The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism.

International audienceAlthough multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions

Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders.

International audienceRare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data

RTK and TGF-β signaling pathways genes in the sea urchin genome

International audienceThe Receptor Tyrosine kinase (RTK) and TGF-beta signaling pathways play essential roles during development in many organisms and regulate a plethora of cellular responses. From the genome sequence of Strongylocentrotus purpuratus, we have made an inventory of the genes encoding receptor tyrosine kinases and their ligands, and of the genes encoding cytokines of the TGF-beta superfamily and their downstream components. The sea urchin genome contains at least 20 genes coding for canonical receptor tyrosine kinases. Seventeen of the nineteen vertebrate RTK families are represented in the sea urchin. Fourteen of these RTK among which ALK, CCK4/PTK7, DDR, EGFR, EPH, LMR, MET/RON, MUSK, RET, ROR, ROS, RYK, TIE and TRK are present as single copy genes while pairs of related genes are present for VEGFR, FGFR and INSR. Similarly, nearly all the subfamilies of TGF-beta ligands identified in vertebrates are present in the sea urchin genome including the BMP, ADMP, GDF, Activin, Myostatin, Nodal and Lefty, as well as the TGF-beta sensu stricto that had not been characterized in invertebrates so far. Expression analysis indicates that the early expression of nodal, BMP2/4 and lefty is restricted to the oral ectoderm reflecting their role in providing positional information along the oral-aboral axis of the embryo. The coincidence between the emergence of TGF-beta-related factors such as Nodal and Lefty and the emergence of the deuterostome lineage strongly suggests that the ancestral function of Nodal could have been related to the secondary opening of the mouth which characterizes this clade, a hypothesis supported by functional data in the extant species. The sea urchin genome contains 6 genes encoding TGF-beta receptors and 4 genes encoding prototypical Smad proteins. Furthermore, most of the transcriptional activators and repressors shown to interact with Smads in vertebrates have orthologues in echinoderms. Finally, the sea urchin genome contains an almost complete repertoire of genes encoding extracellular modulators of BMP signaling including Chordin, Noggin, Sclerotin, SFRP, Gremlin, DAN and Twisted gastrulation. Taken together, these findings indicate that the sea urchin complement of genes of the RTK and TGF-beta signaling pathways is qualitatively very similar to the repertoire present in vertebrates, and that these genes are part of the common genetool kit for intercellular signaling of deuterostomes

The autism simplex collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses

BACKGROUND: There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD. METHODS: In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center. RESULTS: Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children's or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI). CONCLUSIONS: TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples

The Autism Simplex Collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses

Abstract Background There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD. Methods In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center. Results Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children’s or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI). Conclusions TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples

Neuroimaging evidence for structural correlates in adolescents resilient to polysubstance use: A five-year follow-up study.

Early initiation of polysubstance use (PSU) is a strong predictor of subsequent addiction, however scarce individuals present resilience capacity. This neuroimaging study aimed to investigate structural correlates associated with cessation or reduction of PSU and determine the extent to which brain structural features accounted for this resilient outcome. Participants from a European community-based cohort self-reported their alcohol, tobacco and cannabis use frequency at ages 14, 16 and 19 and had neuroimaging sessions at ages 14 and 19. We included three groups in the study: the resilient-to-PSU participants showed PSU at 16 and/or 14 but no more at 19 (n = 18), the enduring polysubstance users at 19 displayed PSU continuation from 14 or 16 (n = 193) and the controls were abstinent or low drinking participants (n = 460). We conducted between-group comparisons of grey matter volumes on whole brain using voxel-based morphometry and regional fractional anisotropy using tract-based spatial statistics. Random-forests machine-learning approach generated individual-level PSU-behavior predictions based on personality and neuroimaging features. Adolescents resilient to PSU showed significant larger grey matter volumes in the bilateral cingulate gyrus compared with enduring polysubstance users and controls at ages 19 and 14 (p<0.05 corrected) but no difference in fractional anisotropy. The larger cingulate volumes and personality trait "openness to experience" were the best precursors of resilience to PSU. Early in adolescence, a larger cingulate gyrus differentiated adolescents resilient to PSU, and this feature was critical in predicting this outcome. This study encourages further research into the neurobiological bases of resilience to addictive behaviors

