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Quantitative genome-wide association study of six phenotypic subdomains identifies novel genome-wide significant variants in autism spectrum disorder.

ABSTRACT: Autism spectrum disorders (ASD) are highly heritable and are characterized by deficits in social communication and restricted and repetitive behaviors. Twin studies on phenotypic subdomains suggest a differing underlying genetic etiology. Studying genetic variation explaining phenotypic variance will help to identify specific underlying pathomechanisms. We investigated the effect of common variation on ASD subdomains in two cohorts including >2500 individuals. Based on the Autism Diagnostic Interview-Revised (ADI-R), we identified and confirmed six subdomains with a SNP-based genetic heritability h2SNP?=?0.2-0.4. The subdomains nonverbal communication (NVC), social interaction (SI), and peer interaction (PI) shared genetic risk factors, while the subdomains of repetitive sensory-motor behavior (RB) and restricted interests (RI) were genetically independent of each other. The polygenic risk score (PRS) for ASD as categorical diagnosis explained 2.3-3.3% of the variance of SI, joint attention (JA), and PI, 4.5% for RI, 1.2% of RB, but only 0.7% of NVC. We report eight genome-wide significant hits-partially replicating previous findings-and 292 known and novel candidate genes. The underlying biological mechanisms were related to neuronal transmission and development. At the SNP and gene level, all subdomains showed overlap, with the exception of RB. However, no overlap was observed at the functional level. In summary, the ADI-R algorithm-derived subdomains related to social communication show a shared genetic etiology in contrast to restricted and repetitive behaviors. The ASD-specific PRS overlapped only partially, suggesting an additional role of specific common variation in shaping the phenotypic expression of ASD subdomains.

SUBMITTER: Yousaf A

PROVIDER: S-EPMC7335742 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Quantitative genome-wide association study of six phenotypic subdomains identifies novel genome-wide significant variants in autism spectrum disorder.

Yousaf Afsheen A Waltes Regina R Haslinger Denise D Klauck Sabine M SM Duketis Eftichia E Sachse Michael M Voran Anette A Biscaldi Monica M Schulte-Rüther Martin M Cichon Sven S Nöthen Markus M Ackermann Jörg J Koch Ina I Freitag Christine M CM Chiocchetti Andreas G AG

Translational psychiatry 20200705 1

Autism spectrum disorders (ASD) are highly heritable and are characterized by deficits in social communication and restricted and repetitive behaviors. Twin studies on phenotypic subdomains suggest a differing underlying genetic etiology. Studying genetic variation explaining phenotypic variance will help to identify specific underlying pathomechanisms. We investigated the effect of common variation on ASD subdomains in two cohorts including >2500 individuals. Based on the Autism Diagnostic Inte ...[more]

PMID: 32624584

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Project description:Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into 3 phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all 3 subgroups of ASD are 5 novel genes which appear to associate with androgen sensitivity, which may underlie the strong 4:1 bias towards affected males. Gene expression profiling of 116 LCL from autistic (87) and nonautistic (29) individuals were obtained using a custom-printed DNA microarray containing 39,936 elements (TIGR 40K Human array, GPL3427) and a reference design in which each sample was compared to the Stratagene Universal Human RNA standard. The 87 autistic samples were divided into phenotypic subgroups (language, mild, savant) on the basis of cluster analyses of scores from an autism diagnostic questionnaire, the Autism Diagnostic Interview-Revised instrument. Differentially expressed genes were determined for all autistic vs. control groups, as well as for each of 3 phenotypic ASD groups and controls.

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-κB 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.

Dataset Information

Quantitative genome-wide association study of six phenotypic subdomains identifies novel genome-wide significant variants in autism spectrum disorder.

Publications

Quantitative genome-wide association study of six phenotypic subdomains identifies novel genome-wide significant variants in autism spectrum disorder.

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