Contribution of autosomal rare and de novo variants to sex differences in autism
Mahmoud Koko, F. Kyle Satterstrom, Branko Aleksic, Mykyta Artomov, Mafalda Barbosa, Elisa Benetti, Catalina Betancur, Monica Biscaldi-Schafer, Anders D. Børglum, Harrison Brand, Alfredo Brusco, Joseph D. Buxbaum, Gabriele Campos, Simona Cardaropoli, Diana Carli, Angel Carracedo, Marcus C.Y. Chan, Andreas G. Chiocchetti, Brian H.Y. Chung, Brett Collins, Ryan L. Collins, Edwin H. Cook, Hilary Coon, Claudia I.S. Costa, Michael L. Cuccaro, David J. Cutler, Mark J. Daly, Silvia De Rubeis, Bernie Devlin, Ryan N. Doan, Enrico Domenici, Shan Dong, Chiara Fallerini, Montserrat Fernández-Prieto, Giovanni Battista Ferrero, Christine M. Freitag, Jack M. Fu, J. Jay Gargus, Sherif Gerges, Elisa Giorgio, Ana Cristina Girardi, Stephen Guter, Emily Hansen-Kiss, Gail E. Herman, Irva Hertz-Picciotto, David M. Hougaard, Christina M. Hultman, Suma Jacob, Miia Kaartinen, Lambertus Klei, Alexander Kolevzon, Itaru Kushima, So Lun Lee, Terho Lehtimäki, Lindsay Liang, Carla Lintas, Alicia Ljungdahl, Caterina Lo Rizzo, Yunin Ludena, Patricia Maciel, Behrang Mahjani, Nell Maltman, Marianna Manara, Dara S. Manoach, Gal Meiri, Idan Menashe, Judith Miller, Nancy Minshew, Matthew Mosconi, Rachel Nguyen, Norio Ozaki, Aarno Palotie, Mara Parellada, Maria Rita Passos-Bueno, Lisa Pavinato, Minshi Peng, Margaret Pericak-Vance, Antonio M. Persico, Isaac N. Pessah, Kaija Puura, Abraham Reichenberg, Alessandra Renieri, Kathryn Roeder, Stephan J. Sanders, Sven Sandin, F. Kyle Satterstrom, Stephen W. Scherer, Sabine Schlitt, Rebecca J. Schmidt, Lauren Schmitt, Katja Schneider-Momm, Paige M. Siper, Laura Sloofman, Moyra Smith, Christine R. Stevens, Pål Suren, James S. Sutcliffe, John A. Sweeney, Michael E. Talkowski, Flora Tassone
Abstract
Autism is four times more prevalent in males than females. To study whether this reflects a difference in genetic predisposition attributed to autosomal rare variants, we evaluated sex differences in effect size of damaging protein-truncating and missense variants on autism predisposition in 47,061 autistic individuals using a liability model with differing thresholds. Given the sex differences in the rates of cognitive impairment among autistic individuals, we also compared effect sizes of rare variants between individuals with and without cognitive impairment or motor delay. Although these variants mediated different likelihoods of autism with versus without cognitive or motor difficulties, their effect sizes on the liability scale did not differ significantly by sex exome wide or in genes sex-differentially expressed in the cortex. De novo mutations were enriched in genes with male-biased expression in the adult cortex, but these genes did not show a significant sex difference on the liability scale, nor did the liability conferred by these genes differ significantly from other genes with similar loss-of-function intolerance and sex-averaged cortical expression. Exome-wide female bias in de novo protein-truncating mutation rates on the observed scale was driven by high-confidence and syndromic autism-predisposition genes. In summary, autosomal rare and damaging coding variants confer similar liability for autism in females and males.