Genetics impact risk of Alzheimer’s disease through mechanisms modulating structural brain morphology in late life

Background Alzheimer’s disease (AD)-related neuropathological changes can occur decades before clinical symptoms. We aimed to investigate whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or increasing brain atrophy, respectively.Methods We used bidirectional two-sample Mendelian randomisation to estimate the effects between genetic liability to AD and global and regional cortical thickness, estimated total intracranial volume, volume of subcortical structures and total white matter in 37 680 participants aged 8–81 years across 5 independent cohorts (Adolescent Brain Cognitive Development, Generation R, IMAGEN, Avon Longitudinal Study of Parents and Children and UK Biobank). We also examined the effects of global and regional cortical thickness and subcortical volumes from the Enhancing NeuroImaging Genetics through Meta‐Analysis (ENIGMA) Consortium on AD risk in up to 37 741 participants.Results Our findings show that AD risk alleles have an age-dependent effect on a range of cortical and subcortical brain measures that starts in mid-life, in non-clinical populations. Evidence for such effects across childhood and young adulthood is weak. Some of the identified structures are not typically implicated in AD, such as those in the striatum (eg, thalamus), with consistent effects from childhood to late adulthood. There was little evidence to suggest brain morphology alters AD risk.Conclusions Genetic liability to AD is likely to affect risk of AD primarily through mechanisms affecting indicators of brain morphology in later life, rather than structural brain reserve. Future studies with repeated measures are required for a better understanding and certainty of the mechanisms at play

Genetics impact risk of Alzheimer’s disease through mechanisms modulating structural brain morphology in late life

Background: Alzheimer’s disease (AD)-related neuropathological changes can occur decades before clinical symptoms. We aimed to investigate whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or increasing brain atrophy, respectively. Methods: We used bidirectional two-sample Mendelian randomisation to estimate the effects between genetic liability to AD and global and regional cortical thickness, estimated total intracranial volume, volume of subcortical structures and total white matter in 37 680 participants aged 8–81 years across 5 independent cohorts (Adolescent Brain Cognitive Development, Generation R, IMAGEN, Avon Longitudinal Study of Parents and Children and UK Biobank). We also examined the effects of global and regional cortical thickness and subcortical volumes from the Enhancing NeuroImaging Genetics through Meta‐Analysis (ENIGMA) Consortium on AD risk in up to 37 741 participants. Results: Our findings show that AD risk alleles have an age-dependent effect on a range of cortical and subcortical brain measures that starts in mid-life, in non-clinical populations. Evidence for such effects across childhood and young adulthood is weak. Some of the identified structures are not typically implicated in AD, such as those in the striatum (eg, thalamus), with consistent effects from childhood to late adulthood. There was little evidence to suggest brain morphology alters AD risk. Conclusions: Genetic liability to AD is likely to affect risk of AD primarily through mechanisms affecting indicators of brain morphology in later life, rather than structural brain reserve. Future studies with repeated measures are required for a better understanding and certainty of the mechanisms at play

Use of early intervention for young children with autism spectrum disorder across Europe.

Little is known about use of early interventions for autism spectrum disorder in Europe. Parents of children with autism spectrum disorder aged 7 years or younger (N = 1680) were recruited through parent organisations in 18 European countries and completed an online survey about the interventions their child received. There was considerable variation in use of interventions, and in some countries more than 20% of children received no intervention at all. The most frequently reported interventions were speech and language therapy (64%) and behavioural, developmental and relationship-based interventions (55%). In some parts of Europe, use of behavioural, developmental and relationship-based interventions was associated with higher parental educational level and time passed since diagnosis, rather than with child characteristics. These findings highlight the need to monitor use of intervention for children with autism spectrum disorder in Europe in order to contrast inequalities.Funding Agencies|COST Action - European Science Foundation [BM1004]; Innovative Medicines Initiative Joint Undertaking [115300]; European Union; EFPIA</p