@article{3e210ce68515409a99f4c3049a13af83,
title = "Recent ultra-rare inherited variants implicate new autism candidate risk genes",
abstract = "Autism is a highly heritable complex disorder in which de novo mutation (DNM) variation contributes significantly to risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare variants. We report and replicate a transmission disequilibrium of private, likely gene-disruptive (LGD) variants in probands but find that 95% of this burden resides outside of known DNM-enriched genes. This variant class more strongly affects multiplex family probands and supports a multi-hit model for autism. Candidate genes with private LGD variants preferentially transmitted to probands converge on the E3 ubiquitin–protein ligase complex, intracellular transport and Erb signaling protein networks. We estimate that these variants are approximately 2.5 generations old and significantly younger than other variants of similar type and frequency in siblings. Overall, private LGD variants are under strong purifying selection and appear to act on a distinct set of genes not yet associated with autism.",
author = "{the SPARK Consortium} and Wilfert, {Amy B.} and Turner, {Tychele N.} and Murali, {Shwetha C.} and Hsieh, {Ping Hsun} and Arvis Sulovari and Tianyun Wang and Coe, {Bradley P.} and Hui Guo and Kendra Hoekzema and Bakken, {Trygve E.} and Winterkorn, {Lara H.} and Evani, {Uday S.} and Marta Byrska-Bishop and Earl, {Rachel K.} and Bernier, {Raphael A.} and Xueya Zhou and Pamela Feliciano and Jacob Hall and Irina Astrovskaya and Simon Xu and Chang Shu and Joseph Obiajulu and Leo Brueggeman and Jessica Wright and Olena Marchenko and Chris Fleisch and Chang, {Timothy S.} and Snyder, {Lee Anne Green} and Barns, {Sarah D.} and Bing Han and William Harvey and Andrew Nishida and Ryan Doan and Aubrey Soucy and O{\textquoteright}Roak, {Brian J.} and Yu, {Timothy W.} and Daniel Geschwind and Jacob Michaelson and Natalia Volfovsky and Yufeng Shen and Chung, {Wendy K.} and Zody, {Michael C.} and Eichler, {Evan E.}",
note = "Funding Information: We thank T. Brown for assistance in editing this manuscript and S. Stray, M. Eng, J. Moore, H. Kortbawi and A. Thornton from the laboratory of Mary-Claire King for the isolation of DNA from whole blood. We thank T. Maniatis and the New York Genome Center for conducting the sequencing and initial quality control. We thank all the families at the participating 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 thank all the families in SPARK, the SPARK clinical sites and SPARK staff. We appreciate obtaining access to the phenotypic and genetic data on SFARI Base. Approved researchers can obtain the SSC population dataset described in this study (https://www.sfari.org/ resource/simons-simplex-collection/) and the SPARK population dataset described in this study (https://www.sfari.org/resource/spark/) by applying at https://base.sfari. org. We gratefully acknowledge the resources provided by the AGRE Consortium and the participating AGRE families. Genomic data for the AGRE cohort was provided by iHART, an initiative led by the Hartwell Foundation and directed by D. Wall and D. Geschwind. This work was supported, in part, by grants from the National Institutes of Health (no. R01 MH101221 to E.E.E.; no. R01 MH100047 to R.A.B.; no. K99 MH117165 to T.N.T.; no. K99 HG011041 to P.H.; and no. UM1 HG008901 to M.C.Z.) and the Simons Foundation (no. SFARI 608045 to E.E.E.). The CCDG is funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The Genome Sequencing Program Coordinating Center (no. U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. AGRE is a program of Autism Speaks and is supported in part by grant no. 1U24MH081810 from the National Institute of Mental Health to C. M. Lajonchere. E.E.E. is an investigator of the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = aug,
doi = "10.1038/s41588-021-00899-8",
language = "English",
volume = "53",
pages = "1125--1134",
journal = "Nature Genetics",
issn = "1061-4036",
number = "8",
}