Global increases in both common and rare copy number load associated with autism

Article · March 2013with54 Reads
DOI: 10.1093/hmg/ddt136 · Source: PubMed
Abstract
Children with autism have an elevated frequency of large, rare copy number variants (CNVs). However, the global load of deletions or duplications, per se, and their size, location and relationship to clinical manifestations of autism have not been documented. We examined CNV data from 516 individuals with autism or typical development from the population-based Childhood Autism Risks from Genetics and Environment (CHARGE) study. We interrogated 120 regions flanked by segmental duplications (genomic hotspots) for events >50 kbp and the entire genomic backbone for variants >300 kbp using a custom targeted DNA microarray. This analysis was complemented by a separate study of five highly dynamic, hotspots associated with autism or developmental delay syndromes using a finely-tiled array platform (>1 kbp) in 142 children matched for gender and ethnicity. In both studies, a significant increase in the number of base pairs of duplication, but not deletion, was associated with autism. Significantly elevated levels of CNV load remained after removal of rare and likely pathogenic events. Further, the entire CNV load detected with the finely-tiled array was contributed by common variants. The impact of this variation was assessed by examining the correlation of clinical outcomes with CNV load. The level of personal and social skills, measured by Vineland Adaptive Behavior Scales, negatively correlated (Spearman's r=-0.13, p=0.034) with the duplication CNV load for the affected children; the strongest association was found for communication (p=0.048) and socialization (p=0.022) scores. We propose that CNV load, predominantly increased genomic base pairs of duplication, predisposes to autism.
3 Figures
    • Genetic data included analysis of the presence or absence of ASD-associated CNVs of a subset (1749) of the SCC children, made available via Girirajan et al. [2013]. In order to set the context for the analysis of that subpopulation that is at the heart of this paper, we analyzed (SPSS Statistical Software, IBM Corporation, Armonk, NY) our data for phenotype differences related to the known presence (n 5 133) or absence (n 5 1616) of a CNV [Mazina et al., 2015] and for differences related to duplications (n 5 56) or deletions (n 5 77) [Girirajan et al., 2013]. Children with ASD and an identified CNV compared with those without a CNV had mothers and fathers of similar age (F(1,147) <0.56, P >0.46), no differences in maternal and paternal education (x 2 (3)<4.2,
    [Show abstract] [Hide abstract] ABSTRACT: Current research suggests that incidence and heterogeneity of autism spectrum disorder (ASD) symptoms may arise through a variety of exogenous and/or endogenous factors. While subject to routine clinical practice and generally considered safe, there exists speculation, though no human data, that diagnostic ultrasound may also contribute to ASD severity, supported by experimental evidence that exposure to ultrasound early in gestation could perturb brain development and alter behavior. Here we explored a modified triple hit hypothesis [Williams & Casanova, ] to assay for a possible relationship between the severity of ASD symptoms and (1) ultrasound exposure (2) during the first trimester of pregnancy in fetuses with a (3) genetic predisposition to ASD. We did so using retrospective analysis of data from the SSC (Simon's Simplex Collection) autism genetic repository funded by the Simons Foundation Autism Research Initiative. We found that male children with ASD, copy number variations (CNVs), and exposure to first trimester ultrasound had significantly decreased non-verbal IQ and increased repetitive behaviors relative to male children with ASD, with CNVs, and no ultrasound. These data suggest that heterogeneity in ASD symptoms may result, at least in part, from exposure to diagnostic ultrasound during early prenatal development of children with specific genetic vulnerabilities. These results also add weight to on-going concerns expressed by the FDA about non-medical use of diagnostic ultrasound during pregnancy. Autism Res 2016. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
    Article · Sep 2016
    • Thus, total genomic copy number burden, as an accumulation of copy number change, is a meaningful measure of genomic change that may contribute to phenotypes that are associated with many genes/regions. Previously, we found that autism is associated with increased levels of copy number burden [12]. However, one of the current limitations of this approach is that it is difficult to interpret biological meaning based on the accumulation of copy number change genome-wide.
    Full-text · Conference Paper · Jan 2016 · Development
    • Even though the DNA copy numbers variations occur frequently in the genome of normal people, especially in the segmental duplication regions (SDs), it has been demonstrated that some variations are associated with behavioral and developmental abnormalities such as cognitive impairment, autism, mental retardation, and possibly psychiatric diseases. Different studies tested the whole genome and detected autism-related abnormalities in 5 SD-rich intervals [50]. Therefore, autism is correlated with DNA copy number variations (DCV).
