Identification of common genetic risk variants for autism spectrum disorder.
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ABSTRACT:
SUBMITTER: Grove J
PROVIDER: S-EPMC6454898 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
Publications
Identification of common genetic risk variants for autism spectrum disorder.
Grove Jakob J Ripke Stephan S Als Thomas D TD Mattheisen Manuel M Walters Raymond K RK Won Hyejung H Pallesen Jonatan J Agerbo Esben E Andreassen Ole A OA Anney Richard R Awashti Swapnil S Belliveau Rich R Bettella Francesco F Buxbaum Joseph D JD Bybjerg-Grauholm Jonas J Bækvad-Hansen Marie M Cerrato Felecia F Chambert Kimberly K Christensen Jane H JH Churchhouse Claire C Dellenvall Karin K Demontis Ditte D De Rubeis Silvia S Devlin Bernie B Djurovic Srdjan S Dumont Ashley L AL Goldstein Jacqueline I JI Hansen Christine S CS Hauberg Mads Engel ME Hollegaard Mads V MV Hope Sigrun S Howrigan Daniel P DP Huang Hailiang H Hultman Christina M CM Klei Lambertus L Maller Julian J Martin Joanna J Martin Alicia R AR Moran Jennifer L JL Nyegaard Mette M Nyegaard Mette M Nærland Terje T Palmer Duncan S DS Palotie Aarno A Pedersen Carsten Bøcker CB Pedersen Marianne Giørtz MG dPoterba Timothy T Poulsen Jesper Buchhave JB Pourcain Beate St BS Qvist Per P Rehnström Karola K Reichenberg Abraham A Reichert Jennifer J Robinson Elise B EB Roeder Kathryn K Roussos Panos P Saemundsen Evald E Sandin Sven S Satterstrom F Kyle FK Davey Smith George G Stefansson Hreinn H Steinberg Stacy S Stevens Christine R CR Sullivan Patrick F PF Turley Patrick P Walters G Bragi GB Xu Xinyi X Stefansson Kari K Geschwind Daniel H DH Nordentoft Merete M Hougaard David M DM Werge Thomas T Mors Ole O Mortensen Preben Bo PB Neale Benjamin M BM Daly Mark J MJ Børglum Anders D AD
Nature genetics 20190225 3
Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genom ...[more]
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Project description:Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)-two genes encoding neuronal cell-adhesion molecules-revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 x 10(-8), odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 x 10(-8) to 2.1 x 10(-10). Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.
| S-EPMC2943511 | biostudies-literature
Project description:BackgroundIn the United States, about 3 million people have autism spectrum disorder (ASD), and around 1 out of 59 children are diagnosed with ASD. People with ASD have characteristic social communication deficits and repetitive behaviors. The causes of this disorder remain unknown; however, in up to 25% of cases, a genetic cause can be identified. Detecting ASD as early as possible is desirable because early detection of ASD enables timely interventions in children with ASD. Identification of ASD based on objective pathogenic mutation screening is the major first step toward early intervention and effective treatment of affected children.ObjectiveRecent investigation interrogated genomics data for detecting and treating autism disorders, in addition to the conventional clinical interview as a diagnostic test. Since deep neural networks perform better than shallow machine learning models on complex and high-dimensional data, in this study, we sought to apply deep learning to genetic data obtained across thousands of simplex families at risk for ASD to identify contributory mutations and to create an advanced diagnostic classifier for autism screening.MethodsAfter preprocessing the genomics data from the Simons Simplex Collection, we extracted top ranking common variants that may be protective or pathogenic for autism based on a chi-square test. A convolutional neural network-based diagnostic classifier was then designed using the identified significant common variants to predict autism. The performance was then compared with shallow machine learning-based classifiers and randomly selected common variants.ResultsThe selected contributory common variants were significantly enriched in chromosome X while chromosome Y was also discriminatory in determining the identification of autistic individuals from nonautistic individuals. The ARSD, MAGEB16, and MXRA5 genes had the largest effect in the contributory variants. Thus, screening algorithms were adapted to include these common variants. The deep learning model yielded an area under the receiver operating characteristic curve of 0.955 and an accuracy of 88% for identifying autistic individuals from nonautistic individuals. Our classifier demonstrated a considerable improvement of ~13% in terms of classification accuracy compared to standard autism screening tools.ConclusionsCommon variants are informative for autism identification. Our findings also suggest that the deep learning process is a reliable method for distinguishing the diseased group from the control group based on the common variants of autism.
