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Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations.

Hayes MG, Urbanek M, Ehrmann DA, Armstrong LL, Lee JY, Sisk R, Karaderi T, Barber TM, McCarthy MI, Franks S, Lindgren CM, Welt CK, Diamanti-Kandarakis E, Panidis D, Goodarzi MO, Azziz R, Zhang Y, James RG, Olivier M, Kissebah AH, Reproductive Medicine NetworkStener-Victorin E, Legro RS, Dunaif A - Nat Commun (2015)

Bottom Line: Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS.Three loci reach genome-wide significance in the case-control meta-analysis, two novel loci mapping to chr 8p32.1 and chr 11p14.1, and a chr 9q22.32 locus previously found in Chinese PCOS.These findings implicate neuroendocrine changes in disease pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [2] Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [3] Department of Anthropology, Northwestern University, Evanston, Illinois 60208, USA.

ABSTRACT
Polycystic ovary syndrome (PCOS) is a common, highly heritable complex disorder of unknown aetiology characterized by hyperandrogenism, chronic anovulation and defects in glucose homeostasis. Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS. Here we map common genetic susceptibility loci in European ancestry women for the National Institutes of Health PCOS phenotype, which confers the highest risk for metabolic morbidities, as well as reproductive hormone levels. Three loci reach genome-wide significance in the case-control meta-analysis, two novel loci mapping to chr 8p32.1 and chr 11p14.1, and a chr 9q22.32 locus previously found in Chinese PCOS. The same chr 11p14.1 SNP, rs11031006, in the region of the follicle-stimulating hormone B polypeptide (FSHB) gene strongly associates with PCOS diagnosis and luteinizing hormone levels. These findings implicate neuroendocrine changes in disease pathogenesis.

No MeSH data available.


Related in: MedlinePlus

ENCODE histone mark profile for genomewide significant PCOS and LH level GWAS loci (http://www.roadmapepigenomics.org/data).Methylation marks in four PCOS relevant human tissue mapping to: (a) Chr. 9 PCOS locus (c9orf3/FANCC), (b) Chr. 11 PCOS and LH level locus (FSHB/ARL14EP) and (c) Chr. 8 PCOS locus (GATA4/NEIL2). Each is a schematic of the genomic region including diagrams of genes mapping to the region. ChipSeq signal tracks for each tissue (AN, adipose nuclei; AL, adult liver; PI, pancreatic islets; SM, skeletal muscle) for six histone marks (H3K27m3, H3K36m3, H3K4m1, H3K4m3, H3K9ac and H3K9m3) are labelled to the left of the panel.
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f3: ENCODE histone mark profile for genomewide significant PCOS and LH level GWAS loci (http://www.roadmapepigenomics.org/data).Methylation marks in four PCOS relevant human tissue mapping to: (a) Chr. 9 PCOS locus (c9orf3/FANCC), (b) Chr. 11 PCOS and LH level locus (FSHB/ARL14EP) and (c) Chr. 8 PCOS locus (GATA4/NEIL2). Each is a schematic of the genomic region including diagrams of genes mapping to the region. ChipSeq signal tracks for each tissue (AN, adipose nuclei; AL, adult liver; PI, pancreatic islets; SM, skeletal muscle) for six histone marks (H3K27m3, H3K36m3, H3K4m1, H3K4m3, H3K9ac and H3K9m3) are labelled to the left of the panel.

Mentions: There was strong evidence for transcriptional activation as assayed by H3K36m3 and H3K4m3 signals in the chr 9q22.32 c9orf3/FANCC PCOS locus (Fig. 3a). Marks indicative of transcriptional activation localized to the 5′ end of FANCC and to a ∼100 kb region encompassing a 3′ terminal transcript of C9orf3 plus a number uncharacterized transcripts in all four ENCODE cell lines (adipose nuclei, adult liver, pancreatic islets and skeletal muscle). Consistent with these observations micro array analysis demonstrated robust FANCC expression in the liver, pancreas, and, at low levels, in skeletal muscle, and c9orf3 expression in pancreatic islets and liver (GNF Expression Atlas 1 Human Data on Affy U95 Chips http://genome.ucsc.edu). The RNAseq tracks (http://genome.ucsc.edu; Fig. 4a) demonstrated virtually universal expression of FANCC, as well as HIATl1, although the latter is outside the bounds of extensive LD from the lead SNP in the region (Fig. 2a).


Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations.

Hayes MG, Urbanek M, Ehrmann DA, Armstrong LL, Lee JY, Sisk R, Karaderi T, Barber TM, McCarthy MI, Franks S, Lindgren CM, Welt CK, Diamanti-Kandarakis E, Panidis D, Goodarzi MO, Azziz R, Zhang Y, James RG, Olivier M, Kissebah AH, Reproductive Medicine NetworkStener-Victorin E, Legro RS, Dunaif A - Nat Commun (2015)

ENCODE histone mark profile for genomewide significant PCOS and LH level GWAS loci (http://www.roadmapepigenomics.org/data).Methylation marks in four PCOS relevant human tissue mapping to: (a) Chr. 9 PCOS locus (c9orf3/FANCC), (b) Chr. 11 PCOS and LH level locus (FSHB/ARL14EP) and (c) Chr. 8 PCOS locus (GATA4/NEIL2). Each is a schematic of the genomic region including diagrams of genes mapping to the region. ChipSeq signal tracks for each tissue (AN, adipose nuclei; AL, adult liver; PI, pancreatic islets; SM, skeletal muscle) for six histone marks (H3K27m3, H3K36m3, H3K4m1, H3K4m3, H3K9ac and H3K9m3) are labelled to the left of the panel.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4557132&req=5

f3: ENCODE histone mark profile for genomewide significant PCOS and LH level GWAS loci (http://www.roadmapepigenomics.org/data).Methylation marks in four PCOS relevant human tissue mapping to: (a) Chr. 9 PCOS locus (c9orf3/FANCC), (b) Chr. 11 PCOS and LH level locus (FSHB/ARL14EP) and (c) Chr. 8 PCOS locus (GATA4/NEIL2). Each is a schematic of the genomic region including diagrams of genes mapping to the region. ChipSeq signal tracks for each tissue (AN, adipose nuclei; AL, adult liver; PI, pancreatic islets; SM, skeletal muscle) for six histone marks (H3K27m3, H3K36m3, H3K4m1, H3K4m3, H3K9ac and H3K9m3) are labelled to the left of the panel.
Mentions: There was strong evidence for transcriptional activation as assayed by H3K36m3 and H3K4m3 signals in the chr 9q22.32 c9orf3/FANCC PCOS locus (Fig. 3a). Marks indicative of transcriptional activation localized to the 5′ end of FANCC and to a ∼100 kb region encompassing a 3′ terminal transcript of C9orf3 plus a number uncharacterized transcripts in all four ENCODE cell lines (adipose nuclei, adult liver, pancreatic islets and skeletal muscle). Consistent with these observations micro array analysis demonstrated robust FANCC expression in the liver, pancreas, and, at low levels, in skeletal muscle, and c9orf3 expression in pancreatic islets and liver (GNF Expression Atlas 1 Human Data on Affy U95 Chips http://genome.ucsc.edu). The RNAseq tracks (http://genome.ucsc.edu; Fig. 4a) demonstrated virtually universal expression of FANCC, as well as HIATl1, although the latter is outside the bounds of extensive LD from the lead SNP in the region (Fig. 2a).

Bottom Line: Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS.Three loci reach genome-wide significance in the case-control meta-analysis, two novel loci mapping to chr 8p32.1 and chr 11p14.1, and a chr 9q22.32 locus previously found in Chinese PCOS.These findings implicate neuroendocrine changes in disease pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [2] Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [3] Department of Anthropology, Northwestern University, Evanston, Illinois 60208, USA.

ABSTRACT
Polycystic ovary syndrome (PCOS) is a common, highly heritable complex disorder of unknown aetiology characterized by hyperandrogenism, chronic anovulation and defects in glucose homeostasis. Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS. Here we map common genetic susceptibility loci in European ancestry women for the National Institutes of Health PCOS phenotype, which confers the highest risk for metabolic morbidities, as well as reproductive hormone levels. Three loci reach genome-wide significance in the case-control meta-analysis, two novel loci mapping to chr 8p32.1 and chr 11p14.1, and a chr 9q22.32 locus previously found in Chinese PCOS. The same chr 11p14.1 SNP, rs11031006, in the region of the follicle-stimulating hormone B polypeptide (FSHB) gene strongly associates with PCOS diagnosis and luteinizing hormone levels. These findings implicate neuroendocrine changes in disease pathogenesis.

No MeSH data available.


Related in: MedlinePlus