{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T22:49:39Z","timestamp":1793141379619,"version":"4.5.0"},"posted":{"date-parts":[[2026,5,7]]},"group-title":"Genetic and Genomic Medicine","reference-count":65,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Autism spectrum disorder (ASD) is estimated to be up to four times as common in males as in females, yet the causes of this prevalence difference are not well established. One possible driver is genetic variation on the X chromosome, as it contains genes capable of contributing to ASD (\n                  <jats:italic>e.g<\/jats:italic>\n                  .,\n                  <jats:italic>PTCHD1, MECP2<\/jats:italic>\n                  ) and is known to play a role in genetic disorders with differential sex prevalence (\n                  <jats:italic>e.g<\/jats:italic>\n                  ., color blindness). However, a lack of power compared to the autosomes combined with the complexities of modeling its biology have led to the X being largely overlooked in sequencing studies. Here, we develop quantitative X-linked TADA, a new model designed specifically for application to this chromosome, and use it to analyze rare variation from 50,663 individuals with ASD (and 136,670 individuals total). We find 9 genes on the X associated with ASD at a false discovery rate (FDR)\n                  <jats:bold>&lt;<\/jats:bold>\n                  0.05 and an additional 9 genes at FDR\n                  <jats:bold>&lt;<\/jats:bold>\n                  0.2, with many of these previously identified as involved in specific neurodevelopmental disorders. Point estimates of the liability conferred by\n                  <jats:italic>de novo<\/jats:italic>\n                  variants on the X are similar in females and males, with both sexes\u2019 estimates elevated\n                  <jats:bold>&gt;<\/jats:bold>\n                  20% above the corresponding autosomal values. We also develop a general theory of how X-linked variation of any additive or non-additive effect influences liability and describe its implications for prevalence. Using this theory and our empirical results, we show how genetic variation on the X could contribute to the sex-differential prevalence of ASD.\n                <\/jats:p>","DOI":"10.64898\/2026.05.04.26352380","type":"posted-content","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T23:10:17Z","timestamp":1778195417000},"source":"Crossref","is-referenced-by-count":2,"title":["Modeling rare coding variation on chromosome X provides insight into the genetics and differential sex prevalence of autism spectrum disorder"],"prefix":"10.64898","author":[{"given":"F. Kyle","family":"Satterstrom","sequence":"first","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA"},{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA"},{"name":"Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiana","family":"Jodeiry","sequence":"additional","affiliation":[{"name":"Department of Psychology, Emory University, Atlanta, Georgia, 30322, USA"},{"name":"Center of Computational and Quantitative Genetics, Emory University School of Medicine, Atlanta, Georgia, 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Behrang","family":"Mahjani","sequence":"additional","affiliation":[{"name":"Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA"},{"name":"Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gad","family":"Hatem","sequence":"additional","affiliation":[{"name":"Center of Computational and Quantitative Genetics, Emory University School of Medicine, Atlanta, Georgia, 30322, USA"},{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se Jun","family":"Park","sequence":"additional","affiliation":[{"name":"Center of Computational and Quantitative Genetics, Emory University School of Medicine, Atlanta, Georgia, 30322, USA"},{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lambertus","family":"Klei","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, 15213, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack M.","family":"Fu","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA"},{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, 02114, MA, USA"},{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie M.","family":"Wigdor","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, University of Oxford, Oxford, OX3 9DU, UK"},{"name":"Institute of Developmental and Regenerative Medicine, University of Oxford, Oxford, OX3 7TY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Autism Sequencing Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catalina","family":"Betancur","sequence":"additional","affiliation":[{"name":"Institut de Biologie Paris Seine, Sorbonne Universit\u00e9, INSERM, CNRS, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0949-8752","authenticated-orcid":false,"given":"Mark J.","family":"Daly","sequence":"additional","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA"},{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA"},{"name":"Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Roeder","sequence":"additional","affiliation":[{"name":"Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, 15213, PA, USA"},{"name":"Computational Biology Department, Carnegie Mellon University, Pittsburgh, 15213, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernie","family":"Devlin","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, 15213, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8898-8313","authenticated-orcid":false,"given":"Joseph D.","family":"Buxbaum","sequence":"additional","affiliation":[{"name":"Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA"},{"name":"Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 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