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Contains fulltext : 248865.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions. METHODS: The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6-30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features. RESULTS: In addition to significant between-group differences in "core" ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals' total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission. CONCLUSIONS: The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.

Autism spectrum disorders (ASDs) are phenotypically as well as genetically heterogeneous developmental disorders with a strong heritability. Clinical and basic science research has described many replicated genetic risk factors. Many findings can well be translated into clinical human genetic practice. The current article summarizes results of genetic studies in ASD, provides a diagnostic algorithm for the clinical human genetic work-up reflecting the German health care system options and gives information with regard to the obligatory genetic counselling after a clinical genetic assessment.

The genetic architecture underlying Autism spectrum disorder (ASD) has been suggested to differ between individuals with lower (IQ ≤ 70; LIQ) and higher intellectual abilities (IQ > 70; HIQ). Among the identified pathomechanisms, the glutamatergic signalling pathway is of specific interest in ASD. We investigated 187 common functional variants of this neurotransmitter system for association with ASD and with symptom severity in two independent samples, a German (German-ALL: N = 583 families) and the Autism Genome Project cohort (AGP-ALL: N = 2001 families), split into HIQ, and LIQ subgroups. We did not identify any association withstanding correction for multiple testing. However, we report a replicated nominal significant under-transmission (OR

Common variants contribute significantly to the genetics of autism spectrum disorder (ASD), although the identification of individual risk polymorphisms remains still elusive due to their small effect sizes and limited sample sizes available for association studies. During the last decade several genome-wide association studies (GWAS) have enabled the detection of a few plausible risk variants. The three main studies are family-based and pointed at SEMA5A (rs10513025), MACROD2 (rs4141463) and MSNP1 (rs4307059). In our study we attempted to replicate these GWAS hits using a case-control association study in five European populations of ASD patients and gender-matched controls, all Caucasians. Results showed no association of individual variants with ASD in any of the population groups considered or in the combined European sample. We performed a meta-analysis study across five European populations for rs10513025 (1,904 ASD cases and 2,674 controls), seven European populations for rs4141463 (2,855 ASD cases and 36,177 controls) and five European populations for rs4307059 (2,347 ASD cases and 2,764 controls). The results showed an odds ratio (OR) of 1.05 (95% CI = 0.84-1.32) for rs10513025, 1.0002 (95% CI = 0.93-1.08) for rs4141463 and 1.01 (95% CI = 0.92-1.1) for rs4307059, with no significant P-values (rs10513025, P = 0.73; rs4141463, P = 0.95; rs4307059, P = 0.9). No association was found when we considered either only high functioning autism (HFA), genders separately or only multiplex families. Ongoing GWAS projects with larger ASD cohorts will contribute to clarify the role of common variation in the disorder and will likely identify risk variants of modest effect not detected previously. Autism Res 2017, 10: 202-211. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

EPHB3 is a critical cellular guidance factor in the intestinal epithelium and an important tumor suppressor in colorectal cancer (CRC) whose expression is frequently lost at the adenoma‐carcinoma transition when tumor cells become invasive. The molecular mechanisms underlying EPHB3 silencing are incompletely understood. Here we show that EPHB3 expression is anti‐correlated with inducers of epithelial‐mesenchymal transition (EMT) in primary tumors and CRC cells. In vitro, SNAIL1 and SNAIL2, but not ZEB1, repress EPHB3 reporter constructs and compete with the stem cell factor ASCL2 for binding to an E‐box motif. At the endogenous EPHB3 locus, SNAIL1 triggers the displacement of ASCL2, p300 and the Wnt pathway effector TCF7L2 and engages corepressor complexes containing HDACs and the histone demethylase LSD1 to collapse active chromatin structure, resulting in rapid downregulation of EPHB3. Beyond its impact on EPHB3, SNAIL1 deregulates markers of intestinal identity and stemness and in vitro forces CRC cells to undergo EMT with altered morphology, increased motility and invasiveness. In xenotransplants, SNAIL1 expression abrogated tumor cell palisading and led to focal loss of tumor encapsulation and the appearance of areas with tumor cells displaying a migratory phenotype. These changes were accompanied by loss of EPHB3 and CDH1 expression. Intriguingly, SNAIL1‐induced phenotypic changes of CRC cells are significantly impaired by sustained EPHB3 expression both in vitro and in vivo. Altogether, our results identify EPHB3 as a novel target of SNAIL1 and suggest that disabling EPHB3 signaling is an important aspect to eliminate a roadblock at the onset of EMT processes.

Background Common single nucleotide polymorphisms (SNPs) explain around 50% of genetic risk underlying Autism-Spectrum-Disorder (ASD). In a previous study we showed that common functional SNPs of genes implicated in Fragile X Syndrome (FXS) were associated with ASD (Waltes et al., 2014). The FXS associated protein FMRP is regulated by the glutamatergic system, a patho-mechanism discussed for ASD. Objective We tested if functional common SNPs of glutamatergic genes were associated with ASD or ASD specific symptoms in two large ASD family cohorts (Autism Genome Project/AGP set, N=2734 families; German data set N=578 families). Since the genetic architecture between individuals with High IQ (HIQ= IQ>70) and Low IQ (LIQ= IQ≤70) differs (Vieland et al., 2010), we also split the two cohorts into high and low functioning (HIQ, LIQ) individuals. Methods 207 functional SNPs of 124 glutamatergic genes with a minor allele frequency over 5% were tested using Plink v 1.9 (DFAM) in the cohort with HIQ, LIQ and the combined cohorts, respectively. Phenotype association was studied by logistic ordinal regression correcting for gender, IQ, clinical site and population stratification. Phenotype measures were taken from the Autism Diagnostic Interview-Revised (ADI-R) scores for Social Interaction (Domain A), Verbal Communication (B1-B4; verbal individuals only), Non-Verbal Communication (Domain B2; B3; all individuals) and Repetitive Behavior (Domain C). Variants significant in both cohorts with effect sizes in the same direction were considered as replicated. Similarly, genes with any nominal significant variant in both cohorts were considered as replicated hits. Results We identified nominal significant associations of variants rs7206796 and rs3790112 (GNAO1) as well as rs3742926 (AKAP6) in both the German and the AGP LIQ cohort. In addition, significant but not overlapping SNPs of AKAP2 were identified (LIQ only). rs731826 (AKT1S1) was associated with Non Verbal Communication in the HIQ cohorts. In addition, we report 24 variants that were nominally associated with ADI-R scores in both cohorts. Genes that were involved in all five phenotypes tested were strongly related to the mTOR Pathway (e.g. genes MTOR and TSC2) or the second messenger system (e.g. G-proteins GNAS, phospholipases PLCB, protein phosphatases PPP1CA). A subset of genes was specific to each phenotype or significant in one of the subgroups (HIQ and LIQ) only. For example AKAP13 or RPS6K are associated with Verbal Communication in Low Functioning Individuals. Discussion Replication and extending previous findings we found that variants of genes that are associated with glutamate signaling, and specifically the mTOR pathway are modulators of ASD symptoms. Genes such as TSC1 or RPS6K are known to mediate glutamatergic signaling through mTOR, whereas AKAP proteins are important interactors of glutamate receptors (Sanderson et al., 2011). Both, the mTOR pathways and AKAP proteins have previously been associated with ASD (Chen et al ., 2014; Poelmans et al., 2013). Further functional analyses of glutamatergic variants are thus recommended to elucidate ASD etiology.