PLoS Genetics (Nov 2016)

Pleiotropic Mechanisms Indicated for Sex Differences in Autism.

  • Ileena Mitra,
  • Kathryn Tsang,
  • Christine Ladd-Acosta,
  • Lisa A Croen,
  • Kimberly A Aldinger,
  • Robert L Hendren,
  • Michela Traglia,
  • Alinoë Lavillaureix,
  • Noah Zaitlen,
  • Michael C Oldham,
  • Pat Levitt,
  • Stanley Nelson,
  • David G Amaral,
  • Irva Hertz-Picciotto,
  • M Daniele Fallin,
  • Lauren A Weiss

DOI
https://doi.org/10.1371/journal.pgen.1006425
Journal volume & issue
Vol. 12, no. 11
p. e1006425

Abstract

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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.