| S-EPMC8060867 | biostudies-literature
Project description:Younger siblings of children with ASD often exhibit elevated internalizing and externalizing problems. We investigated common dopaminergic variants (DRD4 and DRD2) in relation to behavior problems at 36 months. Genotypes linked to less efficient dopaminergic functioning were associated with higher internalizing problems in high-risk siblings.
| S-EPMC5716906 | biostudies-literature
Project description:Autism spectrum conditions (ASC) are a group of neurodevelopmental conditions characterized by difficulties in social interaction and communication alongside repetitive and stereotyped behaviours. ASC are heritable, and common genetic variants contribute substantial phenotypic variability. More than 600 genes have been implicated in ASC to date. However, a comprehensive investigation of candidate gene association studies in ASC is lacking.In this study, we systematically reviewed the literature for association studies for 552 genes associated with ASC. We identified 58 common genetic variants in 27 genes that have been investigated in three or more independent cohorts and conducted a meta-analysis for 55 of these variants. We investigated publication bias and sensitivity and performed stratified analyses for a subset of these variants.We identified 15 variants nominally significant for the mean effect size, 8 of which had P values below a threshold of significance of 0.01. Of these 15 variants, 11 were re-investigated for effect sizes and significance in the larger Psychiatric Genomics Consortium dataset, and none of them were significant. Effect direction for 8 of the 11 variants were concordant between both the datasets, although the correlation between the effect sizes from the two datasets was poor and non-significant.This is the first study to comprehensively examine common variants in candidate genes for ASC through meta-analysis. While for majority of the variants, the total sample size was above 500 cases and 500 controls, the total sample size was not large enough to accurately identify common variants that contribute to the aetiology of ASC.
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Project description:BackgroundCopy number variations (CNVs) and DNA sequence alterations affecting specific neuronal genes are established risk factors for Autism Spectrum Disorder (ASD). In what is largely considered a genetic condition, so far, these mutations account for ~20% of individuals having an ASD diagnosis. However, non-coding genomic sequence also contains functional elements introducing additional disease risk loci for investigation.ResultsWe have performed genome-wide analyses and identified rare inherited CNVs affecting non-genic intervals in 41 of 1491 (3%) of ASD cases examined. Examples of such intergenic CNV regions include 16q21 and 2p16.3 near known ASD risk genes CDH8 and NRXN1 respectively, as well as novel loci contiguous with ZHX2, MOCS1, LRRC4C, SEMA3C, and other genes.ConclusionsRare variants in intergenic regions may implicate new risk loci and genes in ASD and also present useful data for comparison with coming whole genome sequence datasets.
| S-EPMC3734099 | biostudies-literature
Project description:Autism spectrum disorder (ASD) is a group of complex multifactorial neurodevelopmental and neuropsychiatric disorders in children characterized by impairment of communication and social interaction. Several genes with associated single nucleotide polymorphisms (SNPs) have been identified for ASD in different genetic association studies, meta-analyses, and genome-wide association studies (GWAS). However, associations between different SNPs and ASD vary from population to population. Four SNPs in genes CNTNAP2, EIF4E, ATP2B2, CACNA1C, and SNP rs4307059 (which is found between CDH9 and CDH10 genes) have been identified and reported as candidate risk factors for ASD. The aim of the present study was, for the first time, to assess the association of SNPs in these genes with ASD in the Pakistani population. PCR-based genotyping was performed using allele-specific primers in 93 ASD and 93 control Pakistani individuals. All genetic associations, genotype frequencies, and allele frequencies were computed as odds' ratios (ORs) using logistic regression with a threshold of p ≤ 0.01 to determine statistical significance. We found that the homozygous genotypes of mutant T alleles of CNTNAP2 and ATP2B2 were significantly associated with Pakistani ASD patients in unadjusted ORs (p < 0.01), but their significance score was lost in the adjusted model. Other SNPs such as rs4307059, rs17850950 of EIF4E, and rs1006737 of CACNA1C were not statistically significant. Based on this, we conclude that SNPs are not associated with, or are not the main cause of, autism in the Pakistani population, indicating the involvement of additional players, which need to be investigated in future studies in a large population size. One of the limitations of present study is its small sample size. However, this study, being the first on Pakistani ASD patients, may lay the foundations for future studies in larger samples.
