| Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci | 10.15154/1334312 | Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1). | 158/9975 | Secondary Analysis | Shared |
| The evolution and population diversity of human-specific segmental duplications | 10.15154/1338620 | Segmental duplications contribute to human evolution, adaptation and genomic instability but are often poorly characterized. We investigate the evolution, genetic variation and coding potential of human-specific segmental duplications (HSDs). We identify 218 HSDs based on analysis of 322 deeply sequenced archaic and contemporary hominid genomes. We sequence 550 human and nonhuman primate genomic clones to reconstruct the evolution of the largest, most complex regions with protein-coding potential (n=80 genes/33 gene families). We show that HSDs are non-randomly organized, associate preferentially with ancestral ape duplications termed “core duplicons”, and evolved primarily in an interspersed inverted orientation. In addition to Homo sapiens-specific gene expansions (e.g., TCAF1/2), we highlight ten gene families (e.g., ARHGAP11B and SRGAP2C) where copy number never returns to the ancestral state, there is evidence of mRNA splicing, and no common gene-disruptive mutations are observed in the general population. Such duplicates are candidates for the evolution of human-specific adaptive traits. | 29/6360 | Primary Analysis | Shared |
| The striatal matrix compartment is expanded in autism spectrum disorder. | 10.15154/khn8-jf08 | Background: Autism spectrum disorder (ASD) is the second-most common neurodevelopmental disorder in childhood. This complex developmental disorder that manifests with restricted interests, repetitive behaviors, and difficulties in communication and social awareness. The inherited and acquired causes of ASD impact many and diverse brain regions, challenging efforts to identify a shared neuroanatomical substrate for this range of symptoms. The striatum and its connections are among the most implicated sites of abnormal structure and/or function in ASD. Striatal projection neurons develop in segregated tissue compartments, the matrix and striosome, that are histochemically, pharmacologically, and functionally distinct. Immunohistochemical assessment of ASD and animal models of autism described abnormal matrix:striosome volume ratios, with an possible shift from striosome to matrix volume. Shifting the matrix:striosome ratio could result from expansion in matrix, reduction in striosome, spatial redistribution of the compartments, or a combination of these changes. Each type of ratio-shifting abnormality may predispose to ASD but yield different combinations of ASD features.
Methods: We developed a cohort of 426 children and adults (213 matched ASD-control pairs) and
performed connectivity-based parcellation (diffusion tractography) of the striatum. This identified voxels with matrix-like and striosome-like patterns of structural connectivity.
Results: Matrix-like volume was increased in ASD, with no evident change in the volume or organization of the striosome-like compartment. The inter-compartment volume difference (matrix minus striosome) within each individual was 31% larger in ASD. Matrix-like volume was increased in both caudate and putamen, and in somatotopic zones throughout the rostral-caudal extent of the striatum. Subjects with moderate elevations in ADOS (Autism Diagnostic Observation Schedule) scores had increased matrix-like volume, but those with highly elevated ADOS scores had 3.7-fold larger increases in matrix-like volume.
Conclusions: Matrix and striosome are embedded in distinct structural and functional networks, suggesting that compartment-selective injury or maldevelopment may mediate specific and distinct clinical features. Previously, assessing the striatal compartments in humans required post mortem tissue. Striatal parcellation provides a means to assess neuropsychiatric diseases for compartment-specific abnormalities in vivo. While this ASD cohort had increased matrix-like volume, other mechanisms that shift the matrix:striosome ratio may also increase the chance of developing the diverse social, sensory, and motor phenotypes of ASD.
| 1/2166 | Secondary Analysis | Shared |
| Identification of differentially methylated regions (DMRs) and cytosine sites (DMCs) in DNA methylation data of autism cases and unaffected siblings | 10.15154/vpbk-fy21 | We compared blood-based DNA methylation profiles between children with autism spectrum disorder (ASD) and carefully matched, unrelated neurotypical control children. Using sequencing-based method, we identified ASD-specific differentially methylated regions (DMRs) and cytosine sites (DMCs). We carried out comparative analyses with datasets from the NDA Collection 1650 (SFARI - DNA Methylation Analysis Cohort) that measured blood DNA methylation in ASD using microarray technology. We also identified DMRs and DMCs using metilene and minfi pipelines in the DNAm datasets from the NDA Collection 1650. | 12/728 | Secondary Analysis | Shared |
| Phenotypic subtyping and re-analysis of existing methylation data from autistic probands in simplex families reveal ASD subtype-associated differentially methylated genes and biological functions | 10.15154/1522603 | Autism spectrum disorder (ASD) describes a group of neurodevelopmental disorders with core deficits in social communication and manifestation of restricted, repetitive, and stereotyped behaviors. Despite the core symptomatology, ASD is extremely heterogeneous with respect to the severity of symptoms and behaviors. This heterogeneity presents an inherent challenge to all large-scale genome-wide 'omics analyses. In the present study, we address this heterogeneity by stratifying ASD probands from simplex families according to severity of behavioral scores on the Autism Diagnostic Interview-Revised diagnostic instrument, followed by re-analysis of existing DNA methylation data from individuals in three ASD subphenotypes in comparison to that of their respective unaffected siblings. We demonstrate that subphenotyping of cases enables the identification of over 1.6 times the number of statistically significant differentially methylated genes (DMGs) between cases and controls, compared to that identified when all cases are combined. Our analyses also reveal ASD-related neurological functions and comorbidities that are enriched among DMGs in each phenotypic subgroup but not in the combined case group. These findings may aid in the development of subtype-directed diagnostics and therapeutics. | 1/584 | Secondary Analysis | Shared |
| Embryonic lethal genetic variants and chromosomally normal pregnancy loss | 10.15154/1521342 | Objective: To examine whether rare potentially damaging genetic variants are associated with chromosomally normal pregnancy loss and estimate the magnitude of the association.
Design: Case-control.
Setting: Cases comprise 19 chromosomally normal loss conceptus-parent trios. They derive from a consecutive series of karyotyped losses at one hospital. Controls comprise 547 unaffected siblings of autism cases-parent trios from the National Database for Autism Research.
Main outcome measures: The rate of predicted damaging variants in the exome (loss of function and missense–damaging) and the proportions of probands with at least one such variant among cases versus controls.
Results: The proportions of probands with at least one rare predicted damaging variant were 36.8% among cases and 22.9% among controls (odds ratio (OR)=2.0, 99% CI 0.5-7.3). No case has a variant in a fetal anomaly gene. The proportion with variants in possibly embryonic lethal genes was increased in case probands (OR=14.5, 99% CI 1.5-89.7); variants occurred in BAZ1A, FBN2 and TIMP2.
Conclusion: Rare genetic variants in the conceptus may be a cause of chromosomally normal loss. A larger sample is needed to estimate the magnitude of the association with precision and to identify relevant biological pathways.
| 13/547 | Secondary Analysis | Shared |
| Maternal modifiers and parent-of-origin bias of the autism 16p11.2 CNV | 10.15154/1226522 | Recurrent deletions and duplications at chromosome 16p11.2 are a major genetic contributor to autism but also associate with a wider range of pediatric diagnoses. In order to investigate the potential genetic basis for phenotype variability, we assessed the parent-of-origin of the 16p11.2 copy number variant (CNV) and the presence of additional CNVs using commercial SNP microarrays in over 100 families where detailed phenotype data were available.
Additional phenotypic and genotypic data is available to approved researchers from the Simons Foundation SFARI Base (https://sfari.org/resources/sfari-base). | 344/344 | Primary Analysis | Shared |
