Correction: Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

[This corrects the article DOI: 10.1371/journal.pgen.1007813.].

Harmonizing research outcomes for polycystic ovary syndrome (HARP), a marathon not a sprint: current challenges and future research need.

Investing in clinical research and evidence-based medicine has helped to improve the care for women with polycystic ovary syndrome (PCOS). However, several important questions remain unanswered on the optimal prevention and management strategies for PCOS. Addressing this uncertainty is often hindered by suboptimal research conduct leading to inefficient evidence synthesis and research wastage. PCOS research is often practised by varied specialized teams in silo leading to disharmonious and fragmented efforts neglecting the lifelong impact of PCOS on women's wellbeing. Poor engagement among key stakeholders and lay consumers continues to limit the impact and benefits of research to society. Selective reporting on surrogate outcomes with a 'significant' P-value is a common malpractice in PCOS outputs. Effective adoption of the harmonizing research outcomes for PCOS (HARP) core outcome set is needed to minimize heterogeneity in reporting and promote research excellence. Small single-centre studies offer limited value to assess the varied PCOS phenotypes. Efficient large scale data-sharing is needed to address complex research questions and glean the benefits of big data research. We propose a roadmap to address these challenges and remedy future research need by promoting patient and public involvement in PCOS research to guide research efforts and address real patients' needs; engaging all key stakeholder groups to promote a multi-disciplinary lifelong approach to new research; continuously refining research needs and priorities to revise the knowledge gap and allocate resources judiciously; standardizing outcomes definitions and measurement tools to harmonize reporting and promote excellence in research; and by investing in large data-sharing infrastructure to facilitate big data research and govern ethical data sharing.

Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.

Harmonising research outcomes for polycystic ovary syndrome: an international multi-stakeholder core outcome set.

STUDY QUESTION: What are the key core outcomes to be reported in studies on polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: We identified 3 generic and 30 specific core outcomes in 6 specialist domains: metabolic (8), reproductive (7), pregnancy (10), oncological (1), psychological (1) and long-term outcomes (1). WHAT IS KNOWN ALREADY: Research reporting PCOS is heterogeneous with high variation in outcome selection, definition and quality. STUDY DESIGN, SIZE, DURATION: Evidence synthesis and a modified Delphi method with e-surveys were used as well as a consultation meeting. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 71 health professionals and 123 lay consumers (women with lived experience of PCOS and members of advocacy and peer support groups) from 17 high-, middle- and low-income countries were involved in this analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The final core outcome set included 3 generic outcomes (BMI, quality of life, treatment satisfaction) that are applicable to all studies on women with PCOS and 30 specific outcomes that were categorised into six specialist domains: 8 metabolic outcomes (waist circumference, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypertension, coronary heart disease, lipid profile, venous thromboembolic disease); 7 reproductive outcomes [viable pregnancy (confirmed by ultrasound including singleton, twins and higher multiples), clinical and biochemical hyperandrogenism, menstrual regularity, reproductive hormonal profile, chronic anovulation, ovulation stimulation success including the number of stimulated follicles ≥ 12 mm, incidence and severity of ovarian hyperstimulation syndrome]; 10 pregnancy outcomes (live birth, miscarriage, stillbirth, neonatal mortality, gestational weight gain, gestational diabetes, preterm birth, hypertensive disease in pregnancy, baby birth weight, major congenital abnormalities); 3 psychological outcomes (depression, anxiety, eating disorders); 1 oncological (abnormal endometrial proliferation including atypical endometrial hyperplasia and endometrial cancer); and 1 outcome in the long-term domain (long-term offspring metabolic and developmental outcomes). LIMITATIONS, REASONS FOR CAUTION: We involved lay consumers in all stages of study through e-surveys but not through focus groups, thereby limiting our understanding of their choices. We did not address the variations in the definitions and measurement tools for some of the core outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Implementing this core outcome set in future studies on women with PCOS will improve the quality of reporting and aid evidence synthesis. STUDY FUNDING/COMPETING INTEREST(S): Evidence synthesis was funded through the Australian government, National Health and Medical Research Council (NHMRC) Centre for Research Excellence in PCOS, and H.T. is funded through an NHMRC fellowship. B.H.A. is funded through an NIHR lectureship. All authors have no competing interest to declare.

GWAS on prolonged gestation (post-term birth): analysis of successive Finnish birth cohorts.

BACKGROUND: Gestation is a crucial timepoint in human development. Deviation from a term gestational age correlates with both acute and long-term adverse health effects for the child. Both being born preterm and post-term, that is, having short and long gestational ages, are heritable and influenced by the prenatal and perinatal environment. Despite the obvious heritable component, specific genetic influences underlying differences in gestational age are poorly understood. METHODS: We investigated the genetic architecture of gestational age in 9141 individuals, including 1167 born post-term, across two Northern Finland cohorts born in 1966 or 1986. RESULTS: Here we identify one globally significant intronic genetic variant within the ADAMTS13 gene that is associated with prolonged gestation (p=4.85×10-8). Additional variants that reached suggestive levels of significance were identified within introns at the ARGHAP42 and TKT genes, and in the upstream (5') intergenic regions of the B3GALT5 and SSBP2 genes. The variants near the ADAMTS13, B3GALT5, SSBP2 and TKT loci are linked to alterations in gene expression levels (cis-eQTLs). Luciferase assays confirmed the allele specific enhancer activity for the BGALT5 and TKT loci. CONCLUSIONS: Our findings provide the first evidence of a specific genetic influence associated with prolonged gestation. This study forms a foundation for a better understanding of the genetic and long-term health risks faced by induced and post-term individuals. The long-term risks for induced individuals who have a previously overlooked post-term potential may be a major issue for current health providers.

Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.

Obesity-Related Hypogonadism in Women.

Obesity-related hypogonadotropic hypogonadism is a well-characterized condition in men (termed male obesity-related secondary hypogonadism; MOSH); however, an equivalent condition has not been as clearly described in women. The prevalence of polycystic ovary syndrome (PCOS) is known to increase with obesity, but PCOS is more typically characterized by increased gonadotropin-releasing hormone (GnRH) (and by proxy luteinizing hormone; LH) pulsatility, rather than by the reduced gonadotropin levels observed in MOSH. Notably, LH levels and LH pulse amplitude are reduced with obesity, both in women with and without PCOS, suggesting that an obesity-related secondary hypogonadism may also exist in women akin to MOSH in men. Herein, we examine the evidence for the existence of a putative non-PCOS "female obesity-related secondary hypogonadism" (FOSH). We précis possible underlying mechanisms for the occurrence of hypogonadism in this context and consider how such mechanisms differ from MOSH in men, and from PCOS in women without obesity. In this review, we consider relevant etiological factors that are altered in obesity and that could impact on GnRH pulsatility to ascertain whether they could contribute to obesity-related secondary hypogonadism including: anti-Müllerian hormone, androgen, insulin, fatty acid, adiponectin, and leptin. More precise phenotyping of hypogonadism in women with obesity could provide further validation for non-PCOS FOSH and preface the ability to define/investigate such a condition.

Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes.

BACKGROUND: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. RESULTS: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. CONCLUSION: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern.

PCOS Forum: research in polycystic ovary syndrome today and tomorrow.

OBJECTIVE: To summarize promising areas of investigation into polycystic ovary syndrome (PCOS) and to stimulate further research in this area. DESIGN: Summary of a conference held by international researchers in the field of polycystic ovary syndrome. RESULTS: Potential areas of further research activity include the analysis of predisposing conditions that increase the risk of PCOS, particularly genetic background and environmental factors, such as endocrine disruptors and lifestyle. The concept that androgen excess may contribute to insulin resistance needs to be re-examined from a developmental perspective, since animal studies have supported the hypothesis that early exposure to modest androgen excess is associated with insulin resistance. Defining alterations of steroidogenesis in PCOS should quantify ovarian, adrenal and extraglandular contribution, as well as clearly define blood reference levels by some universal standard. Intraovarian regulation of follicle development and mechanisms of follicle arrest should be further elucidated. Finally, PCOS status is expected to have long-term consequences in women, specifically the development of type 2 diabetes, cardiovascular diseases and hormone dependent cancers. Identifying susceptible individuals through genomic and proteomic approaches would help to individualize therapy and prevention. CONCLUSIONS: There are several intriguing areas for future research in PCOS. A potential limitation of our review is that we focused selectively on areas we viewed as the most controversial.

Analysis of multiple data sets reveals no association between the insulin gene variable number tandem repeat element and polycystic ovary syndrome or related traits.

CONTEXT: Variation at the insulin gene VNTR (variable number tandem repeat) minisatellite has been reported to be associated with polycystic ovary syndrome (PCOS), but findings have been inconsistent and all studies have featured small sample sizes. OBJECTIVE: To gain a robust understanding of the role of the INS-VNTR in PCOS susceptibility. DESIGN: Case-control, family-based association and quantitative trait analyses. SETTING AND PARTICIPANTS: A UK population comprising 255 parent-offspring trios, 185 additional cases, and 1062 control subjects (cases and controls all British/Irish) as well as 1599 women from a northern Finland population-based birth cohort characterized for PCO symptomatology and testosterone levels. VNTR class was inferred from genotyping of the -23HphI variant. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): INS-VNTR genotype frequencies between subject groups, body mass index, and testosterone levels by genotype. RESULTS: Case-control analyses in both UK and Finnish samples failed to confirm previously reported class III allele associations with PCOS (UK, P = 0.43, Finnish, P = 0.31; Kruskal-Wallis chi2). Transmission analysis in trios showed no excess transmission of either allele (P = 0.62), regardless of parent of origin (maternal: P = 0.73; paternal: P = 0.66). No association between genotype and testosterone levels was seen in any sample (UK PCOS subjects, P = 0.95; Finnish symptomatic cases, P = 0.38; Finnish control women, P = 0.58). CONCLUSIONS: Despite the strong biological candidacy and supportive data from previous studies, we conclude that variation at the INS-VNTR has no major role in the development of PCOS.

Variation within the type 2 diabetes susceptibility gene calpain-10 and polycystic ovary syndrome.

