title: The female protective effect in autism spectrum disorder is not mediated by a single genetic locus.
abstract: BACKGROUND
  A 4:1 male to female sex bias has consistently been observed in autism spectrum disorder (ASD). Epidemiological and genetic studies suggest a female protective effect (FPE) may account for part of this bias; however, the mechanism of such protection is unknown. Quantitative assessment of ASD symptoms using the Social Responsiveness Scale (SRS) shows a bimodal distribution unique to females in multiplex families. This leads to the hypothesis that a single, common genetic locus on chromosome X might mediate the FPE and produce the ASD sex bias. Such a locus would represent a major therapeutic target and is likely to have been missed by conventional genome-wide association study (GWAS) analysis.
  
  
  METHODS
  To explore this possibility, we performed an association study in affected versus unaffected females, considering three tiers of single nucleotide polymorphisms (SNPs) as follows: 1) regions of chromosome X that escape X-inactivation, 2) all of chromosome X, and 3) genome-wide.
  
  
  RESULTS
  No evidence of a SNP meeting the criteria for a single FPE locus was observed, despite the analysis being well powered to detect this effect.
  
  
  CONCLUSIONS
  The results do not support the hypothesis that the FPE is mediated by a single genetic locus; however, this does not exclude the possibility of multiple genetic loci playing a role in the FPE.
authors.affiliation: Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520 USA.
authors.forename: Jake
authors.initials: J
authors.lastname: Gockley
authors.affiliation: Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520 USA ; Department of Psychiatry, University of California, San Francisco, 401 Parnassus Avenue, San Francisco, CA 94143 USA.
authors.forename: A Jeremy
authors.initials: AJ
authors.lastname: Willsey
authors.affiliation: Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520 USA ; Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, No.5 Yiheyuan Road, Haidian District, Beijing, 100871 People's Republic of China.
authors.forename: Shan
authors.initials: S
authors.lastname: Dong
authors.affiliation: Department of Psychiatry, Washington University, 660 South Euclid Avenue, St Louis, MO 63110 USA ; Department of Genetics, Washington University, 4566 Scott Ave, St Louis, MO 63110 USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Dougherty
authors.affiliation: Department of Psychiatry, Washington University, 660 South Euclid Avenue, St Louis, MO 63110 USA.
authors.forename: John N
authors.initials: JN
authors.lastname: Constantino
authors.affiliation: Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520 USA ; Department of Psychiatry, University of California, San Francisco, 401 Parnassus Avenue, San Francisco, CA 94143 USA.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
keywords: Autism spectrum disorder; Female protective effect; GWAS; Sex bias