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 Herz-Picciotto, M. Daniele Fallin, Lauren A. Weiss

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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.

Original languageEnglish (US)
Article numbere1006425
JournalPLoS Genetics
Volume12
Issue number11
DOIs
StatePublished - Nov 1 2016

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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