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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

PCOS risk loci contain alterations in gene regulation and expression in PCOS adipose tissue.i. Chromosomal co-ordinates, gene structure and gene expression profile (grey = not expressed in adipose, black = expressed in adipose). The index PCOS GWAS risk SNP is marked by a filled black triangle and is labeled with rs number. ii. Methylation sites are shown as open (unmethylated), grey filled (semi-methylated) or black (fully methylated) circles, and meQTL relationships between these sites and local SNPs are shown with a green arrow. eQTL results are shown by an orange star marking the gene and orange arrows marking SNP position of independent signals. iii. UCSC Genome Browser ENCODE tracks show 1 SNP position from dbSNP143, 2 poised enhancer activity, 3 active enhancer activity, 4 active promoter activity and 5 transcriptional activity, in 7 Encode reference cell types. iv. meQTL results are shown with box and whisker plots demonstrating mean methylation (Beta level) in each genotype group.
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pgen.1005455.g003: PCOS risk loci contain alterations in gene regulation and expression in PCOS adipose tissue.i. Chromosomal co-ordinates, gene structure and gene expression profile (grey = not expressed in adipose, black = expressed in adipose). The index PCOS GWAS risk SNP is marked by a filled black triangle and is labeled with rs number. ii. Methylation sites are shown as open (unmethylated), grey filled (semi-methylated) or black (fully methylated) circles, and meQTL relationships between these sites and local SNPs are shown with a green arrow. eQTL results are shown by an orange star marking the gene and orange arrows marking SNP position of independent signals. iii. UCSC Genome Browser ENCODE tracks show 1 SNP position from dbSNP143, 2 poised enhancer activity, 3 active enhancer activity, 4 active promoter activity and 5 transcriptional activity, in 7 Encode reference cell types. iv. meQTL results are shown with box and whisker plots demonstrating mean methylation (Beta level) in each genotype group.

Mentions: Relationships between SNPs and methylation and gene expression were further investigated using a systems genetics approach. meQTL were identified in 19 subjects that had both methylation and genotype data available. Within the LHCGR window, SNPs in the 5’ and intron 1 regions of the LHCGR gene, surrounding the PCOS risk SNP rs13405728, were associated with methylation level of three CpG residues clustered in the STON1-GTF2A1L gene (S5 Table and Fig 3). Association of one of these methylation sites (cg01450842) with local variants has been previously reported in adipose tissue [14], suggesting that variants in the 5’ and intron 1 regions of LHCGR may play a role in methylation, and potentially transcriptional regulation of genes at this locus. The minor allele at each of these three meQTL pairings was associated with decreased methylation level at each site, suggesting these variants reduce methylation and may lead to increased expression (S5 Table and Figs 3 and S1).


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)

PCOS risk loci contain alterations in gene regulation and expression in PCOS adipose tissue.i. Chromosomal co-ordinates, gene structure and gene expression profile (grey = not expressed in adipose, black = expressed in adipose). The index PCOS GWAS risk SNP is marked by a filled black triangle and is labeled with rs number. ii. Methylation sites are shown as open (unmethylated), grey filled (semi-methylated) or black (fully methylated) circles, and meQTL relationships between these sites and local SNPs are shown with a green arrow. eQTL results are shown by an orange star marking the gene and orange arrows marking SNP position of independent signals. iii. UCSC Genome Browser ENCODE tracks show 1 SNP position from dbSNP143, 2 poised enhancer activity, 3 active enhancer activity, 4 active promoter activity and 5 transcriptional activity, in 7 Encode reference cell types. iv. meQTL results are shown with box and whisker plots demonstrating mean methylation (Beta level) in each genotype group.
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1005455.g003: PCOS risk loci contain alterations in gene regulation and expression in PCOS adipose tissue.i. Chromosomal co-ordinates, gene structure and gene expression profile (grey = not expressed in adipose, black = expressed in adipose). The index PCOS GWAS risk SNP is marked by a filled black triangle and is labeled with rs number. ii. Methylation sites are shown as open (unmethylated), grey filled (semi-methylated) or black (fully methylated) circles, and meQTL relationships between these sites and local SNPs are shown with a green arrow. eQTL results are shown by an orange star marking the gene and orange arrows marking SNP position of independent signals. iii. UCSC Genome Browser ENCODE tracks show 1 SNP position from dbSNP143, 2 poised enhancer activity, 3 active enhancer activity, 4 active promoter activity and 5 transcriptional activity, in 7 Encode reference cell types. iv. meQTL results are shown with box and whisker plots demonstrating mean methylation (Beta level) in each genotype group.
Mentions: Relationships between SNPs and methylation and gene expression were further investigated using a systems genetics approach. meQTL were identified in 19 subjects that had both methylation and genotype data available. Within the LHCGR window, SNPs in the 5’ and intron 1 regions of the LHCGR gene, surrounding the PCOS risk SNP rs13405728, were associated with methylation level of three CpG residues clustered in the STON1-GTF2A1L gene (S5 Table and Fig 3). Association of one of these methylation sites (cg01450842) with local variants has been previously reported in adipose tissue [14], suggesting that variants in the 5’ and intron 1 regions of LHCGR may play a role in methylation, and potentially transcriptional regulation of genes at this locus. The minor allele at each of these three meQTL pairings was associated with decreased methylation level at each site, suggesting these variants reduce methylation and may lead to increased expression (S5 Table and Figs 3 and S1).

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