Female Genital Tract Polyp
Background
Female genital tract polyps are common benign growths of tissue that can occur in various parts of the female reproductive system, including the cervix, uterus (endometrial polyps), and less commonly, the vagina or fallopian tubes. These polyps are typically non-cancerous, though some can harbor atypical cells or, rarely, develop into malignancy. They can vary in size and number, and while many remain asymptomatic, others can lead to symptoms such as abnormal vaginal bleeding, pain, or infertility. The exact causes of polyps are not fully understood, but their development is thought to involve a complex interplay of hormonal, inflammatory, and genetic factors.
Biological Basis
The formation of female genital tract polyps involves abnormal cellular proliferation and differentiation, often influenced by hormonal fluctuations and local inflammatory responses. Genetic predispositions play a role in the broader spectrum of gynecologic diseases, which can provide insight into polyp development. Genome-wide association studies (GWAS) have identified genetic variants associated with several gynecologic conditions, such as uterine fibroids, endometriosis, ovarian cancer, uterine endometrial cancer, and uterine cervical cancer, particularly in populations like the Japanese. [1]
For instance, specific genetic loci have been linked to uterine fibroids and endometriosis, including variants near genes like WNT4/CDC42 (e.g., rs7412010), STN1 (OBFC1) (e.g., rs12415148), BET1L/RIC8A (e.g., rs12225799), and TNRC6B (e.g., rs17332320). [1] Some of these variants are noncoding, meaning they do not directly alter protein sequences but may influence gene expression through other mechanisms. For example, a low-frequency noncoding variant, rs567534295, located within an intron of BRCA1, has been associated with ovarian cancer. [1] Alterations in gene regulatory motifs, such as Ets and GATA, may also lead to changes in transcriptional activity, contributing to disease pathology. [1] Heritability estimates from SNP data indicate a genetic component to these conditions, with endometriosis showing a notably higher heritability compared to ovarian cancer [1] suggesting a significant genetic influence on their development.
Clinical Relevance
Female genital tract polyps are clinically relevant due to their potential to cause symptoms and the need to differentiate them from more serious conditions. Abnormal uterine bleeding is a common symptom, which can lead to anemia and affect quality of life. Polyps can also contribute to infertility by interfering with sperm transport or embryo implantation. Diagnosis typically involves imaging techniques, such as ultrasound or hysteroscopy, followed by biopsy or surgical removal (polypectomy) for definitive diagnosis and treatment. The genetic insights gained from studies on related gynecologic diseases can inform a better understanding of individual susceptibility. Identifying genetic risk factors could potentially contribute to improved screening strategies, personalized risk assessments, or novel therapeutic targets for a range of female reproductive health issues. [1]
Social Importance
The prevalence of female genital tract polyps and other gynecologic diseases underscores their significant social importance, impacting women's health, reproductive capabilities, and overall well-being globally. These conditions can cause considerable distress, requiring medical consultations, diagnostic procedures, and treatments, which contribute to healthcare burdens. Research into the genetic underpinnings of these diseases, particularly in diverse populations, is crucial for understanding health disparities and developing more effective, population-specific interventions. [1] By shedding light on the biological mechanisms and genetic predispositions, such studies contribute to public health efforts aimed at improving diagnostic accuracy, prevention strategies, and treatment outcomes for women.
