Over the past few years, substantial effort has been put into the functional annotation of variation in human genome sequences. Such annotations can have a critical role in identifying putatively ...causal variants for a disease or trait among the abundant natural variation that occurs at a locus of interest. The main challenges in using these various annotations include their large numbers and their diversity. Here we develop an unsupervised approach to integrate these different annotations into one measure of functional importance (Eigen) that, unlike most existing methods, is not based on any labeled training data. We show that the resulting meta-score has better discriminatory ability using disease-associated and putatively benign variants from published studies (in both coding and noncoding regions) than the recently proposed CADD score. Across varied scenarios, the Eigen score performs generally better than any single individual annotation, representing a powerful single functional score that can be incorporated in fine-mapping studies.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) characterized by impairments in social communication and social interaction and the presence of repetitive behaviors and/or ...restricted interests. ASD has profound etiological and clinical heterogeneity, which has impeded the identification of risk factors and pathophysiological processes underlying the disorder. A constellation of (i) types of genetic variation, (ii) modes of inheritance and (iii) specific genomic loci and genes have all recently been implicated in ASD risk, and these findings are currently being extended with functional analyses in model organisms and genotype-phenotype correlation studies. The overlap of risk loci between ASD and other NDDs raises intriguing questions around the mechanisms of risk. In this review, we will touch upon these aspects of ASD and how they might be addressed.
Recent developments in sequencing technologies have made it possible to uncover both rare and common genetic variants. Genome-wide association studies (GWASs) can test for the effect of common ...variants, whereas sequence-based association studies can evaluate the cumulative effect of both rare and common variants on disease risk. Many groupwise association tests, including burden tests and variance-component tests, have been proposed for this purpose. Although such tests do not exclude common variants from their evaluation, they focus mostly on testing the effect of rare variants by upweighting rare-variant effects and downweighting common-variant effects and can therefore lose substantial power when both rare and common genetic variants in a region influence trait susceptibility. There is increasing evidence that the allelic spectrum of risk variants at a given locus might include novel, rare, low-frequency, and common genetic variants. Here, we introduce several sequence kernel association tests to evaluate the cumulative effect of rare and common variants. The proposed tests are computationally efficient and are applicable to both binary and continuous traits. Furthermore, they can readily combine GWAS and whole-exome-sequencing data on the same individuals, when available, and are also applicable to deep-resequencing data of GWAS loci. We evaluate these tests on data simulated under comprehensive scenarios and show that compared with the most commonly used tests, including the burden and variance-component tests, they can achieve substantial increases in power. We next show applications to sequencing studies for Crohn disease and autism spectrum disorders. The proposed tests have been incorporated into the software package SKAT.
Recent advances in genetics and genomics have unveiled numerous cases of autism spectrum disorders (ASDs) associated with rare, causal genetic variations. These findings support a novel view of ASDs ...in which many independent, individually rare genetic variants, each associated with a very high relative risk, together explain a large proportion of ASDs. Although these rare variants impact diverse pathways, there is accumulating evidence that synaptic pathways, including those involving synaptic cell adhesion, are disrupted in some subjects with ASD. These findings provide insights into the pathogenesis of ASDs and enable the development of model systems with construct validity for specific causes of ASDs. In several neurodevelopmental disorders frequently associated with ASD, including fragile X syndrome, Rett syndrome and tuberous sclerosis, animal models have led to the development of new therapeutic approaches, giving rise to optimism with other causes of ASDs.
Research during the past decade has seen significant progress in the understanding of the genetic architecture of autism spectrum disorders (ASDs), with gene discovery accelerating as the ...characterization of genomic variation has become increasingly comprehensive. At the same time, this research has highlighted ongoing challenges. Here we address the enormous impact of high-throughput sequencing (HTS) on ASD gene discovery, outline a consensus view for leveraging this technology, and describe a large multisite collaboration developed to accomplish these goals. Similar approaches could prove effective for severe neurodevelopmental disorders more broadly.
Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ...ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations, and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (
NLGN3
,
NLGN4
,
NRXN1
,
CNTNAP2
,
SHANK3
,
MECP2
,
FMR1
,
TSC1/2
), emerging risk genes (
CHD8
,
SCN2A
,
SYNGAP1
,
ARID1B
,
GRIN2B
,
DSCAM
,
TBR1
), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies, and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.
Autism spectrum disorders (ASD) are etiologically heterogeneous, with hundreds of rare, highly penetrant mutations and genomic imbalances involved, each contributing to a very small fraction of ...cases. In this issue of Molecular Autism, Soorya and colleagues evaluated 32 patients with Phelan-McDermid syndrome, caused by either deletion of 22q13.33 or SHANK3 mutations, using gold-standard diagnostic assessments and showed that 84% met criteria for ASD, including 75% meeting criteria for autism. This study and prior studies demonstrate that this syndrome appears to be one of the more penetrant causes of ASD. In this companion review, we show that in samples ascertained for ASD, SHANK3 haploinsufficiency is one of the more prevalent monogenic causes of ASD, explaining at least 0.5% of cases. We note that SHANK3 haploinsufficiency remains underdiagnosed in ASD and developmental delay, although with the increasingly widespread use of chromosomal microarray analysis and targeted sequencing of SHANK3, the number of cases is bound to rise.
Haploinsufficiency of the Shank3 gene, which encodes a scaffolding protein at glutamatergic synapses, is a highly prevalent and penetrant risk factor for autism. Using combined behavioral, ...electrophysiological, biochemical, imaging, and molecular approaches, we find that Shank3-deficient mice exhibit autism-like social deficits and repetitive behaviors, as well as the significantly diminished NMDA receptor (NMDAR) synaptic function and synaptic distribution in prefrontal cortex. Concomitantly, Shank3-deficient mice have a marked loss of cortical actin filaments, which is associated with the reduced Rac1/PAK activity and increased activity of cofilin, the major actin depolymerizing factor. The social deficits and NMDAR hypofunction are rescued by inhibiting cofilin or activating Rac1 in Shank3-deficient mice and are induced by inhibiting PAK or Rac1 in wild-type mice. These results indicate that the aberrant regulation of synaptic actin filaments and loss of synaptic NMDARs contribute to the manifestation of autism-like phenotypes. Thus, targeting actin regulators provides a strategy for autism treatment.
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•Shank3 deficiency induces ASD-like behavioral deficits and NMDAR hypofunction in PFC•Shank3 deficiency leads to reduced synaptic F-actin and altered actin regulators in PFC•Inhibiting cofilin rescues behavioral and synaptic deficits in Shank3-deficient mice•Manipulating cortical Rac1 or PAK controls the manifestation of ASD-like phenotypes
Shank3 haploinsufficiency is an autism risk factor. Duffney et al. reveal that Shank3 deficiency causes the diminished synaptic actin filaments and NMDA receptors in prefrontal cortex. Targeting key actin regulators, including cofilin, Rac1, and PAK, rescues the autism-like behavioral and synaptic deficits, which provides a strategy for autism treatment.
We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished ...trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10
), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10
). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.
Autism spectrum disorder (ASD) is a clinically and etiologically diverse developmental condition characterized by diminished social interactions, impaired communication, and repetitive and/or ...restrictive behaviors. Recent advances in ASD genetics pave the way for implementation of precision medicine in clinical management of autism.
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