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Recessive gene disruptions in autism spectrum disorder

Nature Genetics volume 51, pages 1092–1098 (2019)Cite this article

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Abstract

Autism spectrum disorder (ASD) affects up to 1 in 59 individuals1. Genome-wide association and large-scale sequencing studies strongly implicate both common variants2,3,4 and rare de novo variants5,6,7,8,9,10 in ASD. Recessive mutations have also been implicated11,12,13,14 but their contribution remains less well defined. Here we demonstrate an excess of biallelic loss-of-function and damaging missense mutations in a large ASD cohort, corresponding to approximately 5% of total cases, including 10% of females, consistent with a female protective effect. We document biallelic disruption of known or emerging recessive neurodevelopmental genes (CA2, DDHD1, NSUN2, PAH, RARB, ROGDI, SLC1A1, USH2A) as well as other genes not previously implicated in ASD including FEV (FEV transcription factor, ETS family member), which encodes a key regulator of the serotonergic circuitry. Our data refine estimates of the contribution of recessive mutation to ASD and suggest new paths for illuminating previously unknown biological pathways responsible for this condition.

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Fig. 1: An excess of rare, damaging, biallelic mutation in ASD.
Fig. 2: Biallelic mutations in ASD: the effects of sex.
Fig. 3: Biallelic mutations in ASD: ExAC filtration.

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Data availability

Data included in this manuscript have been deposited at the database of Genotypes and Phenotypes, merged with published data under accession number phs000298.v4.p3. Correspondence and requests for materials should be addressed to Timothy.yu@childrens.harvard.edu.

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Acknowledgements

We thank A. Hossain and N. Hatem for their help with sample preparation, and J. Kerwin for her help with analysis of in situ hybridization results. R.N.D. was supported by an NIH T32 fellowship from the Fundamental Neurobiology Training Grant (no. 5 T32 NS007484-14) and the Nancy Lurie Marks Clinical and Research Fellowship Program in Autism. The ASC is supported by the National Institute of Mental Health (NIMH; grant nos. MH100233, MH100229, MH100209, MH100239, MH111661, MH111660, MH111662 and MH111658). Collection of the PAGES cohort is supported by the NIMH (grant no. MH097849). This work was supported in part through the computational resources provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai, and the Research Information Technology Group at Harvard Medical School, which is partially supported by National Institutes of Health grant no. NCRR 1S10RR028832-01. Human embryonic and fetal material was provided jointly by the MRC/Wellcome Trust (grant no. MR/R006237/1) Human Developmental Biology Resource (www.hdbr.org). C.A.W. is an Investigator of the Howard Hughes Medical Institute. C.A.W. and T.W.Y. were supported by NIMH grant nos. RC2MH089952 and RO1MH083565. T.W.Y. was supported by grant nos. NIH/NIMH R01MH113761, NICHD/NHGRI/NIH U19HD077671 and NIH/NICHD U24HD0938487, and by a SFARI Pilot Research Award. S.D.R. and J.D.B. are supported by the Beatrice and Samuel A. Seaver Foundation.

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  1. A list of members and affiliations appears in the Supplementary Note.

Authors and Affiliations

  1. Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA

    Ryan N. Doan, Elaine T. Lim, Aubrie Soucy, Susanne Goetze, Christopher A. Walsh & Timothy W. Yu

  2. Harvard Medical School, Boston, MA, USA

    Ryan N. Doan, Elaine T. Lim, Mark J. Daly, Christopher A. Walsh & Timothy W. Yu

  3. Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Silvia De Rubeis & Joseph D. Buxbaum

  4. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Silvia De Rubeis & Joseph D. Buxbaum

  5. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Silvia De Rubeis & Joseph D. Buxbaum

  6. Neuroscience Paris Seine, Institut de Biologie Paris Seine, Sorbonne Université, INSERM, CNRS, Paris, France

    Catalina Betancur

  7. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA

    David J. Cutler

  8. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Autism Research and Intervention Center of Excellence, University Hospital Frankfurt, Goethe University, Frankfurt, Germany

    Andreas G. Chiocchetti & Christine M. Freitag

  9. Human Developmental Biology Resource, Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle-upon-Tyne, UK

    Lynne M. Overman

  10. The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Mark J. Daly, Christopher A. Walsh & Timothy W. Yu

  11. Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    Mark J. Daly

  12. Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA, USA

    Christopher A. Walsh

  13. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Joseph D. Buxbaum

  14. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Joseph D. Buxbaum

  15. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Joseph D. Buxbaum

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Consortia

Autism Sequencing Consortium

Contributions

T.W.Y., R.N.D., E.T.L. and M.J.D. designed the study, with important additional contributions from C.B., D.J.C, C.A.W. and J.D.B. R.N.D., E.T.L. and A.S. performed the data analyses. S.D.R. and S.G. performed the Sanger validation. A.G.C. and C.M.F. characterized the FEV family. L.O., S.G. and T.W.Y. designed and performed the in situ expression analyses. R.N.D. and T.W.Y. wrote the manuscript. All authors reviewed and approved the manuscript.

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Correspondence to Timothy W. Yu.

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Doan, R.N., Lim, E.T., De Rubeis, S. et al. Recessive gene disruptions in autism spectrum disorder. Nat Genet 51, 1092–1098 (2019). https://doi.org/10.1038/s41588-019-0433-8

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