Study Design and Statistical Power Limitations
Studies on female genital tract polyps, such as uterine fibroids (UF), often involve sample sizes that, while substantial (e.g., 5236 for UF cases), may still limit the statistical power to detect genetic variants with small effect sizes. [1] This can lead to an inflation of reported effect sizes for initially identified associations and contributes to a high testing burden, where some findings, particularly those not meeting stringent genome-wide significance thresholds, may require further replication in independent cohorts to confirm their validity. [2] Furthermore, the choice of GWAS algorithm can impact the predictive accuracy of polygenic scores, as some methods have been shown to be less predictive than others, influencing the reliability of risk stratification. [3] Additionally, certain methods employed for heritability estimation, such as PCGC-s, may not provide standard errors or P-values for their estimates, thereby complicating a comprehensive understanding of the genetic contributions to these conditions. [1]
Phenotypic Definition and Generalizability Challenges
The precise definition and ascertainment of phenotypes, such as female genital tract polyps, can vary across studies, ranging from self-reported diagnoses to those based on medical records or mixed approaches, introducing heterogeneity in meta-analyses. [4] This variability in phenotype capture can obscure true genetic signals or lead to inconsistent findings. Additionally, while some studies utilize robust methods like genetically-inferred sex matching and careful covariate adjustment for quantitative traits like hormone levels, residual confounding from incompletely captured phenotypic nuances or environmental factors remains a possibility. [1] Genetic association studies often face limitations in generalizability due to restricted population diversity, with many analyses primarily focusing on individuals of European or specific East Asian ancestries. [5] This narrow scope means that findings may not be directly transferable to other populations, and important ancestry-specific genetic factors influencing polyp development might be overlooked. [2] Differences in linkage disequilibrium patterns across diverse populations also necessitate ancestry-matched reference panels for accurate imputation and conditional analyses, posing a challenge for multi-ancestry research. [4]
Unaccounted Environmental Factors and Remaining Knowledge Gaps
Despite efforts to adjust for known covariates such as age and BMI, the complex interplay between genetic predispositions and environmental factors, including gene-environment interactions, is often not fully elucidated. [1] Unmeasured confounders, beyond documented ancestry and case ascertainment, can contribute to observed heterogeneity in genetic effects across studies. [4] This limitation suggests that a substantial portion of the heritability for female genital tract polyps may still be unaccounted for, highlighting the need for more comprehensive data collection on lifestyle and environmental exposures. Current research, while identifying novel genetic associations, still has significant knowledge gaps regarding the full spectrum of genetic and biological mechanisms underlying female genital tract polyps. [2] Many detected loci have small effects, and the precise functional consequences of these variants, particularly non-coding ones, often remain to be fully characterized. [1] Future studies are needed to explore broader populations, incorporate diverse methodologies, and integrate multi-omics data to uncover the complete genetic architecture and environmental influences on these conditions. [2]
Variants
Genetic variations play a crucial role in influencing cellular processes that can contribute to the development of benign growths such as female genital tract polyps. Several variants are implicated in genes that regulate fundamental aspects of cell growth, differentiation, and metabolism. For instance, the rs1702136 variant is associated with EEFSEC, a gene essential for the specific incorporation of selenocysteine into proteins, a process vital for antioxidant defense and overall cellular function. Disruptions in EEFSEC can affect protein integrity and cell viability. Similarly, the rs2865375 variant is linked to BMPR1B, a receptor in the Bone Morphogenetic Protein signaling pathway, which is critical for controlling cell proliferation, differentiation, and tissue development. [1] Alterations in BMPR1B activity can lead to aberrant cell growth and developmental issues, potentially contributing to polyp formation. The rs800578 variant is found near TRPS1 and LINC00536; TRPS1 is a transcriptional repressor involved in cell cycle regulation and differentiation, with its dysregulation implicated in developmental disorders and various cancers. LINC00536, a long non-coding RNA, can modulate gene expression, influencing cellular processes critical for tissue homeostasis, including those relevant to polyp development. [6] The rs2277339 variant is associated with PRIM1 and HSD17B6; PRIM1 is essential for initiating DNA replication, while HSD17B6 is involved in steroid hormone metabolism, particularly the inactivation of androgens. Variations affecting these genes could influence the balance of cell proliferation and steroid hormone levels, both significant factors in the growth of female genital tract polyps.
