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

doi:10.1371/journal.pgen.1006425

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

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

35 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 language	English (US)
Article number	e1006425
Journal	PLoS genetics
Volume	12
Issue number	11
DOIs	https://doi.org/10.1371/journal.pgen.1006425
State	Published - Nov 2016

ASJC Scopus subject areas

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

Access to Document

10.1371/journal.pgen.1006425

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), Article e1006425. https://doi.org/10.1371/journal.pgen.1006425

@article{6471b812074745a5b9f38a025ccf1a12,

title = "Pleiotropic Mechanisms Indicated for Sex Differences in Autism",

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.",

author = "Ileena Mitra and Kathryn Tsang and Christine Ladd-Acosta and Croen, {Lisa A.} and Aldinger, {Kimberly A.} and Hendren, {Robert L.} and Michela Traglia and Alino{\"e} Lavillaureix and Noah Zaitlen and Oldham, {Michael C.} and Pat Levitt and Stanley Nelson and Amaral, {David G.} and Irva Herz-Picciotto and Fallin, {M. Daniele} and Weiss, {Lauren A.}",

note = "Publisher Copyright: {\textcopyright} 2016 Mitra et al.",

year = "2016",

month = nov,

doi = "10.1371/journal.pgen.1006425",

language = "English (US)",

volume = "12",

journal = "PLoS genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "11",

}

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85000763485&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85000763485&partnerID=8YFLogxK

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 -

Pleiotropic Mechanisms Indicated for Sex Differences in Autism

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this