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 the sex differences in effect size of damaging protein-truncating and missense variants on autism predisposition in 47,061 autistic individuals, then compared effect sizes between individuals with and without cognitive impairment or motor delay. Although these variants mediated differential likelihood of autism with versus without motor or cognitive impairment, their effect sizes on the liability scale did not differ significantly by sex exome-wide or in genes sex-differentially expressed in the cortex. Although de novo mutations were enriched in genes with male-biased expression in the fetal cortex, the liability they conferred did not differ significantly from other genes with similar loss-of-function intolerance and sex-averaged cortical expression. In summary, autosomal rare coding variants confer similar liability for autism in females and males.

The authors have declared no competing interest.

We thank the participants and investigators who contributed to the datasets of the Simons Powering Autism Research for Knowledge project, the Autism Sequencing Consortium, the Simons Simplex Collection, and the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) project. This work was supported by the Simons Foundation Autism Research Initiative (SFARI) through grant RNAG/669 G10 9280 to H.M., V.W. and other principal investigators of the Autism Prenatal Sex Differences Consortium (APEX). The Autism Sequencing Consortium (ASC) received support from: SFARI (574598 to S.J.S., 575097 to B.D. and K.R., 573206 to M.E.T. and M.J.D., 571009 to J.D., 736613 and 647371 to S.J.S., 606362 and 608540 to M.E.T., M.J.D., J.D.B., B.D., K.R. and S.J.S.), NHGRI (HG008895 to M.J.D., S.G. and M.E.T.), NIMH (MH115957 and MH123155 to M.E.T., MH111658 and MH057881 to B.D., MH097849, MH111661 and MH100233 to J.D.B., MH109900 and MH123184 to K.R., MH111660 and MH129722 to M.J.D., MH111662 and MH100027 to S.J.S.), NICHD (HD081256 and HD096326 to M.E.T.), AMED (JP21WM0425007 to N.O.), and the Beatrice and Samuel Seaver Foundation.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The IRB of Mass General Brigham Human Research Committee gave ethical approval for the Autism Sequencing Consortium (ASC) studies under protocols no. 2012P001018 and 2013P000323. Western IRB of Wayne State University gave ethical approval for the Simons Foundation Autism Research Initiative (SPARK) study under protocol no. 20151664.

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The data analyzed in this work were obtained from the Simons Foundation Autism Research Initiative (SFARI) and the Autism Sequencing Consortium (ASC). The Simons Foundation Powering Autism Research for Knowledge study (SPARK) phenotypes and exome data are available for approved users through SFARI Base (https://www.sfari.org/resource/sfari-base/). The ASC data used in this study are available for approved users at NHGRI AnVIL (https://anvilproject.org/data) with the accession ID: phs000298. The data produced in the present work are contained in the manuscript and the Supplementary Information.