Other variants highlight genes that govern cell structure, adhesion, and signaling, processes fundamental to maintaining tissue integrity and proper cellular communication. The rs193097753 variant is associated with SH3PXD2A, a gene critical for cell adhesion, migration, and the formation of invadopodia, which are structures important for tissue remodeling and potentially invasive growth. Changes in SH3PXD2A function can lead to altered cellular movement and contribute to the disorganized growth characteristic of polyps. The rs7728894 variant is located in ARHGAP26, a Rho GTPase activating protein that regulates Rho family GTPases, which are key molecular switches controlling the actin cytoskeleton, cell shape, and motility. Dysregulation of ARHGAP26 can disrupt normal cell migration and tissue architecture, potentially fostering abnormal tissue development. [1] Additionally, the rs77478686 variant is associated with RAC1P3 and NAA16; RAC1P3 is a pseudogene related to RAC1, a Rho GTPase involved in cell proliferation, survival, and motility, suggesting potential regulatory roles in these processes. NAA16 is a subunit of the N-terminal acetyltransferase complex, which modifies proteins and affects their stability and function, with implications for overall cellular health and disease development. [6]
Finally, a set of variants are linked to genes involved in fundamental regulatory processes, including transcription and immune response, which are pertinent to abnormal tissue growth. The rs12751005 variant is associated with NFIA, a nuclear factor I family transcription factor that plays a crucial role in tissue-specific gene expression and development. Variants in NFIA could alter the transcriptional programs essential for normal cellular differentiation and growth, potentially contributing to the aberrant cell growth seen in female genital tract polyps. The rs2967684 variant is linked to NFILZ, or Nuclear Factor, Interleukin 3 Regulated, a transcription factor that may be involved in immune and inflammatory responses. [1] Chronic inflammation is a known contributor to the development and progression of various benign growths, including polyps, making variants in genes like NFILZ relevant. Lastly, the rs7705526 variant is associated with TERT, the gene encoding the telomerase reverse transcriptase, an enzyme vital for maintaining telomere length and thus cellular immortality. Alterations in TERT function or expression can impact cell lifespan and proliferation, a key factor in the development of abnormal growths. [6]
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| rs1702136 | EEFSEC | prostate cancer female genital tract polyp |
| rs800578 | TRPS1 - LINC00536 | female genital tract polyp |
| rs2277339 | PRIM1, HSD17B6 | platelet crit erythrocyte volume age at menopause BMI-adjusted waist-hip ratio age at menarche |
| rs2865375 | BMPR1B | female genital tract polyp |
| rs12751005 | NFIA | female genital tract polyp |
| rs193097753 | SH3PXD2A | Uterine leiomyoma female genital tract polyp |
| rs77478686 | RAC1P3 - NAA16 | female genital tract polyp |
| rs7728894 | ARHGAP26 | endometriosis female genital tract polyp |
| rs7705526 | TERT | leukocyte quantity platelet crit neutrophil count, eosinophil count granulocyte count neutrophil count, basophil count |
| rs2967684 | NFILZ | endometriosis female genital tract polyp |
Genetic Susceptibility and Polygenic Risk
The development of female genital tract polyps is significantly influenced by an individual's genetic makeup, with evidence pointing to both specific inherited variants and broader polygenic risk. Genome-wide association studies (GWAS) have identified several loci associated with gynecologic diseases, such as uterine fibroids and endometrial cancer, which are relevant to polyp formation. [1] For instance, specific single nucleotide polymorphisms (SNPs) like rs7412010 at 1p36 (near CDC42/WNT4), rs12415148 at 10q24 (near STN1 (OBFC1)), rs12225799 at 11p15 (near BET1L/RIC8A), and rs17332320 at 22q31 (near TNRC6B) have been significantly associated with uterine fibroids, suggesting key genetic predispositions for abnormal tissue growth within the female reproductive system. [1]
These genetic associations highlight a polygenic architecture, where multiple genes and their variants collectively contribute to the overall risk. Furthermore, there is evidence of shared genetic architecture and comorbidity between female infertility and other reproductive disorders like endometriosis and polycystic ovary syndrome (PCOS), indicating that genetic factors predisposing to one condition may also influence the risk of polyp development. [4] Such genetic predispositions can interact, potentially leading to varied susceptibilities and clinical presentations of polyps.
