TY  - JOUR
A1  - Yousaf, Afsheen
A1  - Waltes, Regina
A1  - Haslinger, Denise
A1  - Klauck, Sabine M.
A1  - Duketis, Eftichia
A1  - Sachse, Michael
A1  - Voran, Anette
A1  - Biscaldi, Monica
A1  - Schulte-Rüther, Martin
A1  - Cichon, Sven
A1  - Nöthen, Markus Maria
A1  - Ackermann, Jörg
A1  - Koch, Ina
A1  - Freitag, Christine M.
A1  - Geburtig-Chiocchetti, Andreas
T1  - Quantitative genome-wide association study of six phenotypic subdomains identifies novel genome-wide significant variants in autism spectrum disorder
T2  - Translational Psychiatry
N2  - 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.
KW  - Genetics
KW  - Psychology
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/55461
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-554613
SN  - 2158-3188
N1  - This article is licensed under a Creative Commons Attribution 4.0 International License.
VL  - 10
IS  - art. 215
SP  - 1
EP  - 11
PB  - Nature Publishing Group
CY  - Berlin
ER  -