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@ARTICLE{Yousaf:877954,
author = {Yousaf, Afsheen and Waltes, Regina and Haslinger, Denise
and Klauck, Sabine M and Duketis, Eftichia and Sachse,
Michael and Voran, Anette and Biscaldi, Monica and
Schulte-Rüther, Martin and Cichon, Sven and Nöthen, Markus
and Ackermann, Jörg and Koch, Ina and Freitag, Christine M
and Chiocchetti, Andreas G},
title = {{Q}uantitative genome-wide association study of six
phenotypic subdomains identifies novel genome-wide
significant variants in autism spectrum disorder.},
journal = {Translational Psychiatry},
volume = {10},
number = {1},
issn = {2158-3188},
address = {London},
publisher = {Nature Publishing Group},
reportid = {FZJ-2020-02533},
pages = {215},
year = {2020},
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.},
cin = {INM-1 / INM-11},
ddc = {610},
cid = {I:(DE-Juel1)INM-1-20090406 / I:(DE-Juel1)INM-11-20170113},
pnm = {571 - Connectivity and Activity (POF3-571) / HBP SGA3 -
Human Brain Project Specific Grant Agreement 3 (945539) /
HBP SGA2 - Human Brain Project Specific Grant Agreement 2
(785907)},
pid = {G:(DE-HGF)POF3-571 / G:(EU-Grant)945539 /
G:(EU-Grant)785907},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:32624584},
pmc = {pmc:PMC7335742},
UT = {WOS:000549816200002},
doi = {10.1038/s41398-020-00906-2},
url = {https://juser.fz-juelich.de/record/877954},
}