    [Show abstract] [Hide abstract] ABSTRACT: Automated autism detection is needed to facilitate urgently required therapy. However, contrary to cancer, autism detection using genetic data has not attracted much attention. In this paper, we investigate autism detection using machine learning techniques. The main goal is to test whether genetic data with machine learning tools can result in an abbreviated and accurate instrument for classification of autism. For this, a system comprising four stages is proposed, where at each stage, we experiment with different feature reduction, classification and combination methods to find if it is possible to detect autism. The experimental results show that our classifier-based system can achieve optimum accuracy of early screening. We achieved optimum accuracy when examined on independent and unseen test data. The optimum performance was mostly achieved using a three-layer back-propagation neural network classifier combined using the feature selection-based combiner. This was achievable only when the data dimensionality was reduced using our proposed feature selection method. The maximum number of features varied for the different chromosomes and ranged between 150 and 500.
    Full-text · Article · Jan 2016
    • For example, in schizophrenia, deletions were enriched in cases to a greater extent than duplications, and the largest CNVs (> 500 kb) were enriched in cases to a greater extent than other size categories[8][9][10][11][12]. Girirajan et al.[21]found that the total duplication length is significantly elevated in autism cases compared with controls. On the other hand, SNP collapsing methods target only one feature (i.e., mutation burden).
    [Show abstract] [Hide abstract] ABSTRACT: Copy number variants (CNVs) play an important role in the etiology of many diseases such as cancers and psychiatric disorders. Due to a modest marginal effect size or the rarity of the CNVs, collapsing rare CNVs together and collectively evaluating their effect serves as a key approach to evaluating the collective effect of rare CNVs on disease risk. While a plethora of powerful collapsing methods are available for sequence variants (e.g., SNPs) in association analysis, these methods cannot be directly applied to rare CNVs due to the CNV-specific challenges, i.e., the multi-faceted nature of CNV polymorphisms (e.g., CNVs vary in size, type, dosage, and details of gene disruption), and etiological heterogeneity (e.g., heterogeneous effects of duplications and deletions that occur within a locus or in different loci). Existing CNV collapsing analysis methods (a.k.a. the burden test) tend to have suboptimal performance due to the fact that these methods often ignore heterogeneity and evaluate only the marginal effects of a CNV feature. We introduce CCRET, a random effects test for collapsing rare CNVs when searching for disease associations. CCRET is applicable to variants measured on a multi-categorical scale, collectively modeling the effects of multiple CNV features, and is robust to etiological heterogeneity. Multiple confounders can be simultaneously corrected. To evaluate the performance of CCRET, we conducted extensive simulations and analyzed large-scale schizophrenia datasets. We show that CCRET has powerful and robust performance under multiple types of etiological heterogeneity, and has performance comparable to or better than existing methods when there is no heterogeneity.
    Full-text · Article · Oct 2015
    • Using gene expression, protein–protein interactions, and CNV pathway analysis, a few reports have highlighted the role of synapse formation and maintenance and supported a role for these interconnected pathways in neuronal stem cell fate determination, differentiation and synaptic formation in ASD cases and animal models [14,16,33,34] . The Wnt signaling pathway plays a crucial role in diverse processes associated with formation of neural circuits [14]. These pathways provide potential drug targets for ASD.
    [Show abstract] [Hide abstract] ABSTRACT: Autism spectrum disorder (ASD) is a spectral neurodevelopment disorder affecting approximately 1% of the population. ASD is characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Multiple factors, including genetic/genomic, epigenetic/epigenomic and environmental, are thought to be necessary for autism development. Recent reviews have provided further insight into the genetic/genomic basis of ASD. It has long been suspected that epigenetic mechanisms, including DNA methylation, chromatin structures and long non-coding RNAs may play important roles in the pathology of ASD. In addition to genetic/genomic alterations and epigenetic/epigenomic influences, environmental exposures have been widely accepted as an important role in autism etiology, among which immune dysregulation and gastrointestinal microbiota are two prominent ones.
    Article · Oct 2015
    • Large genomic duplications, deletions and rearrangements (Fig. 1) are relatively rare, but they encompass many developmental loci owing to their size, which is usually thousands of base pairs (Coe et al., 2014; Girirajan et al., 2011 Girirajan et al., , 2013 Ma et al., 2006). For example, segmental duplications are typically defined as regions greater than one kilobase (kb) with >97% sequence identity (Marques-Bonet et al., 2009).
    [Show abstract] [Hide abstract] ABSTRACT: Changes in developmental regulatory programs drive both disease and phenotypic differences among species. Linking human-specific traits to alterations in development is challenging, because we have lacked the tools to assay and manipulate regulatory networks in human and primate embryonic cells. This field was transformed by the sequencing of hundreds of genomes – human and non-human – that can be compared to discover the regulatory machinery of genes involved in human development. This approach has identified thousands of human-specific genome alterations in developmental genes and their regulatory regions. With recent advances in stem cell techniques, genome engineering, and genomics, we can now test these sequences for effects on developmental gene regulation and downstream phenotypes in human cells and tissues.
    Full-text · Article · Sep 2015
Show more