those that incur a large degree of selection against the phenotype. In this paper, we examine these data and use classic genetic epidemiological approaches to gain insights into the genetic architecture of ASD. Future studies using next generation sequencing should elucidate the precise role de novo mutations play in disorders traditionally thought to have resulted from polygenic or common disease, common variants inheritance. http://www.molecularautism.com/content/2/1/12 Rob Gillis Guy Rouleau Molecular Autism 2011, null:12 2011-07-08T00:00:00Z doi:10.1186/2040-2392-2-12 /content/figures/2040-2392-2-12-toc.gif Molecular Autism 2040-2392 ${item.volume} 12 2011-07-08T00:00:00Z XML Background: Stimulus-related γ-band oscillations, which may be related to perceptual binding, are reduced in people with autism spectrum disorders (ASD). The purpose of this study was to examine auditory transient and steady-state γ-band findings in first-degree relatives of people with ASD to assess the potential familiality of these findings in ASD. Methods: Magnetoencephalography (MEG) recordings in 21 parents who had a child with an autism spectrum disorder (pASD) and 20 healthy adult control subjects (HC) were obtained. Gamma-band phase locking factor (PLF), and evoked and induced power to 32, 40 and 48 Hz amplitude-modulated sounds were measured for transient and steady-state responses. Participants were also tested on a number of behavioral and cognitive assessments related to the broad autism phenotype (BAP). Results: Reliable group differences were seen primarily for steady-state responses. In the left hemisphere, pASD subjects exhibited lower phase-locked steady-state power in all three conditions. Total γ-band power, including the non-phase-locked component, was also reduced in the pASD group. In addition, pASD subjects had significantly lower PLF than the HC group. Correlations were seen between MEG measures and BAP measures. Conclusions: The reduction in steady-state γ-band responses in the pASD group is consistent with previous results for children with ASD. Steady-state responses may be more sensitive than transient responses to phase-locking errors in ASD. Together with the lower PLF and phase-locked power in first-degree relatives, correlations between γ-band measures and behavioral measures relevant to the BAP highlight the potential of γ-band deficits as a potential new autism endophenotype. http://www.molecularautism.com/content/2/1/11 Donald Rojas Peter Teale Keeran Maharajh Eugene Kronberg Katie Youngpeter Lisa Wilson Alissa Wallace Susan Hepburn Molecular Autism 2011, null:11 2011-07-05T00:00:00Z doi:10.1186/2040-2392-2-11 /content/figures/2040-2392-2-11-toc.gif Molecular Autism 2040-2392 ${item.volume} 11 2011-07-05T00:00:00Z XML Background: From an early age, humans look longer at preferred stimuli and also typically look longer at facial expressions of emotion, particularly happy faces. Atypical gaze patterns towards social stimuli are common in autism spectrum conditions (ASC). However, it is unknown whether gaze fixation patterns have any genetic basis. In this study, we tested whether variations in the cannabinoid receptor 1 (CNR1) gene are associated with gaze duration towards happy faces. This gene was selected because CNR1 is a key component of the endocannabinoid system, which is involved in processing reward, and in our previous functional magnetic resonance imaging (fMRI) study, we found that variations in CNR1 modulate the striatal response to happy (but not disgust) faces. The striatum is involved in guiding gaze to rewarding aspects of a visual scene. We aimed to validate and extend this result in another sample using a different technique (gaze tracking). Methods: A total of 30 volunteers (13 males and 17 females) from the general population observed dynamic emotional expressions on a screen while their eye movements were recorded. They were genotyped for the identical four single-nucleotide polymorphisms (SNPs) in the CNR1 gene tested in our earlier fMRI study. Results: Two SNPs (rs806377 and rs806380) were associated with differential gaze duration for happy (but not disgust) faces. Importantly, the allelic groups associated with a greater striatal response to happy faces in the fMRI study were associated with longer gaze duration at happy faces. Conclusions: These results suggest that CNR1 variations modulate the striatal function that underlies the perception of signals of social reward, such as happy faces. This suggests that CNR1 is a key element in the molecular architecture of perception of certain basic emotions. This may have implications for understanding neurodevelopmental conditions marked by atypical eye contact and facial emotion processing, such as ASC. http://www.molecularautism.com/content/2/1/10 Bhismadev Chakrabarti Simon Baron-Cohen Molecular Autism 2011, null:10 2011-06-29T00:00:00Z doi:10.1186/2040-2392-2-10 Looking at happy faces Variations in the CNR1 gene are associated with how long people look at facial expression of emotion, particularly happy faces; these findings could lead to further understanding of clinical conditions marked by atypical eye contact and facial emotion processing such as autism. /content/figures/2040-2392-2-10-toc.gif Molecular Autism 2040-2392 ${item.volume} 10 2011-06-29T00:00:00Z XML