1. Chakrabarti B, Dudbridge F, Kent L, Wheelwright S, Hill-Cawthorne G, Allison C, Banerjee-Basu S, Baron-Cohen S. {{Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and asperger syndrome}}. {Autism Res};2009 (Jul 13)
Genetic studies of autism spectrum conditions (ASC) have mostly focused on the « low functioning » severe clinical subgroup, treating it as a rare disorder. However, ASC is now thought to be relatively common ( approximately 1%), and representing one end of a quasi-normal distribution of autistic traits in the general population. Here we report a study of common genetic variation in candidate genes associated with autistic traits and Asperger syndrome (AS). We tested single nucleotide polymorphisms in 68 candidate genes in three functional groups (sex steroid synthesis/transport, neural connectivity, and social-emotional responsivity) in two experiments. These were (a) an association study of relevant behavioral traits (the Empathy Quotient (EQ), the Autism Spectrum Quotient (AQ)) in a population sample (n=349); and (b) a case-control association study on a sample of people with AS, a « high-functioning » subgroup of ASC (n=174). 27 genes showed a nominally significant association with autistic traits and/or ASC diagnosis. Of these, 19 genes showed nominally significant association with AQ/EQ. In the sex steroid group, this included ESR2 and CYP11B1. In the neural connectivity group, this included HOXA1, NTRK1, and NLGN4X. In the socio-responsivity behavior group, this included MAOB, AVPR1B, and WFS1. Fourteen genes showed nominally significant association with AS. In the sex steroid group, this included CYP17A1 and CYP19A1. In the socio-emotional behavior group, this included OXT. Six genes were nominally associated in both experiments, providing a partial replication. Eleven genes survived family wise error rate (FWER) correction using permutations across both experiments, which is greater than would be expected by chance. CYP11B1 and NTRK1 emerged as significantly associated genes in both experiments, after FWER correction (P<0.05). This is the first candidate-gene association study of AS and of autistic traits. The most promising candidate genes require independent replication and fine mapping.
2. Di Martino A, Shehzad Z, Kelly C, Roy AK, Gee DG, Uddin LQ, Gotimer K, Klein DF, Castellanos FX, Milham MP. {{Relationship Between Cingulo-Insular Functional Connectivity and Autistic Traits in Neurotypical Adults}}. {Am J Psychiatry};2009 (Jul 15)
Objective The Social Responsiveness Scale-Adult Version (SRS-A) measures autistic traits that are continuously distributed in the general population. Based on increased recognition of the dimensional nature of autistic traits, the authors examined the neural correlates of these traits in neurotypical individuals using the SRS-A and established a novel approach to assessing the neural basis of autistic characteristics, attempting to directly relate SRS-A scores to patterns of functional connectivity observed in the pregenual anterior cingulate cortex, a region commonly implicated in social cognition. Method Resting state functional magnetic resonance imaging scans were collected for 25 neurotypical adults. All participants provided SRS-A ratings completed by an informant who had observed them in natural social settings. Whole brain-corrected connectivity analyses were then conducted using SRS-A scores as a covariate of interest. Results Across participants, a significant negative relationship between SRS-A scores and the functional connectivity of the pregenual anterior cingulate cortex with the anterior portion of the mid-insula was found. Specifically, low levels of autistic traits were observed when a substantial portion of the anterior mid-insula showed positive connectivity with the pregenual anterior cingulate cortex. In contrast, elevated levels of autistic traits were associated with negative connectivity between these two regions. Conclusions Resting state functional connectivity of the pregenual anterior cingulate cortex-insula social network was related to autistic traits in neurotypical adults. Application of this approach in samples with autism spectrum disorders is needed to confirm whether this circuit is dimensionally related to the severity of autistic traits in clinical populations.
3. Hah M, Lotspeich LJ, Phillips JM, Torres AD, Cleveland SC, Hallmayer JF. {{Twins with KBG Syndrome and Autism}}. {J Autism Dev Disord};2009 (Jul 14)
4. Halladay AK, Amaral D, Aschner M, Bolivar VJ, Bowman A, Dicicco-Bloom E, Hyman SL, Keller F, Lein P, Pessah I, Restifo L, Threadgill DW. {{Animal Models of Autism Spectrum Disorders: Information for Neurotoxicologists}}. {Neurotoxicology};2009 (Jul 8)
Recent findings derived from large scale datasets and biobanks link multiple genes to autism spectrum disorders. Consequently, novel rodent mutants with deletions, truncations and in some cases, overexpression of these candidate genes have been developed and studied both behaviorally and biologically. At the Annual Neurotoxicology Meeting in Rochester, NY in October of 2008, a symposium of clinicians and basic scientists gathered to present the behavioral features of autism, as well as strategies to model those behavioral features in mice and primates. The aim of the symposium was to provide researchers with up-to -date information on both the genetics of autism and how they are used in differing in vivo and in-vitro animal models as well as to provide a background on the environmental exposures being tested on several animal models. In addition, researchers utilizing complementary approaches, presented on cell culture, in-vitro or more basic models, which target neurobiological mechanisms, including Drosophila. Following the presentation, a panel convened to explore the opportunities and challenges of using model systems to investigate genetic and environment interactions in autism spectrum disorders. The following paper represents a summary of each presentation, as well as the discussion that followed at the end of the symposium.
