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Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population


Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology.

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Figure 1: The genetic correlation between ASDs and pediatric social and communication difficulties in the general population.
Figure 2: The distribution of Vineland score overlaps between SSC cases and controls.
Figure 3: De novo variation influences a continuum of functional outcomes in ASD cases and controls.


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We thank S. Hyman, T. Lehner and N. Kanwisher for comments on the manuscript. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council, the Wellcome Trust (grant 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Autism Speaks (7132) provided support for the analysis of autistic trait–related data in ALSPAC (to B.S.P.). This work was also supported by the Medical Research Council Integrative Epidemiology Unit (MC_UU_12013/1-9). This publication is the work of the authors, and E.B.R. and M.J.D. will serve as guarantors for the contents of this paper. The ALSPAC GWAS data were generated by the Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. E.B.R. was funded by National Institute of Mental Health grant 1K01MH099286-01A1 and Brain Behavior Research Foundation (NARSAD) Young Investigator grant 22379. 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.). 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). This work was also supported by a grant from the Simons Foundation (SFARI 307705; to S.J.S.).

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Authors and Affiliations




E.B.R., B.S.P., V.A., J.A.K., B.B.-S., J.G., J. Maller, K.E.S., S.J.S., D.M.E., S.R., J. Martin, M.V.H., T.W., D.M.H., P.B.M. and A.D.B. generated data and/or conducted analyses. E.B.R., B.S.P., B.B.-S., B.M.N., J. Martin, D.S. and M.J.D. designed the experiment and tools. P.B.M., A.D.B., A.R., G.D.S. and M.J.D. supervised the research. E.B.R., B.S.P. and M.J.D. wrote the manuscript.

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Correspondence to Elise B Robinson or Mark J Daly.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 De novo variant continuum without the ExAC filter.

P values were derived from Poisson regression. LoF, loss of function; DCM, probably damaging constrained missense; ExAC, Exome Aggregation Consortium.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1 and Supplementary Tables 1–3. (PDF 328 kb)

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Robinson, E., St Pourcain, B., Anttila, V. et al. Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. Nat Genet 48, 552–555 (2016).

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