Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders.
Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
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|PubMed Central ID||
K01 MH099286 / MH / NIMH NIH HHS / United States
P30 ES013508 / ES / NIEHS NIH HHS / United States
MC_UU_12013/1 / Medical Research Council / United Kingdom
U01 MH109514 / MH / NIMH NIH HHS / United States
R00 MH101367 / MH / NIMH NIH HHS / United States
U54 HD086984 / HD / NICHD NIH HHS / United States
U01 MH109539 / MH / NIMH NIH HHS / United States
U01 MH094432 / MH / NIMH NIH HHS / United States
MR/L010305/1 / Medical Research Council / United Kingdom
647648 / European Research Council / International