| S-EPMC7602870 | biostudies-literature
Project description:BackgroundGenetic studies have implicated rare and common variations in liability for autism spectrum disorder (ASD). Of the discovered risk variants, those rare in the population invariably have large impact on liability, while common variants have small effects. Yet, collectively, common risk variants account for the majority of population-level variability. How these rare and common risk variants jointly affect liability for individuals requires further study.MethodsTo explore how common and rare variants jointly affect liability, we assessed two cohorts of ASD families characterized for rare and common genetic variations (Simons Simplex Collection and Population-Based Autism Genetics and Environment Study). We analyzed data from 3011 affected subjects, as well as two cohorts of unaffected individuals characterized for common genetic variation: 3011 subjects matched for ancestry to ASD subjects and 11,950 subjects for estimating allele frequencies. We used genetic scores, which assessed the relative burden of common genetic variation affecting risk of ASD (henceforth "burden"), and determined how this burden was distributed among three subpopulations: ASD subjects who carry a potentially damaging variant implicated in risk of ASD ("PDV carriers"); ASD subjects who do not ("non-carriers"); and unaffected subjects who are assumed to be non-carriers.ResultsBurden harbored by ASD subjects is stochastically greater than that harbored by control subjects. For PDV carriers, their average burden is intermediate between non-carrier ASD and control subjects. Both carrier and non-carrier ASD subjects have greater burden, on average, than control subjects. The effects of common and rare variants likely combine additively to determine individual-level liability.LimitationsOnly 305 ASD subjects were known PDV carriers. This relatively small subpopulation limits this study to characterizing general patterns of burden, as opposed to effects of specific PDVs or genes. Also, a small fraction of subjects that are categorized as non-carriers could be PDV carriers.ConclusionsLiability arising from common and rare risk variations likely combines additively to determine risk of any individual diagnosed with ASD. On average, ASD subjects carry a substantial burden of common risk variation, even if they also carry a rare PDV affecting risk.
| S-EPMC8495987 | biostudies-literature
Project description:Autism spectrum disorder (autism) is a heterogeneous group of neurodevelopmental conditions characterized by early childhood-onset impairments in communication and social interaction alongside restricted and repetitive behaviors and interests. This review summarizes recent developments in human genetics research in autism, complemented by epigenetic and transcriptomic findings. The clinical heterogeneity of autism is mirrored by a complex genetic architecture involving several types of common and rare variants, ranging from point mutations to large copy number variants, and either inherited or spontaneous (de novo). More than 100 risk genes have been implicated by rare, often de novo, potentially damaging mutations in highly constrained genes. These account for substantial individual risk but a small proportion of the population risk. In contrast, most of the genetic risk is attributable to common inherited variants acting en masse, each individually with small effects. Studies have identified a handful of robustly associated common variants. Different risk genes converge on the same mechanisms, such as gene regulation and synaptic connectivity. These mechanisms are also implicated by genes that are epigenetically and transcriptionally dysregulated in autism. Major challenges to understanding the biological mechanisms include substantial phenotypic heterogeneity, large locus heterogeneity, variable penetrance, and widespread pleiotropy. Considerable increases in sample sizes are needed to better understand the hundreds or thousands of common and rare genetic variants involved. Future research should integrate common and rare variant research, multi-omics data including genomics, epigenomics, and transcriptomics, and refined phenotype assessment with multidimensional and longitudinal measures.
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Project description:Background and objectivesLatino-white disparities in age at autism spectrum disorder (ASD) diagnosis may be modified by primary care pediatrician (PCP) practices and beliefs. The objectives of this study were to assess ASD and developmental screening practices, attitudes toward ASD identification in Latino children, and barriers to ASD identification for Latino children, in a sample of 267 California PCPs.MethodsIn mail-based PCP survey, we assessed rates of bilingual general developmental and ASD screening, perceptions of parent ASD knowledge in Latino and white families, reports of difficulty assessing for ASDs in Latino and white children, and perceptions of barriers to early ASD identification for Latinos.ResultsAlthough 81% of PCPs offered some form of developmental screening, 29% of PCPs offered Spanish ASD screening per American Academy of Pediatrics guidelines, and only 10% offered both Spanish general developmental and Spanish ASD screening per American Academy of Pediatrics guidelines. Most PCPs thought that Latino (English and Spanish primary family language) parents were less knowledgeable about ASDs than white parents. PCPs had more difficulty assessing ASD risk for Latino children with Spanish primary family language than for white children, even when the PCP conducted recommended ASD screening or had >25% Latino patients. The most frequent barrier to ASD identification in Latinos was access to developmental specialists.ConclusionsMultiple factors in the primary care setting may contribute to delayed ASD identification for Latinos. Promoting language-appropriate screening, disseminating culturally appropriate ASD materials to Latino families, improving the specialist workforce, and providing PCP support in screening and referral of Latino children may be important ways to reduce racial and ethnic differences in care.
| S-EPMC3876760 | biostudies-literature
Project description:While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
| S-EPMC3471395 | biostudies-literature