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Family-based analysis of candidate genes for polycystic ovary syndrome.

ABSTRACT: Polycystic ovary syndrome (PCOS) is a complex disorder having both genetic and environmental components. A number of association studies based on candidate genes have reported significant association, but few have been replicated. D19S884, a polymorphic marker in fibrillin 3 (FBN3), is one of the few association findings that has been replicated in independent sets of families.The aims of the study are: 1) to genotype single nucleotide polymorphisms (SNPs) in the region of D19S884; and 2) to follow up with an independent data set, published results reporting evidence for PCOS candidate gene associations.The transmission disequilibrium test (TDT) was used to analyze linkage and association between PCOS and SNPs in candidate genes previously reported by us and by others as significantly associated with PCOS.The study was conducted at academic medical centers.A total of 453 families having a proband with PCOS participated in the study. Sisters with PCOS were also included. There was a total of 502 probands and sisters with PCOS.There were no interventions.The outcome measure was transmission frequency of SNP alleles.We identified a six-SNP haplotype block spanning a 6.7-kb region on chromosome 19p13.2 that includes D19S884. SNP haplotype allele-C alone and in combination with D19S884-allele 8 is significantly associated with PCOS: haplotype-C TDT chi(2) = 10.0 (P = 0.0016) and haplotype-C/A8 TDT chi(2) = 7.6 (P = 0.006). SNPs in four of the other 26 putative candidate genes that were tested using the TDT were nominally significant (ACVR2A, POMC, FEM1B, and SGTA). One SNP in POMC (rs12473543, chi(2) = 9.1; P(corrected) = 0.042) is significant after correction for multiple testing.A polymorphic variant, D19S884, in FBN3 is associated with risk of PCOS. POMC is also a candidate gene of interest.

SUBMITTER: Ewens KG

PROVIDER: S-EPMC2869537 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Family-based analysis of candidate genes for polycystic ovary syndrome.

Ewens Kathryn G KG Stewart Douglas R DR Ankener Wendy W Urbanek Margrit M McAllister Jan M JM Chen Chen C Baig K Maravet KM Parker Stephen C J SC Margulies Elliot H EH Legro Richard S RS Dunaif Andrea A Strauss Jerome F JF Spielman Richard S RS

The Journal of clinical endocrinology and metabolism 20100303 5

<h4>Context</h4>Polycystic ovary syndrome (PCOS) is a complex disorder having both genetic and environmental components. A number of association studies based on candidate genes have reported significant association, but few have been replicated. D19S884, a polymorphic marker in fibrillin 3 (FBN3), is one of the few association findings that has been replicated in independent sets of families.<h4>Objective</h4>The aims of the study are: 1) to genotype single nucleotide polymorphisms (SNPs) in th ...[more]

PMID: 20200332

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Project description:Polycystic Ovary Syndrome (PCOS) is a multifactorial syndrome with reproductive, endocrine, and metabolic symptoms, affecting about 10% women of reproductive age. Pathogenesis of the syndrome is poorly understood with genetic and fetal origins being the focus of the conundrum. Genetic predisposition of PCOS has been confirmed by candidate gene studies and Genome-Wide Association Studies (GWAS). Recently, the expression of PCOS candidate genes across gestation has been studied in human and bovine fetal ovaries. The current study sought to identify potential upstream regulators and mechanisms associated with PCOS candidate genes. Using RNA sequencing data of bovine fetal ovaries (62-276 days, n = 19), expression of PCOS candidate genes across gestation was analysed using Partek Flow. A supervised heatmap of the expression data of all 24,889 genes across gestation was generated. Most of the PCOS genes fell into one of four clusters according to their expression patterns. Some genes correlated negatively (early genes; C8H9orf3, TOX3, FBN3, GATA4, HMGA2, and DENND1A) and others positively (late genes; FDFT1, LHCGR, AMH, FSHR, ZBTB16, and PLGRKT) with gestational age. Pathways associated with PCOS candidate genes and genes co-expressed with them were determined using Ingenuity pathway analysis (IPA) software as well as DAVID Bioinformatics Resources for KEGG pathway analysis and Gene Ontology databases. Genes expressed in the early cluster were mainly involved in mitochondrial function and oxidative phosphorylation and their upstream regulators included PTEN, ESRRG/A and MYC. Genes in the late cluster were involved in stromal expansion, cholesterol biosynthesis and steroidogenesis and their upstream regulators included TGFB1/2/3, TNF, ERBB2/3, VEGF, INSIG1, POR, and IL25. These findings provide insight into ovarian development of relevance to the origins of PCOS, and suggest that multiple aetiological pathways might exist for the development of PCOS.

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Family-based analysis of candidate genes for polycystic ovary syndrome.

Publications

Family-based analysis of candidate genes for polycystic ovary syndrome.

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