Genome-Wide Association Studies for Polycystic Ovary Syndrome

Liu, Hong Bin; Zhao, Han; Chen, Zi‐Jiang

doi:10.1055/s-0036-1585403

Cited by 33 publications

(21 citation statements)

References 36 publications

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“…Finally, as these changes in the oocyte mitochondria are transferred to the offspring, this may explain the inheritance pattern seen in the offspring of PCOS patients (53). PCOS is well known to be hereditary, though numerous studies investigating the genetic contributions to the disease have been unable to identify strong gene candidates to explain this pattern (54,55,56). Other alternative explanations may include alterations in mitochondrial DNA, increased cellular stress resulting in apoptosis or perhaps via direct effects to the mitochondria itself (26,29,42).…”

Section: Figurementioning

confidence: 99%

Prenatal androgen induced lean PCOS impairs mitochondria and mRNA profiles in oocytes

Chappell

Zhou

Schutt

et al. 2020

Endocrine Connections

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Polycystic ovary syndrome (PCOS) is the most common ovulatory defect in women. Although most PCOS patients are obese, a subset of PCOS women are lean but show similar risks for adverse fertility outcomes. A lean PCOS mouse model was created using prenatal androgen administration. This developmentally programmed mouse model was used for this study. Our objective was to investigate if mitochondrial structure and functions were compromised in oocytes obtained from lean PCOS mouse. The lean PCOS mouse model was validated by performing glucose tolerance test, HbA1c levels, body weight and estrous cycle analyses. Oocytes were isolated and were used to investigate inner mitochondrial membrane potential, oxidative stress, lipid peroxidation, ATP production, mtDNA copy number, transcript abundance and electron microscopy. Our results demonstrate that lean PCOS mice have similar weight to that of the controls but exhibit glucose intolerance and hyperinsulinemia along with dysregulated estrus cycle. Analysis of their oocytes show impaired inner mitochondrial membrane function, elevated reactive oxygen species (ROS) and increased RNA transcript abundance. Electron microscopy of the oocytes showed impaired mitochondrial ultrastructure. In conclusion, the lean PCOS mouse model shows a decreased oocyte quality related to impaired mitochondrial ultrastructure and function.

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Section: Figurementioning

confidence: 99%

Prenatal androgen induced lean PCOS impairs mitochondria and mRNA profiles in oocytes

Chappell

Zhou

Schutt

et al. 2020

Endocrine Connections

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“…While suggesting that future PCOS risk assessments for women may be possible based on an individual's genotype, and may lead to tailored clinical management, currently identified putative PCOS risk genes account for <10% of PCOS heritability [24]. At least 26 replicated PCOS risk genes have emerged from studies of human populations [24,28,[39][40][41][42], regulating a variety of reproductive functions, including gonadotropin secretion (FSHB), gonadotropin action and ovarian function (AMH and AMHR2; LHCGR, STON1 and GTF2A1L; FSHR; DENND1A; RAB5B and SUOX: HMGA2; C9orf3; YAP1; TOX3; RAD50; FBN3) as well as metabolic (THADA, GATA4 and NEIL2, ERBB2, ERBB3, ERBB4, SUMO1P1, INSR, KRR1) and neural (KCNA4) function. In particular, the post-transcription truncated isoform of DENND1A (DENND1A.V2) is over-expressed in women with PCOS and is functionally implicated in ovarian theca cell hyperandrogenism [43].…”

Section: The Evidence For Genetic Origins Of Pcosmentioning

confidence: 99%

Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application

et al. 2019

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Indian rhesus macaque nonhuman primate models for polycystic ovary syndrome (PCOS) implicate both female hyperandrogenism and developmental molecular origins as core components of PCOS etiopathogenesis. Establishing and exploiting macaque models for translational impact into the clinic, however, has required multi-year, integrated basic-clinical science collaborations. Paradigm shifting insight has accrued from such concerted investment, leading to novel mechanistic understanding of PCOS, including hyperandrogenic fetal and peripubertal origins, epigenetic programming, altered neural function, defective oocytes and embryos, adipogenic constraint enhancing progression to insulin resistance, pancreatic decompensation and type 2 diabetes, together with placental compromise, all contributing to transgenerational transmission of traits likely to manifest in adult PCOS phenotypes. Our recent demonstration of PCOS-related traits in naturally hyperandrogenic (High T) female macaques additionally creates opportunities to employ whole genome sequencing to enable exploration of gene variants within human PCOS candidate genes contributing to PCOS-related traits in macaque models. This review will therefore consider Indian macaque model contributions to various aspects of PCOS-related pathophysiology, as well as the benefits of using macaque models with compellingly close homologies to the human genome, phenotype, development and aging.

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“…Wide Association Studies (GWAS) have identified other several promising genes that may be related to the syndrome (Liu et al 2016;Zhao et al 2016). INSR, LHCGR, FSHR, YAP1, and C9orf3 are some examples of genes highlighted by these studies based on GWAS (Liu et al 2016).…”

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confidence: 99%

Polycystic Ovary Syndrome as a systemic disease with multiple molecular pathways: a narrative review

Carvalho

Reis

Cândido

et al. 2018

Endocrine Regulations

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Polycystic Ovary Syndrome (PCOS) is characterized by hyperandrogenism, amenorrhea, and polycystic ovaries. This endocrinopathy is associated with many metabolic disorders such as dyslipidemia and insulin resistance, with increased risk of type 2 diabetes mellitus, metabolic syndrome, and cardiovascular complications. Inflammation is likely to play an important role in the promoting these metabolic imbalances, while prothrombotic and pro-oxidative mechanisms further contribute to the cardiovascular risk of these patients. The etiology of PCOS is still not fully understood, but there is evidence of genetic and environmental components. This review aims to discuss some molecular pathways associated with PCOS that could contribute to the better understanding about this syndrome. Recent evidence suggests that intrauterine exposure of female mice to an excess of anti-Müllerian hormone may induce PCOS features in their post-natal life. High cytokine levels and cytokine gene polymorphisms also appear to be associated with the pathophysiology of PCOS. Furthermore, high levels of microparticles may contribute to the altered hemostasis and enhanced inflammation in PCOS. All these mechanisms may be relevant to clarify some aspects of PCOS pathogenesis and inspire new strategies to prevent the syndrome as well as treat its symptoms and mitigate the risk of long-term complications.

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Genome-Wide Association Studies for Polycystic Ovary Syndrome

Cited by 33 publications

References 36 publications

Prenatal androgen induced lean PCOS impairs mitochondria and mRNA profiles in oocytes

Prenatal androgen induced lean PCOS impairs mitochondria and mRNA profiles in oocytes

Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application

Polycystic Ovary Syndrome as a systemic disease with multiple molecular pathways: a narrative review

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