Variation within the calpain-10 gene (CAPN10) has been proposed to account for linkage to type 2 diabetes on chromosome 2q in Mexican-Americans, and associations with diabetes have been reported in several other populations. Given the epidemiological, physiological, and genetic overlap between type 2 diabetes and polycystic ovary syndrome (PCOS), CAPN10 represents a strong candidate gene for a role in PCOS susceptibility. Using both family based and case-control association resources (146 parent-offspring trios; 185 additional PCOS cases; 525 control subjects, all of European ancestry), we sought association between CAPN10 variation and PCOS, focusing on four single nucleotide polymorphism (SNP) variants (SNP-44, SNP-43; SNP-19; SNP-63). On single-locus transmission disequilibrium analysis in the 146 trios, there was nominal evidence (P = 0.03) of excess transmission of the more common allele at SNP-63. This association was not, however, replicated in the case-control analysis. No other significant associations were observed at the single-locus or haplotype level in either the transmission-disequilibrium or case-control analyses. The relative risk for the high-risk diabetes susceptibility 112/121 genotype (SNPs 43-19-63) was 0.84 (95% confidence intervals, 0.40-1.71). No associations were seen with intermediate traits of relevance to diabetes and PCOS pathogenesis. We have found no evidence from these analyses that CAPN10 gene variation influences susceptibility to PCOS.

Large-scale analysis of the relationship between CYP11A promoter variation, polycystic ovarian syndrome, and serum testosterone.

CYP11A, the gene encoding p450scc, a key enzyme in steroid biosynthesis, is a strong biological candidate for polycystic ovary syndrome (PCOS) susceptibility. Four of the five published studies that have examined CYP11A for evidence of linkage and/or association have reported significant relationships with polycystic ovary (PCO) status and/or serum testosterone levels. However, study sizes have been modest, and the current study aimed to reevaluate these findings using significantly larger clinical resources. A pair of CYP11A promoter microsatellites, including the pentanucleotide (D15S520) previously implicated in trait susceptibility, were genotyped in 371 PCOS patients of United Kingdom origin, using both case-control and family-based association methods, and in 1589 women from a population-based birth cohort from Finland characterized for PCO symptomatology and testosterone levels. Although nominally significant differences in allele and genotype frequencies at both loci were observed in the United Kingdom case-control study (for example, an excess of the pentanucleotide four-repeat allele in cases, P = 0.005), these findings were not substantiated in the other analyses, and no discernable relationship was seen between variation at these loci and serum testosterone levels. These studies indicate that the strength of, and indeed the existence of, associations between CYP11A promoter variation and androgen-related phenotypes has been substantially overestimated in previous studies.

Variants implicated in cortisone reductase deficiency do not contribute to susceptibility to common forms of polycystic ovary syndrome.

OBJECTIVE: There are close phenotypic similarities between cortisone reductase deficiency (CRD), a rare abnormality of cortisone metabolism, and polycystic ovary syndrome (PCOS). As there is evidence that CRD results from digenic mutations involving the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) and hexose-6-phosphate dehydrogenase (H6PD), we sought to establish whether CRD-associated variants in these genes, individually or in combination, influence susceptibility to PCOS. DESIGN: Case-control, family-based association and quantitative-trait analyses. PATIENTS: A UK case sample comprising 256 nuclear families ascertained from a PCOS offspring and 213 singleton PCOS cases plus 549 control subjects. MEASUREMENTS: All subjects were genotyped for CRD-related variants in HSD11B1 (rs12086634) and H6PD (rs6688832). Testosterone was measured with an in-house radioimmunoassay using ether extraction and dextran-coated charcoal separation. RESULTS: Case-control analyses revealed no differences in genotype distribution between PCOS and controls for rs12086634 or rs6688832 (both P = 0.84). Three per cent of cases and 2.4% of controls had genotype combinations (three or more variant alleles at the two sites) considered characteristic of CRD (P = 0.73). There were no departures from expectation in the family-based association studies, and no significant associations between genotypes (individually or in combination) and BMI, WHR or testosterone. CONCLUSIONS: The variants in HSD11B1 and H6PD typed, though implicated in causation of CRD, do not influence susceptibility to PCOS. It seems likely that additional variants within these genes are required for the development of CRD.

A steroid cell tumor outside the ovary is a rare cause of virilization.

OBJECTIVE: To report the case of a female who presented in childhood with symptoms and signs of hyperandrogenism secondary to an extraovarian steroid cell tumor. DESIGN: Case report. SETTING: Endocrine investigation unit of a university teaching hospital. PATIENT(S): An 11-year-old female presented with symptoms and signs of hyperandrogenism. INTERVENTION(S): Ultrasonography, MRI imaging, bilateral adrenal and ovarian venous sampling, laparoscopy, and laparotomy. MAIN OUTCOME MEASURE(S): Ultrasonography, laboratory tests. RESULT(S): Hyperandrogenism was due to an extraovarian steroid cell tumor located in the broad ligament. The tumor was successfully removed at laparotomy with biochemical and clinical resolution of the hyperandrogenism. CONCLUSION(S): Extraovarian steroid cell tumor is a rare cause of hyperandrogenism.