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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

Locuszoom plot of association results, linkage disequilibrium and recombination rates around the genome-wide significant loci.(a) Chr. 9 PCOS locus (c9orf3/FANCC), (b) Chr. 11 PCOS locus (FSHB/ARL14EP), (c) Chr. 8 PCOS locus (GATA4/NEIL2), (d) Chr. 11 LH locus (FSHB/ARL14EP). In each, the top panel reflects the meta-analysis results of the combined GWAS and replication phases. The LD estimates are colour coded as a heatmap from dark blue (0≥r2>0.2) to red (0.8≥r2>1.0). Recombination hotspots are indicated by the yellow lines (recombination rate in cM Mb-1 from HapMap (http://hapmap.ncbi.nlm.nih.gov/downloads/recombination/2008-03_rel22_B36/rates/)). The bottom panel shows the genes and their orientation for each region. For (a–c) PCOS loci, P values are from sample-size weighted two-strata meta-analysis of strata-specific logistic regression P values (Stage 1: 984 cases and 2,964 population control women; Stage 2: 1,799 PCOS cases and 1,231 phenotyped reproductively normal control women). For (d) LH level locus, P values are from sample-size weighted two-strata meta-analysis of strata-specific linear regression P values (Stage 1: 645 PCOS cases; Stage 2: 399 PCOS cases).
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f2: Locuszoom plot of association results, linkage disequilibrium and recombination rates around the genome-wide significant loci.(a) Chr. 9 PCOS locus (c9orf3/FANCC), (b) Chr. 11 PCOS locus (FSHB/ARL14EP), (c) Chr. 8 PCOS locus (GATA4/NEIL2), (d) Chr. 11 LH locus (FSHB/ARL14EP). In each, the top panel reflects the meta-analysis results of the combined GWAS and replication phases. The LD estimates are colour coded as a heatmap from dark blue (0≥r2>0.2) to red (0.8≥r2>1.0). Recombination hotspots are indicated by the yellow lines (recombination rate in cM Mb-1 from HapMap (http://hapmap.ncbi.nlm.nih.gov/downloads/recombination/2008-03_rel22_B36/rates/)). The bottom panel shows the genes and their orientation for each region. For (a–c) PCOS loci, P values are from sample-size weighted two-strata meta-analysis of strata-specific logistic regression P values (Stage 1: 984 cases and 2,964 population control women; Stage 2: 1,799 PCOS cases and 1,231 phenotyped reproductively normal control women). For (d) LH level locus, P values are from sample-size weighted two-strata meta-analysis of strata-specific linear regression P values (Stage 1: 645 PCOS cases; Stage 2: 399 PCOS cases).

Mentions: Three loci were associated with PCOS in our cohort (Table 1) at a genome-wide significant threshold after Stage 3: the 8p32.1 GATA4/NEIL2 locus, the 9q22.32 c9orf3/FANCC locus, and 11p14.1 FSHB/ARL14EP locus with sample-size weighted three-strata meta-analyses Pmeta-all=8.0 × 10−10; Pmeta-all=4.6 × 10−13; and Pmeta-all=1.9 × 10−8, respectively (Table 2; Figs 1a and 2a–c; Supplementary Data 1, 2).


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)

Locuszoom plot of association results, linkage disequilibrium and recombination rates around the genome-wide significant loci.(a) Chr. 9 PCOS locus (c9orf3/FANCC), (b) Chr. 11 PCOS locus (FSHB/ARL14EP), (c) Chr. 8 PCOS locus (GATA4/NEIL2), (d) Chr. 11 LH locus (FSHB/ARL14EP). In each, the top panel reflects the meta-analysis results of the combined GWAS and replication phases. The LD estimates are colour coded as a heatmap from dark blue (0≥r2>0.2) to red (0.8≥r2>1.0). Recombination hotspots are indicated by the yellow lines (recombination rate in cM Mb-1 from HapMap (http://hapmap.ncbi.nlm.nih.gov/downloads/recombination/2008-03_rel22_B36/rates/)). The bottom panel shows the genes and their orientation for each region. For (a–c) PCOS loci, P values are from sample-size weighted two-strata meta-analysis of strata-specific logistic regression P values (Stage 1: 984 cases and 2,964 population control women; Stage 2: 1,799 PCOS cases and 1,231 phenotyped reproductively normal control women). For (d) LH level locus, P values are from sample-size weighted two-strata meta-analysis of strata-specific linear regression P values (Stage 1: 645 PCOS cases; Stage 2: 399 PCOS cases).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4557132&req=5

f2: Locuszoom plot of association results, linkage disequilibrium and recombination rates around the genome-wide significant loci.(a) Chr. 9 PCOS locus (c9orf3/FANCC), (b) Chr. 11 PCOS locus (FSHB/ARL14EP), (c) Chr. 8 PCOS locus (GATA4/NEIL2), (d) Chr. 11 LH locus (FSHB/ARL14EP). In each, the top panel reflects the meta-analysis results of the combined GWAS and replication phases. The LD estimates are colour coded as a heatmap from dark blue (0≥r2>0.2) to red (0.8≥r2>1.0). Recombination hotspots are indicated by the yellow lines (recombination rate in cM Mb-1 from HapMap (http://hapmap.ncbi.nlm.nih.gov/downloads/recombination/2008-03_rel22_B36/rates/)). The bottom panel shows the genes and their orientation for each region. For (a–c) PCOS loci, P values are from sample-size weighted two-strata meta-analysis of strata-specific logistic regression P values (Stage 1: 984 cases and 2,964 population control women; Stage 2: 1,799 PCOS cases and 1,231 phenotyped reproductively normal control women). For (d) LH level locus, P values are from sample-size weighted two-strata meta-analysis of strata-specific linear regression P values (Stage 1: 645 PCOS cases; Stage 2: 399 PCOS cases).
Mentions: Three loci were associated with PCOS in our cohort (Table 1) at a genome-wide significant threshold after Stage 3: the 8p32.1 GATA4/NEIL2 locus, the 9q22.32 c9orf3/FANCC locus, and 11p14.1 FSHB/ARL14EP locus with sample-size weighted three-strata meta-analyses Pmeta-all=8.0 × 10−10; Pmeta-all=4.6 × 10−13; and Pmeta-all=1.9 × 10−8, respectively (Table 2; Figs 1a and 2a–c; Supplementary Data 1, 2).

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