TY - JOUR
T1 - Pleiotropic Mechanisms Indicated for Sex Differences in Autism
AU - Mitra, Ileena
AU - Tsang, Kathryn
AU - Ladd-Acosta, Christine
AU - Croen, Lisa A.
AU - Aldinger, Kimberly A.
AU - Hendren, Robert L.
AU - Traglia, Michela
AU - Lavillaureix, Alinoë
AU - Zaitlen, Noah
AU - Oldham, Michael C.
AU - Levitt, Pat
AU - Nelson, Stanley
AU - Amaral, David G.
AU - Herz-Picciotto, Irva
AU - Fallin, M. Daniele
AU - Weiss, Lauren A.
N1 - Publisher Copyright:
© 2016 Mitra et al.
PY - 2016/11
Y1 - 2016/11
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pgen.1006425
DO - 10.1371/journal.pgen.1006425
M3 - Article
C2 - 27846226
AN - SCOPUS:85000763485
SN - 1553-7390
VL - 12
JO - PLoS genetics
JF - PLoS genetics
IS - 11
M1 - e1006425
ER -