Abstract

To assess the relative impact of inherited and de novo variants on autism risk, we generated a comprehensive set of exonic single-nucleotide variants (SNVs) and copy number variants (CNVs) from 2,377 families with autism. We find that private, inherited truncating SNVs in conserved genes are enriched in probands (odds ratio = 1.14, P = 0.0002) in comparison to unaffected siblings, an effect involving significant maternal transmission bias to sons. We also observe a bias for inherited CNVs, specifically for small (<100 kb), maternally inherited events (P = 0.01) that are enriched in CHD8 target genes (P = 7.4 × 10−3). Using a logistic regression model, we show that private truncating SNVs and rare, inherited CNVs are statistically independent risk factors for autism, with odds ratios of 1.11 (P = 0.0002) and 1.23 (P = 0.01), respectively. This analysis identifies a second class of candidate genes (for example, RIMS1, CUL7 and LZTR1) where transmitted mutations may create a sensitized background but are unlikely to be completely penetrant.

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Acknowledgements

We thank D. Obenshain, D. Hall, B. Koser and S. Novikova for providing support for usage of the Amazon Cloud and for assistance in the deposition of SNV and CNV call sets into the National Database for Autism Research (NDAR). We are grateful to the laboratories of M. Wigler and M. State for providing early access to exome sequencing data as well as access to SNP microarray data. We also thank T. Brown for assistance in editing this manuscript. Funding for this study was provided, in part, by the US National Institutes of Health (1U01MH100233 to E.E.E.), by the National Institute for Mental Health (R01MH101221 to E.E.E. and R01MH100047 to R.B.) and by the Simons Foundation (SFARI 89368 to R.B. and SFARI 137578 to E.E.E.). E.E.E. is an investigator of the Howard Hughes Medical Institute. We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren and E. Wijsman). We appreciate obtaining access to phenotypic data on Simons Foundation Autism Research Initiative (SFARI) Base. Approved researchers can obtain the SSC population data set described in this study by applying at https://base.sfari.org/.

Author information

Author notes

    • Niklas Krumm
    •  & Tychele N Turner

    These authors contributed equally to this work.

Affiliations

  1. Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.

    • Niklas Krumm
    • , Tychele N Turner
    • , Carl Baker
    • , Laura Vives
    • , Kiana Mohajeri
    • , Kali Witherspoon
    • , Archana Raja
    • , Bradley P Coe
    • , Holly A Stessman
    •  & Evan E Eichler
  2. Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.

    • Archana Raja
    •  & Evan E Eichler
  3. Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

    • Zong-Xiao He
    •  & Suzanne M Leal
  4. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.

    • Raphael Bernier

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Contributions

N.K., T.N.T. and E.E.E. designed experiments and wrote and edited the manuscript. N.K. performed sequence data reanalysis and created and analyzed the SNV call set. T.N.T. created and analyzed the CNV call set, analyzed SNP microarray data, performed statistical analyses for SNV and CNV quality control, and examined epidemiological features for the full data set. C.B., L.V., K.M., K.W. and H.A.S. performed validation experiments and sample handling. A.R. and B.P.C. provided additional computational support. Z.-X.H. and S.M.L. performed the TDT tests and statistical analyses. R.B. provided phenotype data and additional SSC variables where needed.

Competing interests

E.E.E. is on the scientific advisory board (SAB) of DNAnexus, Inc., and is a consultant for the Kunming University of Science and Technology (KUST) as part of the 1000 China Talent Program.

Corresponding author

Correspondence to Evan E Eichler.

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DOI

https://doi.org/10.1038/ng.3303

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