|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Lim, ET, Raychaudhuri, S, Sanders, SJ, Stevens, C, Sabo, A, Macarthur, DG, Neale, BM, Kirby, A, Ruderfer, DM, Fromer, M, Lek, M, Liu, L, Flannick, J, Ripke, S, Nagaswamy, U, Muzny, D, Reid, JG, Hawes, A, Newsham, I, Wu, Y, Lewis, L, Dinh, H, Gross, S, Wang, LS, Lin, CF, Valladares, O, Gabriel, SB, DePristo, M, Altshuler, DM, Purcell, SM, NHLBI Exome Sequencing, P, State, MW, Boerwinkle, E, Buxbaum, JD, Cook, EH, Gibbs, RA, Schellenberg, GD, Sutcliffe, JS, Devlin, B, Roeder, K, Daly, MJ|
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.