Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Identification of a polycystic ovary syndrome susceptibility variant in fibrillin-3 and association with a metabolic phenotype. Urbanek M et al. (2007) Polycystic ovary syndrome (PCOS), the most common reproductive endocrine disorder of premenopausal women, is also associated with metabolic abnormalities including insulin resistance and an increased risk for diabetes mellitus. We previously mapped a PCOS susceptibility locus to chromosome 19p13.2 near the dinucleotide repeat marker D19S884. Our objective is to localize the chromosome 19p13.2 PCOS susceptibility locus and determine its impact on metabolic features of PCOS. Resequencing and family-based association testing were used to examine the effect of sequence variation within 100 kb of D19S884 on the reproductive and metabolic phenotypes of PCOS. The study was conducted in an academic medical center. Genetic analyses were performed on DNA obtained from1723 individuals in 412 families with 412 index cases and 43 affected sisters of predominantly European origin (>94%). Genotype-phenotype associations were assessed in 601 women with PCOS and 168 brothers of affected women. D19S884 allele 8 (A8) within intron 55 of the fibrillin-3 (FBN3) gene showed the strongest evidence for association with PCOS of 53 variants tested (P(corrected) = 0.0037). A8 was also associated with higher levels of fasting insulin and homeostasis model assessment for insulin resistance in women with PCOS and higher fasting levels of proinsulin and proinsulin/insulin ratio in brothers. These findings strongly suggest that A8 of D19S884 is the chromosome 19p13.2 PCOS susceptibility locus. The association of D19S884 with markers of insulin resistance and pancreatic beta-cell dysfunction suggests that the same variant contributes to the reproductive and metabolic abnormalities of PCOS in affected women and their brothers.////////////////// The Role of the Polycystic Ovary Syndrome Susceptibility Locus D19S884 Allele 8 in Maternal Glycemia and Fetal Size. Ackerman CM et al. Context: The high incidence of insulin resistance, type 2 diabetes, and metabolic syndrome in Western societies and their impact on quality of life emphasize the importance of identifying underlying susceptibility loci for metabolic diseases. The polycystic ovary syndrome (PCOS) susceptibility locus D19S884 allele 8 (A8) is associated with measures of insulin resistance, beta-cell dysfunction, and other metabolic phenotypes in PCOS families. We now investigate the role of D19S884 A8 in pregnancy. Objective: Using the multiethnic Hyperglycemia and Adverse Pregnancy Outcome cohort, we assessed the associations of D19S884 A8 with measures of maternal glycemia and fetal size. Design: We tested for association of maternal D19S884 A8 with maternal outcomes (fasting, 1-h, and 2-h plasma glucose, and fasting and 1-h C-peptide from an oral glucose tolerance test) and fetal and maternal D19S884 A8 with fetal outcomes (birth weight, length, head circumference, sum of skin folds, fat mass, cord C-peptide, and 2-h neonatal plasma glucose). Subjects: We analyzed 4424 Caucasian mothers and 3347 offspring of northern European ancestry, 1957 Thai mothers and 2089 offspring from Bangkok, 1208 Afro-Caribbean mothers and 1209 offspring from Barbados, and 774 Hispanic mothers and 762 offspring from Bellflower, California. Results: After adjusting for confounding variables and multiple testing, neither maternal nor fetal D19S884 A8 showed significant evidence for association with any of the outcomes tested. Conclusions: The PCOS susceptibility locus, D19S884 A8, is not a major factor contributing to glycemia during pregnancy or fetal size in a general obstetric population.Association of Fibrillin-3 and Transcription Factor-7-Like 2 Gene Variants With Metabolic Phenotypes in PCOS. Yalamanchi SK et al. Polycystic ovary syndrome (PCOS) is a complex genetic disease characterized by heritable reproductive and metabolic abnormalities. Genetic variants associated with the reproductive phenotype have been mapped to the fibrillin-3 (FBN3) gene and to a novel transcription factor-7-like 2 (TCF7L2) locus (rs11196236 G). The association of these genetic variants with metabolic phenotypes was investigated in 31 PCOS and 18 control women of European ancestry. The insulinogenic index during an oral glucose tolerance test (?I30/?G30) and insulin secretion rates at the maximal dose during a graded-glucose infusion (ISRmax) were used as indexes of insulin secretion. Endogenous glucose production (EGP) and insulin sensitivity (M/I) were determined during a euglycemic clamp. The disposition index (DI) was calculated using M/I and ?I30/?G30 or ISRmax. Compared with noncarriers (n = 10) and control (n = 10), M/I was decreased (P = 1.1 ?10(-5)) in heterozygous and homozygous PCOS carriers (n = 14) of rs11196236 G and this variant predicted M/I (partial r(2) = 0.34, P = 0.005) in a regression analysis. Postabsorptive EGP tended to be higher (P = 0.040) in heterozygous and homozygous PCOS carriers of the FBN3-associated allele (n = 12), allele 8 of D19S884 (FBN3(+)), compared to PCOS noncarriers (n = 19). PCOS carriers of the rs12255372 T (TCF7L2 Caucasian type 2 diabetes mellitus (T2D) locus) had no significant associated metabolic phenotypes. We conclude that rs11196236 G TCF7L2 variant is associated with peripheral insulin resistance in PCOS but this effect is not seen in control women. The FBN3 risk allele may be associated with changes in basal glucose homeostasis in PCOS. These findings require replication in additional PCOS cohorts.

