Analysis of recent shared ancestry in a familial cohort identifies coding and noncoding autism spectrum disorder variants
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PROVIDER: EGAC00001002558 | EGA |
REPOSITORIES: EGA
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Project description:Autism spectrum disorder (ASD) is a collection of neurodevelopmental disorders characterized by deficits in social communication and restricted, repetitive patterns of behavior or interests. ASD is highly heritable, but genetically and phenotypically heterogeneous, reducing the power to identify causative genes. We performed whole genome sequencing (WGS) in an ASD cohort of 68 individuals from 22 families enriched for recent shared ancestry. We identified an average of 3.07 million variants per genome, of which an average of 112,512 were rare. We mapped runs of homozygosity (ROHs) in affected individuals and found an average genomic homozygosity of 9.65%, consistent with expectations for multiple generations of consanguineous unions. We identified potentially pathogenic rare exonic or splice site variants in 12 known (including KMT2C, SCN1A, SPTBN1, SYNE1, ZNF292) and 12 candidate (including CHD5, GRB10, PPP1R13B) ASD genes. Furthermore, we annotated noncoding variants in ROHs with brain-specific regulatory elements and identified putative disease-causing variants within brain-specific promoters and enhancers for 5 known ASD and neurodevelopmental disease genes (ACTG1, AUTS2, CTNND2, CNTNAP4, SPTBN4). We also identified copy number variants in two known ASD and neurodevelopmental disease loci in two affected individuals. In total we identified potentially etiological variants in known ASD or neurodevelopmental disease genes for ~61% (14/23) of affected individuals. We combined WGS with homozygosity mapping and regulatory element annotations to identify candidate ASD variants. Our analyses add to the growing number of ASD genes and variants and emphasize the importance of leveraging recent shared ancestry to map disease variants in complex neurodevelopmental disorders.
| EGAS00001006058 | EGA
Project description:To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of "homozygosity mapping" in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.
| S-EPMC2586171 | biostudies-literature
Project description:Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders. Evidence indicates both disorders co-occur with a high frequency, in 20-50% of children with ADHD meeting criteria for ASD and in 30-80% of ASD children meeting criteria for ADHD. This review will provide an overview on all available studies [family based, twin, candidate gene, linkage, and genome wide association (GWA) studies] shedding light on the role of shared genetic underpinnings of ADHD and ASD. It is concluded that family and twin studies do provide support for the hypothesis that ADHD and ASD originate from partly similar familial/genetic factors. Only a few candidate gene studies, linkage studies and GWA studies have specifically addressed this co-occurrence, pinpointing to some promising pleiotropic genes, loci and single nucleotide polymorphisms (SNPs), but the research field is in urgent need for better designed and powered studies to tackle this complex issue. We propose that future studies examining shared familial etiological factors for ADHD and ASD use a family-based design in which the same phenotypic (ADHD and ASD), candidate endophenotypic, and environmental measurements are obtained from all family members. Multivariate multi-level models are probably best suited for the statistical analysis.
| S-EPMC2839489 | biostudies-literature
Project description:BACKGROUND:To determine whether familial transmission is shared between autism spectrum disorders and attention-deficit/hyperactivity disorder, we assessed the prevalence, rates of comorbidity, and familial transmission of both disorders in a large population-based sample of children during a recent 7 year period. METHODS:Study participants included all children born to parents with the Kaiser Permanente Northwest (KPNW) Health Plan between 1 January 1998 and 31 December 2004 (n = 35,073). Children and mothers with physician-identified autism spectrum disorders (ASD) and/or attention-deficit/hyperactivity disorder (ADHD) were identified via electronic medical records maintained for all KPNW members. RESULTS:Among children aged 6-12 years, prevalence was 2.0% for ADHD and 0.8% for ASD; within those groups, 0.2% of the full sample (19% of the ASD sample and 9.6% of the ADHD sample) had co-occurring ASD and ADHD, when all children were included. When mothers had a diagnosis of ADHD, first born offspring were at 6-fold risk of ADHD alone (OR = 5.02, p < .0001) and at 2.5-fold risk of ASD alone (OR = 2.52, p < .01). Results were not accounted for by maternal age, child gestational age, child gender, and child race. CONCLUSIONS:Autism spectrum disorders shares familial transmission with ADHD. ADHD and ASD have a partially overlapping diathesis.
| S-EPMC4211282 | biostudies-literature
Project description:De novo mutation is highly implicated in autism spectrum disorder (ASD). However, the contribution of post-zygotic mutation to ASD is poorly characterized. We performed both exome sequencing of paired samples and analysis of de novo variants from whole-exome sequencing of 2,388 families. While we find little evidence for tissue-specific mosaic mutation, multi-tissue post-zygotic mutation (i.e. mosaicism) is frequent, with detectable mosaic variation comprising 5.4% of all de novo mutations. We identify three mosaic missense and likely-gene disrupting mutations in genes previously implicated in ASD (KMT2C, NCKAP1, and MYH10) in probands but none in siblings. We find a strong ascertainment bias for mosaic mutations in probands relative to their unaffected siblings (p = 0.003). We build a model of de novo variation incorporating mosaic variants and errors in classification of mosaic status and from this model we estimate that 33% of mosaic mutations in probands contribute to 5.1% of simplex ASD diagnoses (95% credible interval 1.3% to 8.9%). Our results indicate a contributory role for multi-tissue mosaic mutation in some individuals with an ASD diagnosis.
| S-EPMC5024993 | biostudies-literature
Project description:Autism spectrum disorder (ASD) is a highly heritable condition caused by a combination of environmental and genetic factors such as de novo and inherited variants, as well as rare or common variants among hundreds of related genes. Previous genome-wide association studies have identified susceptibility genes; however, most ASD-associated genes remain undiscovered. This study aimed to examine rare de novo variants to identify genetic risk factors of ASD using whole exome sequencing (WES), functional characterization, and genetic network analyses of identified variants using Korean familial dataset. We recruited children with ASD and their biological parents. The clinical best estimate diagnosis of ASD was made according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5TM), using comprehensive diagnostic instruments. The final analyses included a total of 151 individuals from 51 families. Variants were identified and filtered using the GATK Best Practices for bioinformatics analysis, followed by genome alignments and annotation to the reference genome assembly GRCh37 (liftover to GRCh38), and further annotated using dbSNP 154 build databases. To evaluate allele frequencies of de novo variants, we used the dbSNP, gnomAD exome v2.1.1, and genome v3.0. We used Ingenuity Pathway Analysis (IPA, Qiagen) software to construct networks using all identified de novo variants with known autism-related genes to find probable relationships. We identified 36 de novo variants with potential relations to ASD; 27 missense, two silent, one nonsense, one splice region, one splice site, one 5' UTR, and one intronic SNV and two frameshift deletions. We identified six networks with functional relationships. Among the interactions between de novo variants, the IPA assay found that the NF-?B signaling pathway and its interacting genes were commonly observed at two networks. The relatively small cohort size may affect the results of novel ASD genes with de novo variants described in our findings. We did not conduct functional experiments in this study. Because of the diversity and heterogeneity of ASD, the primary purpose of this study was to investigate probable causative relationships between novel de novo variants and known autism genes. Additionally, we based functional relationships with known genes on network analysis rather than on statistical analysis. We identified new variants that may underlie genetic factors contributing to ASD in Korean families using WES and genetic network analyses. We observed novel de novo variants that might be functionally linked to ASD, of which the variants interact with six genetic networks.
| S-EPMC7822011 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-02-27 | GSE111176 | GEO
Project description:Autism spectrum disorder (ASD) is highly heritable, yet how its familial risk and heritability may vary by cognitive ability is not well understood. In this population-based cohort study, we examined the familial risk and heritability of ASD with and without co-occurring intellectual disability (ID). We estimated odds ratios and heritability of ASD with ID (ASD+ID) and ASD without ID (ASD-ID) using register-based diagnosis data of 567,436 index persons born in 1984-2009 in Stockholm County, Sweden, and their parents, siblings, cousins, aunts, and uncles. The familial risk profile exhibited differences between ASD-ID and ASD+ID, most notably for index persons with affected parents. For example, for an index person who had at least one parent with ASD, the child's odds of ASD-ID and ASD+ID (95% confidence interval (CI)) increased by 16.2 (14.2-18.6) and 7.4 (5.5-10.0) folds, respectively. The more closely related a family member with ASD was, the greater the observed risk was of ASD in the index person, especially for ASD-ID. The broad-sense heritability (95% CI) for ASD - ID and ASD+ID were 64.6% (46.0-100.0%) and 33.4% (14.4-58.4%), respectively. Familial risk and heritability of ASD may vary by intellectual ability, which implies that risk factors between these ASD phenotypes may differ. Our findings from the heritability analysis and familial risk analysis suggest that ASD-ID may have a greater genetic basis than ASD+ID, although this should be verified in future studies. LAY SUMMARY: Autism spectrum disorder (ASD) is highly heritable, yet how its familial risk and heritability may vary by cognitive ability is not well-understood. In a population-based cohort study on families of 567,436 index persons using Swedish registers data, we found that the familial risk profile differed between ASD with and without intellectual disability. Our findings from the heritability analysis and familial risk analysis suggest that ASD-ID may have a greater genetic basis than ASD+ID, although this should be verified in future studies.
| S-EPMC7821228 | biostudies-literature
Project description:Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.
| S-EPMC4313871 | biostudies-literature
Project description:More than 98% of the human genome is made up of non-coding DNA, but techniques to ascertain its contribution to human disease have lagged far behind our understanding of protein coding variations. Autism spectrum disorder (ASD) has been mostly associated with coding variations via de novo single nucleotide variants (SNVs), recessive/homozygous SNVs, or de novo copy number variants (CNVs); however, most ASD cases continue to lack a genetic diagnosis. We analyzed 187 consanguineous ASD families for biallelic CNVs. Recessive deletions were significantly enriched in affected individuals relative to their unaffected siblings (17% versus 4%, p?<?0.001). Only a small subset of biallelic deletions were predicted to result in coding exon disruption. In contrast, biallelic deletions in individuals with ASD were enriched for overlap with regulatory regions, with 23/28 CNVs disrupting histone peaks in ENCODE (p?<?0.009). Overlap with regulatory regions was further demonstrated by comparisons to the 127-epigenome dataset released by the Roadmap Epigenomics project, with enrichment for enhancers found in primary brain tissue and neuronal progenitor cells. Our results suggest a novel noncoding mechanism of ASD, describe a powerful method to identify important noncoding regions in the human genome, and emphasize the potential significance of gene activation and regulation in cognitive and social function.
| S-EPMC7441318 | biostudies-literature