Epigenetic Regulation and Developmental Influences
Beyond direct genetic sequence variations, epigenetic mechanisms play a crucial role in the etiology of female genital tract polyps by regulating gene expression without altering the underlying DNA sequence. Modifications such as DNA methylation and histone modifications can profoundly affect cellular processes, including proliferation and differentiation, which are fundamental to polyp formation. [1] Research indicates that alterations in specific regulatory elements, such as Ets and GATA motifs, can lead to changes in transcriptional activity, potentially driving aberrant cell growth and the development of polyps. [1]
These epigenetic changes can be influenced by early life experiences and developmental processes, suggesting that environmental exposures or physiological states during critical periods could leave lasting marks on the genome. Such modifications, including specific histone marks, may lead to sustained alterations in gene expression patterns in relevant tissues, thereby contributing to an increased lifetime risk for polyp development. [1]
Interactions with Environmental Factors and Comorbidities
The etiology of female genital tract polyps is not solely genetic but also involves complex interactions with environmental factors and the presence of other health conditions. While specific environmental factors for female genital tract polyps are not extensively detailed, studies on other polyp types, such as serrated colorectal polyps, highlight the influence of lifestyle risk factors. [7] These broader insights suggest that diet, exposure to certain substances, and general lifestyle choices may modulate an individual's susceptibility to polyp development, especially when combined with a genetic predisposition. [8]
Furthermore, gene-environment interactions are critical, where an individual's genetic background can modify their response to environmental triggers, thus influencing their overall risk. [9] Comorbidities also significantly contribute to polyp development. There is a recognized genetic overlap and shared susceptibility between female infertility and reproductive disorders like endometriosis and polycystic ovary syndrome (PCOS), suggesting that these conditions might share underlying causal pathways that also predispose to polyp formation. [4] The presence of such inflammatory or hormonal imbalances in the genital tract could create an environment conducive to abnormal tissue growth.
Cellular Proliferation and Tissue Homeostasis
Female genital tract polyps represent benign, localized overgrowths of tissue, which are characterized by an imbalance in normal cellular proliferation and programmed cell death. These proliferative diseases, similar to uterine fibroids, involve the disruption of the delicate homeostatic mechanisms that regulate cell growth and tissue architecture within specific organs. [1] The development of polyps suggests an uncontrolled expansion of certain cell populations, leading to the formation of a mass that protrudes from the mucosal surface. This process often involves a dysregulation of the signaling pathways that normally control cell division, differentiation, and tissue repair, resulting in an accumulation of cells rather than their orderly turnover.
These benign growths are analogous in some ways to benign prostatic hyperplasia (BPH) in males, which is also a non-malignant enlargement of tissue, specifically the prostate, and becomes more prevalent with age. [6] Such conditions underscore a general biological principle where intrinsic factors, potentially including age-related changes, can compromise the strict control over cell numbers. The specific tissue environment within the female genital tract, encompassing its unique cellular composition and physiological demands, contributes to the distinct characteristics and locations of polyp formation, necessitating precise regulatory networks to maintain its integrity.
Genetic Predisposition and Regulatory Networks
Genetic mechanisms play a significant role in an individual's susceptibility to proliferative conditions like polyps, with specific gene functions and regulatory elements influencing cellular behavior. Genome-wide association studies (GWAS) are employed to identify genetic variants, such as single nucleotide polymorphisms (SNPs), that are significantly associated with these diseases. [10] These variants can impact gene expression patterns by altering regulatory elements like transcription factor binding sites. For instance, alterations in Ets and GATA motifs have been shown to affect transcriptional activity [1] with transcription factors such as GATA3 being essential in tissue development and implicated in conditions like benign prostatic hyperplasia. [11]
Beyond direct gene sequence variations, epigenetic modifications, such as changes in histone marks, can also modulate gene expression without altering the underlying DNA sequence. These modifications can influence how genes are turned on or off, thereby contributing to the abnormal cell proliferation seen in polyp formation. [1] Furthermore, variants in genes like PSCA, a glycosylphosphatidylinositol-anchored membrane glycoprotein, can affect transcriptional repressors such as CTCF (CCCTC-binding factor) motifs in promoter regions. [12] Such genetic and epigenetic alterations collectively disrupt the finely tuned regulatory networks that govern normal tissue development and maintenance, leading to the initiation and progression of benign growths.
Hormonal and Inflammatory Influences
The formation of female genital tract polyps is often influenced by the intricate interplay of hormonal and inflammatory processes, which are critical in maintaining reproductive health. Sex hormones, particularly estrogens, are known to regulate cell growth and differentiation within the female reproductive system, and functional genetic polymorphisms in genes like the estrogen receptor alpha (ESR1) can influence female reproductive disorders. [13] Dysregulation in hormonal signaling pathways, potentially due to altered receptor sensitivity or hormone levels, can promote uncontrolled cellular proliferation, contributing to the development of polyps. These hormonal factors are also implicated in other benign proliferative conditions, such as benign prostatic hyperplasia, alongside age and metabolic factors. [6]
In addition to hormonal effects, chronic inflammation within the genital tract can act as a potent driver of cellular proliferation and tissue remodeling, fostering an environment conducive to polyp formation. Inflammatory conditions are recognized as comorbidities with other gynecologic diseases like endometriosis, highlighting their broader impact on reproductive health. [4] The sustained presence of inflammatory mediators and immune cells can disrupt normal tissue repair mechanisms, leading to persistent cellular activation and an increased risk of abnormal tissue growth. Therefore, the combined influence of hormonal imbalances and inflammatory responses creates a complex pathophysiological landscape that can predispose individuals to the development of female genital tract polyps.
Key Biomolecules and Molecular Pathways
The development of female genital tract polyps is orchestrated by the dysregulation of key biomolecules and molecular signaling pathways that govern cellular behavior. Critical proteins, enzymes, and receptors mediate the intricate processes of cell growth, division, and adhesion. Hormones, such as estrogens, act as important signaling molecules, binding to specific receptors and activating downstream pathways that promote cell proliferation. [13] Transcription factors like GATA proteins, which bind to specific DNA motifs, are crucial for regulating gene expression and cellular differentiation, and their altered activity can contribute to abnormal tissue growth. [1]
Furthermore, structural components within the extracellular matrix and cell-to-cell adhesion molecules are vital for maintaining tissue integrity and architecture. Disruptions in these components can lead to altered cellular interactions and migration, facilitating the disorganized growth characteristic of polyps. Molecular pathways involved in cell cycle control, apoptosis, and cellular metabolism are also frequently implicated. For instance, pathways related to glycosphingolipid biosynthesis and ceramide signaling, identified in other immune and proliferative contexts, highlight the complexity of metabolic and lipid signaling in cellular regulation. [12] Understanding these biomolecules and their interconnected pathways is fundamental to elucidating the precise mechanisms underlying polyp formation.