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Family-Based Analysis of Candidate Genes for Polycystic Ovary Syndrome. Ewens KG et al. 2010 Context: 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. Objective: 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. Design: 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. Setting: The study was conducted at academic medical centers. Patients or Other Participants: 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. Intervention(s): There were no interventions. Main Outcome Measure(s): The outcome measure was transmission frequency of SNP alleles. Results: 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; Pcorrected = 0.042) is significant after correction for multiple testing. Conclusions: A polymorphic variant, D19S884, in FBN3 is associated with risk of PCOS. POMC is also a candidate gene of interest.

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Microsatellite polymorphism in the fibrillin 3 gene and susceptibility to PCOS: a case-control study and meta-analysis. Xie GB et al 2013. The D19S884 marker at the fibrillin 3 gene has been analysed as a candidate location for polycystic ovary syndrome (PCOS) mainly in Caucasian descendants. A case-control study was performed with 272 PCOS women and 271 controls to test the hypothesis that variants in the D19S884 marker increase susceptibility to PCOS in Chinese women and a meta-analysis was undertaken to clarify whether there is an allele consistently contributing to the susceptibility. The association analysis showed that PCOS women were significantly different from controls in the distribution of D19S884 allele frequencies. Instead of the well-known A8 allele, the most common allele in Chinese population was proved to be A7, and the allele frequencies of A7 were statistically different between cases and controls (P=0.037). The meta-analysis of A8 and A7 only identified A8 as a significant allelic association at the D19S884 marker in all combined samples (A8: OR 1.391, 95% CI 1.169-1.654; A7: OR 1.154, 95% CI 0.894-1.490). In conclusion, the association study showed a potential association of the D19S884 marker with PCOS in Chinese Han women and the meta-analysis identified that A8 may increase susceptibility to PCOS. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, and it affects an estimated 15% of women worldwide based on the Rotterdam criteria. Many studies in Caucasian descendants suggested that variants of the D19S884 marker at the fibrillin 3 gene are associated with the risk of this syndrome. Here we performed a case-control study with 272 PCOS women and 271 controls to investigate whether variants in the D19S884 marker increase susceptibility to PCOS in Chinese women. We also carried out a meta-analysis of some relevant studies to find a more reliable result. Our association analysis showed that PCOS women were significantly different from controls in the distribution of D19S884 allele frequencies, and instead of the well-known A8 (the letter 'A' represents 'allele'), the most common allele in Chinese population was proved to be A7, whose allele frequencies were statistically different between cases and controls. The meta-analysis of A8 and A7 only identified A8 as a significant allelic association at the D19S884 marker in all combined samples. In conclusion, our association study showed a potential association of the D19S884 marker with PCOS in Chinese Han women and the meta-analysis identified that A8 may increase susceptibility to PCOS. Evaluating reported candidate gene associations with polycystic ovary syndrome. Pau C et al. 2013 OBJECTIVE: To replicate variants in candidate genes associated with polycystic ovary syndrome (PCOS) in a population of European women with PCOS and control subjects. DESIGN: Case-control association analysis and meta-analysis. SETTING: Major academic hospital. PATIENT(S): Women of European ancestry with PCOS (n = 525) and controls (n = 472), aged 18-45 years. INTERVENTION(S): Variants previously associated with PCOS in candidate gene studies were genotyped (n = 39). Metabolic, reproductive, and anthropomorphic parameters were examined as a function of the candidate variants. All genetic association analyses were adjusted for age, body mass index, and ancestry and were reported after correction for multiple testing. MAIN OUTCOME MEASURE(S): Association of candidate gene variants with PCOS. RESULT(S): Three variants, rs3797179 (SRD5A1), rs12473543 (POMC), and rs1501299 (ADIPOQ), were nominally associated with PCOS. However, they did not remain significant after correction for multiple testing, and none of the variants replicated in a sufficiently powered meta-analysis. Variants in the FBN3 gene (rs17202517 and rs73503752) were associated with smaller waist circumferences, and variant rs727428 in the SHBG gene was associated with lower sex hormone-binding globulin levels. CONCLUSION(S): Previously identified variants in candidate genes do not seem to be associated with PCOS risk. CLINICAL TRIAL REGISTRATION NUMBER: NCT00166569.

