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

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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

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ASJC Scopus subject areas

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

Cite this

Mitra, I., Tsang, K., Ladd-Acosta, C., Croen, L. A., Aldinger, K. A., Hendren, R. L., Traglia, M., Lavillaureix, A., Zaitlen, N., Oldham, M. C., Levitt, P., Nelson, S., Amaral, D. G., Herz-Picciotto, I., Fallin, M. D., & Weiss, L. A. (2016). Pleiotropic Mechanisms Indicated for Sex Differences in Autism. PLoS Genetics, 12(11), [e1006425]. https://doi.org/10.1371/journal.pgen.1006425