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

  • 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.
Author:Afsheen Yousaf, Regina Waltes, Denise Haslinger, Sabine M. Klauck, Eftichia Duketis, Michael Sachse, Anette Voran, Monica Biscaldi, Martin Schulte-RütherORCiD, Sven CichonORCiDGND, Markus Maria NöthenORCiDGND, Jörg AckermannORCiDGND, Ina KochORCiD, Christine M. FreitagORCiDGND, Andreas Geburtig-ChiocchettiORCiDGND
Parent Title (English):Translational Psychiatry
Publisher:Nature Publishing Group
Place of publication:Berlin
Document Type:Article
Date of Publication (online):2020/07/05
Date of first Publication:2020/07/05
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/08/25
Tag:Genetics; Psychology
Issue:art. 215
Page Number:11
First Page:1
Last Page:11
This article is licensed under a Creative Commons Attribution 4.0 International License.
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0