5. Kumbier E, Domes G, Herpertz-Dahlmann B, Herpertz SC. {{[Autism and autistic disorders : Historical and current aspects.]}}. {Nervenarzt};2009 (Jul 15)Autismus und autistische Storungen : Historische Entwicklung und aktuelle Aspekte.
Since its first use in medical literature the meaning of the term autism has constantly changed. An historical overview indicates that in both adult and child psychiatry autism was first used to refer to a symptom of schizophrenia. Later on the use of the term in child psychiatry took a different independent course, which led to present-day conceptualization of autism, mainly due to the work of Leo Kanner and Hans Asperger. Currently autism and autistic disorders are regarded as severe developmental disorders and, due to their stable nature, have gained considerable attention in adult psychiatry. In order to better understand this development, the path from onset to reception is traced via Kanner and Asperger. In the search for central characteristics of autism, one finds restrictions in social communication and interaction, which can be explained by fundamental deficits in social cognition. These restrictions in social cognition can be considered the central characteristic of autism – one which has been a constant since the phenomenon was first described. Our historical review considers to what extent experimental psychopathological research can deepen our understanding of the disorder.
6. Mattila ML, Jussila K, Kuusikko S, Kielinen M, Linna SL, Ebeling H, Bloigu R, Joskitt L, Pauls D, Moilanen I. {{When does the Autism Spectrum Screening Questionnaire (ASSQ) predict autism spectrum disorders in primary school-aged children?}} {Eur Child Adolesc Psychiatry};2009 (Jul 14)
The aims of this study were, firstly, to study the association between parents’ and teachers’ ratings for the Finnish version of the Autism Spectrum Screening Questionnaire (ASSQ), secondly, to find out whether the original cut-off scores of the ASSQ identify primary school-aged children with Asperger syndrome (AS) or autism by using the Finnish ASSQ, and thirdly, to evaluate the validity of the ASSQ. Parents and/or teachers of higher-functioning (full-scale intelligence quotient >/= 50) 8-year-old total population school children (n = 4,408) and 7-12-year-old outpatients with AS/autism (n = 47) completed the Finnish version of the ASSQ. Agreement between informants was slight. In the whole total population, low positive correlation was found between parents’ and teachers’ ratings, while in the sample of high-scoring children the correlation turned out to be negative. A cut-off of 30 for parents’ and teacher’s summed score and 22 for teachers’ single score is recommended. A valid cut-off for parents’ single score could not been estimated. The clinicians are reminded that the ASSQ is a screening instrument, not a diagnosing instrument. The importance of using both parents’ and teachers’ ratings for screening in clinical settings is underlined.
7. Mitchell SR, Reiss AL, Tatusko DH, Ikuta I, Kazmerski DB, Botti JA, Burnette CP, Kates WR. {{Neuroanatomic Alterations and Social and Communication Deficits in Monozygotic Twins Discordant for Autism Disorder}}. {Am J Psychiatry};2009 (Jul 15)
Objective Investigating neuroanatomic differences in monozygotic twins who are discordant for autism can help unravel the relative contributions of genetics and environment to this pervasive developmental disorder. The authors used magnetic resonance imaging (MRI) to investigate several brain regions of interest in monozygotic twins who varied in degree of phenotypic discordance for narrowly defined autism. Method The subjects were 14 pairs of monozygotic twins between the ages of 5 and 14 years old and 14 singleton age- and gender-matched typically developing comparison subjects. The monozygotic twin group was a cohort of children with narrowly defined autistic deficits and their co-twins who presented with varying levels of autistic deficits. High-resolution MRIs were acquired and volumetric/area measurements obtained for the frontal lobe, amygdala, and hippocampus and subregions of the prefrontal cortex, corpus callosum, and cerebellar vermis. Results No neurovolumetric/area differences were found between twin pairs. Relative to typically developing comparison subjects, dorsolateral prefrontal cortex volumes and anterior areas of the corpus callosum were significantly altered in autistic twins, and volumes of the posterior vermis were altered in both autistic twins and co-twins. Intraclass correlation analysis of brain volumes between children with autism and their co-twins indicated that the degree of within-pair neuroanatomic concordance varied with brain region. In the group of subjects with narrowly defined autism only, dorsolateral prefrontal cortex, amygdala, and posterior vermis volumes were significantly associated with the severity of autism based on scores from the Autism Diagnostic Observation Schedule-Generic. Conclusions These findings support previous research demonstrating alterations in the prefrontal cortex, corpus callosum, and posterior vermis in children with autism and further suggest that alterations are associated with the severity of the autism phenotype. Continued research involving twins who are concordant and discordant for autism is essential to disentangle the genetic and environmental contributions to autism.