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin. Urbanek M et al. (1999) Polycystic ovary syndrome (PCOS) is a common endocrine disorder of women, characterized by hyperandrogenism and chronic anovulation. It is a leading cause of female infertility and is associated with polycystic ovaries, hirsutism, obesity, and insulin resistance. We tested a carefully chosen collection of 37 candidate genes for linkage and association with PCOS or hyperandrogenemia in data from 150 families. The strongest evidence for linkage was with the follistatin gene, for which affected sisters showed increased identity by descent (72%; chi(2) = 12.97; nominal P = 3.2 x 10(-4)). After correction for multiple testing (33 tests), the follistatin findings were still highly significant (P(c) = 0.01). Although the linkage results for CYP11A were also nominally significant (P = 0.02), they were no longer significant after correction. In 11 candidate gene regions, at least one allele showed nominally significant evidence for population association with PCOS in the transmission/disequilibrium test (chi(2) >/= 3.84; nominal P < 0.05). The strongest effect in the transmission/disequilibrium test was observed in the INSR region (D19S884; allele 5; chi(2) = 8.53) but was not significant after correction. Our study shows how a systematic screen of candidate genes can provide strong evidence for genetic linkage in complex diseases and can identify those genes that should have high (or low) priority for further study./////////////////Candidate gene region for polycystic ovary syndrome on chromosome 19p13.2. Urbanek M et al. (2005) Polycystic ovary syndrome (PCOS) is a common endocrine disorder that is believed to have a genetic basis. However, no specific susceptibility gene or region has been conclusively identified. The objective of this study was to duplicate a previous study that localized a PCOS susceptibility region to chromosome 19p13.2 and to narrow the susceptibility region. This study was designed to test for genetic linkage and association between PCOS and short tandem repeat polymorphisms in 367 families, by analysis of linkage and family-based association. The study was conducted at academic medical centers. We studied 367 families of predominantly European origin with at least one PCOS patient. Families included 107 affected sibling (sister) pairs (ASPs) in 83 families, and 390 trios with both parents and an affected daughter. The data set comprises two independent groups. Set 1 consists of 44 ASPs and 163 trios. Set 2 consists of 63 ASPs and 227 trios. The intervention was the drawing of blood for DNA extraction. We employed measures of evidence for linkage and association between PCOS and 19 STRs. Linkage with PCOS was observed over a broad region of chromosome 19p13.2. The strongest evidence for association was observed with D19S884 (chi2 = 11.85; nominal P < 0.0006; permutation P = 0.034) and duplicated our earlier findings. The present analysis suggests that a PCOS susceptibility locus maps very close to D19S884. Additional studies that systematically characterize DNA sequence variation in the immediate area of D19S884 are required to identify the PCOS susceptibility variant.//////////////////

Species: human
Mutation name:
type: None
fertility: None
Comment: Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Shi Y et al. (2012) Following a previous genome-wide association study (GWAS 1) including 744 cases and 895 controls, we analyzed genome-wide association data from a new cohort of Han Chinese () with 1,510 polycystic ovary syndrome (PCOS) cases and 2,016 controls. We followed up significantly associated signals identified in the combined results of GWAS 1 and 2 in a total of 8,226 cases and 7,578 controls. In addition to confirming the three loci we previously reported, we identify eight new PCOS association signals at P < 5 × 10(-8): 9q22.32, 11q22.1, 12q13.2, 12q14.3, 16q12.1, 19p13.3, 20q13.2 and a second independent signal at 2p16.3 (the FSHR gene). These PCOS association signals show evidence of enrichment for candidate genes related to insulin signaling, sexual hormone function and type 2 diabetes (T2D). Other candidate genes were related to calcium signaling and endocytosis. Our findings provide new insight and direction for discovering the biological mechanisms of PCOS. Fig. 2 At 19p13.3, rs2059807 (PGWAS-rep-meta = 1.09 × 10−8; ORGWAS-rep-meta = 1.14) is located in the intron of the INSR gene (MIM 147670) (Fig. 2, Table 1 and Supplementary Table 3). Controlling for rs2059807, conditional logistic regression analysis identified no additional association signals. //////////////////