Hormonal and Developmental Signaling Pathways
The genesis of female genital tract polyps can involve intricate hormonal and developmental signaling pathways that regulate tissue growth and differentiation. For instance, the TRH receptor signaling pathway, part of the hypothalamus–pituitary axis, plays a crucial role in stimulating the release of thyroid-stimulating hormone and prolactin, with thyroid hormones being essential for normal sexual development. [14] Dysregulation within such neuroendocrine axes can impact the delicate hormonal balance governing female reproductive tissues. Furthermore, sex hormones and metabolic factors are implicated in benign tissue enlargements, suggesting that an imbalance or altered sensitivity to these cues could drive abnormal proliferation in the female genital tract. [6] Developmental pathways, such as those involving Wnt4, which is critical for gonadal development, and the signaling of inhibins and activins, important regulators in reproductive biology, also represent potential mechanisms where altered activity could contribute to polyp formation. [15]
Cellular Proliferation, Apoptosis, and Tissue Remodeling
The formation of polyps is fundamentally linked to an imbalance between cell proliferation and programmed cell death, or apoptosis, which is a hallmark of tissue remodeling. [14] Pathways that regulate cell growth and differentiation, such as the TGF-b and Hippo signaling pathways, are critical for controlling stem cell pluripotency, proliferation, invasion, and migration. [16] While often studied in the context of malignant progression, dysregulation of these fundamental pathways can also lead to non-malignant tissue overgrowth, as seen in various benign conditions. Additionally, transcription factors like GATA family members, which have an essential role in adult murine glandular tissues, are key regulators of gene expression involved in cell fate and tissue maintenance, and their aberrant activity could contribute to uncontrolled cellular expansion characteristic of polyps. [11]
Inflammation and Immune Response Pathways
Chronic inflammation and dysregulated immune responses are significant contributors to the development of benign tissue growths, including those in the female genital tract. Research indicates that genes associated with benign traits are frequently enriched in pathways related to chronic inflammation and immune responses. [16] This includes processes such as cellular responses to interferon-gamma, mechanisms underlying intestinal inflammation, MHC class II receptor activity, and the production of immunoglobulins like IgA. [16] The persistent inflammatory state can create a microenvironment conducive to abnormal cell proliferation and tissue remodeling, fostering the conditions for polyp formation. This is consistent with observations in other gynecologic diseases, such as endometriosis, which often involve a significant inflammatory component. [4]
Gene Regulation and Metabolic Homeostasis
The precise regulation of gene expression and maintenance of metabolic homeostasis are crucial for preventing abnormal tissue growth. Transcription factors, such as those in the GATA family, exert hierarchical control over gene regulation, influencing cell differentiation and tissue development. [11] Alterations in these regulatory mechanisms can lead to the inappropriate activation or suppression of genes, driving cellular changes that predispose to polyp formation. Furthermore, metabolic factors are implicated in the etiology of benign tissue enlargements, suggesting that disruptions in energy metabolism, biosynthesis, or catabolism can fuel aberrant cell growth. [6] Specific metabolic pathways like glycosphingolipid biosynthesis and ceramide signaling, along with the glucocorticoid receptor regulatory network, represent critical points where metabolic regulation and cellular function intersect, potentially contributing to the development of polyps when dysregulated. [12]
Frequently Asked Questions About Female Genital Tract Polyp
These questions address the most important and specific aspects of female genital tract polyp based on current genetic research.
1. My mom had polyps. Am I more likely to get them too?
Yes, there can be a genetic component to gynecologic conditions, including polyps. While the exact genes specific to polyps are still being researched, related conditions like uterine fibroids and endometriosis show significant heritability. This means a family history of these issues can suggest an increased susceptibility for you.
2. My sister has endometriosis. Does that mean I'm at higher risk for polyps?
It's possible. The article highlights that polyps and other gynecologic diseases, like endometriosis, can share some underlying genetic predispositions. For instance, specific genetic variants linked to endometriosis might indicate a broader genetic susceptibility that could influence your risk for related conditions such as polyps.
3. Can my diet or lifestyle prevent me from getting polyps?
The exact causes of polyps involve a complex interplay of hormonal, inflammatory, and genetic factors, with environmental factors also playing a role. While a healthy lifestyle is generally beneficial for overall well-being, the article doesn't specifically detail how diet or lifestyle directly prevent polyp formation based on genetic insights.
4. I have abnormal bleeding. Could polyps be causing my fertility problems?
Yes, they absolutely can. Polyps, especially those in the uterus, can interfere with crucial processes like sperm transport or embryo implantation, making it harder to conceive. If you're experiencing abnormal bleeding and struggling to get pregnant, it's important to investigate polyps as a potential cause.
5. Why do some women get polyps while others never do?
It's a complex interplay, but genetics plays a significant role in individual susceptibility. Just like some women are more prone to conditions like uterine fibroids or endometriosis due to specific genetic variations, similar predispositions are thought to influence polyp development. Hormonal fluctuations and local inflammation also contribute to why some women develop them.
