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

Jones MR, Brower MA, Xu N, Cui J, Mengesha E, Chen YD, Taylor KD, Azziz R, Goodarzi MO - PLoS Genet. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Methylation (Beta) levels at CpG sites with significantly different methylation between PCOS and controls.On the X axis are the significant CpG sites in the windows around the PCOS GWAS SNPs. On the Y axis is the methylation status, measured as the mean beta level. Error bars represent standard deviation.
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pgen.1005455.g002: Methylation (Beta) levels at CpG sites with significantly different methylation between PCOS and controls.On the X axis are the significant CpG sites in the windows around the PCOS GWAS SNPs. On the Y axis is the methylation status, measured as the mean beta level. Error bars represent standard deviation.

Mentions: Mean beta methylation level at a total of 650 CpG sites across the 11 PCOS risk loci windows were analyzed in 13 cases and 11 controls. A total of 17 CpG sites across the 11 windows demonstrated significant differences in methylation levels between PCOS subjects and controls (empirical P<0.05) (Fig 2). Four CpG sites were differentially methylated across the RAB5B window, including two sites located in the intergenic region 5’ to IKZF4 with increased methylation in PCOS subjects (Fig 2). Within the INSR window a single CpG was hypermethylated in PCOS subjects. Three CpG sites in the LHCGR window, all located near STON1-GTF2A1L, were hypomethylated in PCOS subjects. CpG sites in the C9orf3, DENND1A, YAP1, HMGA2, TOX3 and SUMO1P1 loci were also differentially methylated between PCOS and controls (Fig 2). We applied FDR correction for multiple testing and did not identify any methylation sites that retained significance; however, due to the highly correlated nature of methylation probes we would consider this approach conservative. Correlation analysis between differentially methylated sites and expression level of genes within the local window did not reveal any significant expression quantitative methylation (eQTM).


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

Jones MR, Brower MA, Xu N, Cui J, Mengesha E, Chen YD, Taylor KD, Azziz R, Goodarzi MO - PLoS Genet. (2015)

Methylation (Beta) levels at CpG sites with significantly different methylation between PCOS and controls.On the X axis are the significant CpG sites in the windows around the PCOS GWAS SNPs. On the Y axis is the methylation status, measured as the mean beta level. Error bars represent standard deviation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4549292&req=5

pgen.1005455.g002: Methylation (Beta) levels at CpG sites with significantly different methylation between PCOS and controls.On the X axis are the significant CpG sites in the windows around the PCOS GWAS SNPs. On the Y axis is the methylation status, measured as the mean beta level. Error bars represent standard deviation.
Mentions: Mean beta methylation level at a total of 650 CpG sites across the 11 PCOS risk loci windows were analyzed in 13 cases and 11 controls. A total of 17 CpG sites across the 11 windows demonstrated significant differences in methylation levels between PCOS subjects and controls (empirical P<0.05) (Fig 2). Four CpG sites were differentially methylated across the RAB5B window, including two sites located in the intergenic region 5’ to IKZF4 with increased methylation in PCOS subjects (Fig 2). Within the INSR window a single CpG was hypermethylated in PCOS subjects. Three CpG sites in the LHCGR window, all located near STON1-GTF2A1L, were hypomethylated in PCOS subjects. CpG sites in the C9orf3, DENND1A, YAP1, HMGA2, TOX3 and SUMO1P1 loci were also differentially methylated between PCOS and controls (Fig 2). We applied FDR correction for multiple testing and did not identify any methylation sites that retained significance; however, due to the highly correlated nature of methylation probes we would consider this approach conservative. Correlation analysis between differentially methylated sites and expression level of genes within the local window did not reveal any significant expression quantitative methylation (eQTM).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus