Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity

Michelle R. Jones, Meredith A. Brower, Ning Xu, Jinrui Cui, Emebet Mengesha, Yii Der I. Chen, Kent D. Taylor, Ricardo Azziz, Mark O. Goodarzi

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.

Original languageEnglish (US)
Article numbere1005455
JournalPLoS Genetics
Volume11
Issue number8
DOIs
StatePublished - Aug 1 2015

Fingerprint

polycystic ovary syndrome
Genetic Loci
Polycystic Ovary Syndrome
gene expression
androgen
Molecular Biology
methylation
loci
polymorphism
androgens
Androgens
obesity
gene
secretion
Gene Expression
genetic variation
Methylation
single nucleotide polymorphism
Single Nucleotide Polymorphism
genome

ASJC Scopus subject areas

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

Cite this

Jones, M. R., Brower, M. A., Xu, N., Cui, J., Mengesha, E., Chen, Y. D. I., ... Goodarzi, M. O. (2015). Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity. PLoS Genetics, 11(8), [e1005455]. https://doi.org/10.1371/journal.pgen.1005455

Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity. / Jones, Michelle R.; Brower, Meredith A.; Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii Der I.; Taylor, Kent D.; Azziz, Ricardo; Goodarzi, Mark O.

In: PLoS Genetics, Vol. 11, No. 8, e1005455, 01.08.2015.

Research output: Contribution to journalArticle

Jones, MR, Brower, MA, Xu, N, Cui, J, Mengesha, E, Chen, YDI, Taylor, KD, Azziz, R & Goodarzi, MO 2015, 'Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity', PLoS Genetics, vol. 11, no. 8, e1005455. https://doi.org/10.1371/journal.pgen.1005455
Jones, Michelle R. ; Brower, Meredith A. ; Xu, Ning ; Cui, Jinrui ; Mengesha, Emebet ; Chen, Yii Der I. ; Taylor, Kent D. ; Azziz, Ricardo ; Goodarzi, Mark O. / Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity. In: PLoS Genetics. 2015 ; Vol. 11, No. 8.
@article{1828fe8d6a2340de917ce8fe1969607f,
title = "Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity",
abstract = "Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.",
author = "Jones, {Michelle R.} and Brower, {Meredith A.} and Ning Xu and Jinrui Cui and Emebet Mengesha and Chen, {Yii Der I.} and Taylor, {Kent D.} and Ricardo Azziz and Goodarzi, {Mark O.}",
year = "2015",
month = "8",
day = "1",
doi = "10.1371/journal.pgen.1005455",
language = "English (US)",
volume = "11",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "8",

}

TY - JOUR

T1 - Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity

AU - Jones, Michelle R.

AU - Brower, Meredith A.

AU - Xu, Ning

AU - Cui, Jinrui

AU - Mengesha, Emebet

AU - Chen, Yii Der I.

AU - Taylor, Kent D.

AU - Azziz, Ricardo

AU - Goodarzi, Mark O.

PY - 2015/8/1

Y1 - 2015/8/1

N2 - Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.

AB - Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.

UR - http://www.scopus.com/inward/record.url?scp=84940762484&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84940762484&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1005455

DO - 10.1371/journal.pgen.1005455

M3 - Article

VL - 11

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 8

M1 - e1005455

ER -