8. Schmidt GL, Rey MM, Oram Cardy JE, Roberts TP. {{Absence of M100 source asymmetry in autism associated with language functioning}}. {Neuroreport};2009 (Jul 15);20(11):1037-1041.
Various clinical populations display atypical volume asymmetry of language structures and also the auditory M100 source. Although such atypical volume asymmetries have also been observed in autism, M100 source asymmetries have not yet been investigated. We examined M100 asymmetry in autism and its relationship with language functioning. Evoked neural activity to a 1 kHz tone was recorded using whole-cortex 151-channel magnetoencephalography in three groups of individuals. A single-dipole model identified the M100 generator in auditory cortex in each hemisphere. Healthy adults and control children displayed the expected right-sided M100 anteriority, whereas children with autism showed no such asymmetry. An association was found between language functioning and the degree of asymmetry across the two groups of children, suggesting a possible relationship between functional-structural asymmetry and language ability.
9. Serajee FJ, Huq AH. {{Association of Y Chromosome Haplotypes With Autism}}. {J Child Neurol};2009 (Jul 15)
There is significant male excess in autism. In this study, we investigated a possible Y chromosome effect by haplotype analysis. We investigated 12 single-nucleotide polymorphisms in Y-linked neuroligin 4, transducin beta-like 1, and eukaryotic translation initiation factor 1a genes in 146 autistic participants and 102 control participants of European American origin. The set of 12 single-nucleotide polymorphisms defined 9 Y chromosome haplotypes in autistic and control participants. Although the 2 most frequent haplotypes were equally distributed in the autistic and control participants, some haplotypes were overrepresented or underrepresented in autistic participants. The distribution of haplotypes between the autistic and control groups, as determined by Monte Carlo tests with Clump software, was significantly different (P = .0001 with 100 000 simulations). Our results are suggestive of a Y chromosome effect in autism.
10. Williams JM, Beck TF, Pearson DM, Proud MB, Cheung SW, Scott DA. {{A 1q42 deletion involving DISC1, DISC2, and TSNAX in an autism spectrum disorder}}. {Am J Med Genet A};2009 (Jul 15)
Individuals with autism spectrum disorders have impairments in social, communicative, and behavior development that are often accompanied by abnormalities in cognitive functioning, learning, attention, and sensory processing. In this report, we describe a 3-year-old male child with an autism spectrum disorder who carries a 2 Mb deletion of chromosome 1q42. Array comparative genome hybridization revealed that this deletion involves at least three genes-DISC1, DISC2, and TSNAX-which have been found to be associated with neuropsychiatric disorders and are likely to play key roles in normal CNS development. Further studies revealed that the deletion was inherited from his unaffected mother. This suggests that other genetic and/or environmental factors, some of which may be sex specific, may modify the phenotypic effects of this deletion. While this case provides evidence for the potential role of DISC1, DISC2, and TSNAX in the development of autism spectrum disorders, it is equally clear that caution must be taken when providing families with prognostic information and genetic counseling regarding such deletions. (c) 2009 Wiley-Liss, Inc.
11. Windham GC, Fessel K, Grether JK. {{Autism spectrum disorders in relation to parental occupation in technical fields}}. {Autism Res};2009 (Jul 15)
A previous study reported that fathers of children with autism spectrum disorders (ASD) were more likely to work as engineers, requiring « systemizing skills, » and suggesting a distinct phenotype, but alternatively this may have been related to selection biases. We conducted a population-based study to explore whether fathers, or mothers, of children with ASD are over-represented in fields requiring highly technical skills. Subjects included 284 children with ASD and 659 gender-matched controls, born in 1994 in the San Francisco Bay Area. Parental occupation and industry were abstracted verbatim from birth certificates. Engineering, computer programming, and science were examined as highly technical occupations. To limit bias by parental socio-economic status, we selected a referent group of occupations that seemed professionally similar but of a less technical nature. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated by logistic regression, adjusting for parental age, education, and child race. Mothers of cases were somewhat more likely to work in hi-tech occupations (6.7%) than mothers of controls (4.0%, P=0.07), but little difference was observed among fathers, nor for engineering separately. Compared to parents in other « white collar » occupations, the adjusted OR for highly technical occupations among mothers was 2.5 (95% CI: 1.2-5.3) and among fathers was 1.3 (95% CI: 0.79-2.1), with no evidence of a joint effect observed. Our results regarding maternal occupation in technical fields being associated with ASD in offspring suggest further study to distinguish parental occupation as a phenotypic marker of genetic loading vs. other social or exposure factors.