6. I'm not of European descent. Does my ethnic background affect my polyp risk?
Yes, it can. Genetic association studies often reveal different risk factors across diverse populations, with many analyses primarily focusing on European or specific East Asian ancestries. Your ethnic background might have unique genetic factors that influence your risk, which underscores the importance of research in diverse populations.
7. Is there any way to know my personal risk of getting polyps?
Currently, there isn't a simple test to predict your individual polyp risk. However, understanding your family history of gynecologic issues and discussing any symptoms like abnormal bleeding with your doctor are important steps. Future genetic insights could potentially lead to more personalized risk assessments.
8. Can stress or how much sleep I get influence if I get polyps?
Polyps involve abnormal cellular proliferation and differentiation, often influenced by hormonal fluctuations and local inflammatory responses. While stress and sleep can impact your overall hormonal balance and inflammation, the article doesn't specifically detail a direct genetic link or the extent to which these daily habits influence polyp development.
9. If I get a polyp removed, will it grow back again later?
The article focuses on the initial development of polyps, driven by hormonal, inflammatory, and genetic factors, rather than their recurrence after removal. While genetic predispositions suggest an underlying susceptibility, the article doesn't provide specific information on whether polyps are likely to grow back after being removed.
10. Can I take something to prevent polyps instead of needing surgery?
Diagnosis for polyps typically involves imaging, followed by biopsy or surgical removal (polypectomy) for definitive diagnosis and treatment. While genetic insights could eventually contribute to novel therapeutic targets, the article doesn't mention any current medications that prevent polyps from forming or requiring surgical intervention.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
[1] Masuda T, et al. "GWAS of five gynecologic diseases and cross-trait analysis in Japanese." Eur J Hum Genet, 2019.
[2] Lesseur, C., et al. "Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers." PLoS Genetics, vol. 17, no. 3, 2021.
[3] Loya, H., et al. "A scalable variational inference approach for increased mixed-model association power." Nature Genetics, 2024.
[4] Rahmioglu N, et al. "The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions." Nat Genet, 2023.
[5] Choe, E. K., et al. "Leveraging deep phenotyping from health check-up cohort with 10,000 Korean individuals for phenome-wide association study of 136 traits." Scientific Reports, vol. 12, no. 1, 2022.
[6] Gudmundsson J, et al. "Genome-wide associations for benign prostatic hyperplasia reveal a genetic correlation with serum levels of PSA." Nat Commun, 2017.
[7] Bailie, L., Loughrey, M. B. & Coleman, H. G. "Lifestyle risk factors for serrated colorectal polyps: A systematic review and meta-analysis." Gastroenterology, vol. 152, 2017, pp. 92–104.
[8] Huang, Y., et al. "Air pollution, genetic factors, and the risk of Lung cancer: A prospective study in the UK Biobank." American Journal of Respiratory and Critical Care Medicine, vol. 204, 2021, pp. 817–825.
[9] Hunter, D. J. "Gene-environment interactions in human diseases." Nature Reviews Genetics, vol. 6, 2005, pp. 287–298.
[10] Kerns SL, et al. "A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of urinary symptoms after radiotherapy for prostate cancer." J Urol, 2013.
[11] Na R, et al. "A genetic variant near GATA3 implicated in inherited susceptibility and etiology of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS)." Prostate, 2017.
[12] Tian C, et al. "Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections." Nat Commun, 2017.
[13] Aschebrook-Kilfoy B, et al. "Genome-wide association study of parity in Bangladeshi women." PLoS One, 2015.
[14] Cousminer, D. L. et al. "Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty." Hum Mol Genet, 2014.
[15] Venkatesh, S. S. et al. "Genome-wide analyses identify 25 infertility loci and relationships with reproductive traits across the allele frequency spectrum." Nat Genet, 2024.
[16] Jiang, Y. et al. "A cross-disorder study to identify causal relationships, shared genetic variants, and genes across 21 digestive disorders." iScience, 2023.