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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We thank S. Hyman and R. Hosking for their thoughtful comments. We also thank A. Pai for his help in the development of the pTDT analytic software. E.B.R. and D.J.W. were funded by National Institute of Mental Health grant 1K01MH099286-01A1 and Brain Behavior Research Foundation (NARSAD) Young Investigator grant 22379. E.M.W. was funded by the Stanley Center for Psychiatric Research at the Broad Institute. A.O. was funded by an ERC Consolidator Grant (647648 EdGe). We thank the families who took part in the Simons Simplex Collection study and the clinicians who collected data at each of the study sites. The iPSYCH project is funded by the Lundbeck Foundation and the universities and university hospitals of Aarhus and Copenhagen. Genotyping of iPSYCH and PGC samples was supported by grants from the Stanley Foundation, the Simons Foundation (SFARI 311789 to M.J.D.), and the National Institute of Mental Health (5U01MH094432-02 to M.J.D.). This work was also supported by a grant from the Simons Foundation (SFARI 402281 to S.J.S.). The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found on the ExAC website (see URLs).
Integrated supplementary information
Supplementary Figures 1–12, Supplementary Tables 1–22 and Supplementary Note