- Lim, Elaine T;
- Raychaudhuri, Soumya;
- Sanders, Stephan J;
- Stevens, Christine;
- Sabo, Aniko;
- MacArthur, Daniel G;
- Neale, Benjamin M;
- Kirby, Andrew;
- Ruderfer, Douglas M;
- Fromer, Menachem;
- Lek, Monkol;
- Liu, Li;
- Flannick, Jason;
- Ripke, Stephan;
- Nagaswamy, Uma;
- Muzny, Donna;
- Reid, Jeffrey G;
- Hawes, Alicia;
- Newsham, Irene;
- Wu, Yuanqing;
- Lewis, Lora;
- Dinh, Huyen;
- Gross, Shannon;
- Wang, Li-San;
- Lin, Chiao-Feng;
- Valladares, Otto;
- Gabriel, Stacey B;
- dePristo, Mark;
- Altshuler, David M;
- Purcell, Shaun M;
- Project, NHLBI Exome Sequencing;
- State, Matthew W;
- Boerwinkle, Eric;
- Buxbaum, Joseph D;
- Cook, Edwin H;
- Gibbs, Richard A;
- Schellenberg, Gerard D;
- Sutcliffe, James S;
- Devlin, Bernie;
- Roeder, Kathryn;
- Daly, Mark J
To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤ 5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD.