title: Pleiotropic Mechanisms Indicated for Sex Differences in Autism.
abstract: Sexual dimorphism in common disease is pervasive, including a dramatic male preponderance in autism spectrum disorders (ASDs). Potential genetic explanations include a liability threshold model requiring increased polymorphism risk in females, sex-limited X-chromosome contribution, gene-environment interaction driven by differences in hormonal milieu, risk influenced by genes sex-differentially expressed in early brain development, or contribution from general mechanisms of sexual dimorphism shared with secondary sex characteristics. Utilizing a large single nucleotide polymorphism (SNP) dataset, we identify distinct sex-specific genome-wide significant loci. We investigate genetic hypotheses and find no evidence for increased genetic risk load in females, but evidence for sex heterogeneity on the X chromosome, and contribution of sex-heterogeneous SNPs for anthropometric traits to ASD risk. Thus, our results support pleiotropy between secondary sex characteristic determination and ASDs, providing a biological basis for sex differences in ASDs and implicating non brain-limited mechanisms.
authors.affiliation: Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, California, United States of America.
authors.forename: Ileena
authors.identifier: 0000-0002-9882-3165
authors.initials: I
authors.lastname: Mitra
authors.affiliation: Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, California, United States of America.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Tsang
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Christine
authors.initials: C
authors.lastname: Ladd-Acosta
authors.affiliation: Division of Research, Kaiser Permanente Northern California, California, United States of America.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Croen
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Aldinger
authors.affiliation: Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, California, United States of America.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hendren
authors.affiliation: Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, California, United States of America.
authors.forename: Michela
authors.initials: M
authors.lastname: Traglia
authors.affiliation: Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, California, United States of America.|Université Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, France.
authors.forename: Alinoë
authors.identifier: 0000-0002-3727-9530
authors.initials: A
authors.lastname: Lavillaureix
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Noah
authors.initials: N
authors.lastname: Zaitlen
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Oldham
authors.affiliation: Program in Developmental Neurogenetics, Institute for the Developing Mind, Children's Hospital Los Angeles and Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Pat
authors.initials: P
authors.lastname: Levitt
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Stanley
authors.initials: S
authors.lastname: Nelson
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Medicine and Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute, University of California, Davis School of Medicine, Sacramento, California, United States of America.
authors.forename: David G
authors.initials: DG
authors.lastname: Amaral
authors.affiliation: Department of Public Health Sciences and Medicine and Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute, University of California, Davis School of Medicine, Sacramento, California, United States of America.
authors.forename: Irva
authors.identifier: 0000-0001-6952-2390
authors.initials: I
authors.lastname: Hertz-Picciotto
authors.affiliation: Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: M Daniele
authors.initials: MD
authors.lastname: Fallin
authors.affiliation: Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, California, United States of America.
authors.forename: Lauren A
authors.identifier: 0000-0002-5700-135X
authors.initials: LA
authors.lastname: Weiss
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000254:growth & development / Q000473:pathology; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000473:pathology; D041321:Chromosomes, Human, X / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012727:Sex Characteristics