Open AccessRecent ultra-rare inherited variants implicate new autism candidate risk genes
Author(s) -
Amy B. Wilfert,
Tychele N. Turner,
Shwetha C. Murali,
PingHsun Hsieh,
Arvis Sulovari,
Tianyun Wang,
Bradley P. Coe,
Hui Guo,
Kendra Hoekzema,
Trygve E. Bakken,
Lara Winterkorn,
Uday S. Evani,
Marta Byrska-Bishop,
Rachel K. Earl,
Raphael Bernier,
Xueya Zhou,
Pamela Feliciano,
Jacob B. Hall,
Irina Astrovskaya,
Simon Xu,
Chang Shu,
Joseph Obiajulu,
Leo Brueggeman,
Jessica Wright,
Олена Геннадіївна Марченко,
Chris Fleisch,
T. S. Chang,
LeeAnne Green Snyder,
Sarah Barns,
Bing Han,
William T. Harvey,
Andrew Nishida,
Ryan Doan,
Aubrey Soucy,
Brian J. O’Roak,
Timothy W. Yu,
Daniel H. Geschwind,
Jacob Michaelson,
Natalia Volfovsky,
Yufeng Shen,
Wendy K. Chung,
Michael C. Zody,
Evan E. Eichler
Publication year - 2021
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-021-00899-8
Subject(s) - biology , genetics , proband , autism , gene , candidate gene , genome wide association study , exome sequencing , autism spectrum disorder , mutation , single nucleotide polymorphism , genotype , psychology , developmental psychology
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.