Genetic Infertility Loci: Why Some People Struggle to Have a Baby

We begin this important topic with the question, what is infertility? Infertility is a medical condition where a person or couple is unable to conceive a child after one year of regular, unprotected sexual intercourse. It affects both men and women and can result from a variety of biological, environmental, genetic, and lifestyle-related factors. Therefore, infertility is a deeply personal and growing health concern. According to the World Health Organization (WHO) reported data, about one in six individuals will experience infertility during their lifetime. That equates to over 180 million people worldwide today. The journey toward building a family can be fraught with emotional, financial, and medical challenges—particularly when tests reveal no obvious cause. 

But recent genetic research is shedding light on some of these mysteries. A large-scale study involving more than 1.5 million participants has identified 25 genetic infertility loci—distinct regions on our chromosomes that may influence fertility outcomes.

These genetic signals help explain why some people struggle to conceive even when conventional medical investigations are clear. This post explores the current study’s findings, genetic mechanisms, examines clinical applications, and considers future directions in fertility science.

What Are Genetic Infertility Loci?

Basically, infertility loci are genetic loci. A genetic locus (plural: loci) refers to a specific, fixed position on a chromosome—much like an address in your genetic instruction manual. It is estimated that human genome consists of approximately 20,000 to 30,000 loci. Each locus often contains one or more genes that help build proteins or regulate functions essential for life.

When biotechnology scientists refer to genetic infertility loci, they mean regions in the genome where changes (variants or mutations) have a statistically significant association with infertility—either male, female, or both. These variants can subtly impair processes like:

1. Hormone signaling (e.g., estrogen receptors)
2. Gonadal development (e.g., uterine or testicular formation)
3. Gametogenesis (egg or sperm maturation)
4. Immune tolerance (particularly critical during early pregnancy)
5. Cell cycle and DNA repair (vital for healthy eggs or sperm)

Understanding these loci gives researchers a map of where to look for biological clues when fertility problems are otherwise unexplained.

Discovery of 25 Genetic Infertility Loci

Recently, the Nature Genetics 2025 publication, titled “Genome-wide analyses identify 25 infertility loci and relationships with reproductive traits across the allele frequency spectrum,” represents a landmark in reproductive genetics. Through the analysis of genome-wide association study (GWAS) data from 1.5 million individuals of diverse backgrounds, researchers:

1. First, discovered 25 significant loci linked to infertility,
2. Specifically, found 22 loci associated with female infertility and 3 loci linked to male infertility.
3. Furthermore, observed that many variants fell at or near genes involved in reproductive organ development, hormone function, and cellular processes,

Importantly, this large, multi-ethnic cohort adds robustness—findings are not limited to a single population or region, increasing their usability in global clinical settings.

Key Genetic Infertility Loci in Women

Female fertility depends on a complex, finely coordinated biological process, and disruption at any stage can lead to infertility. The journey begins with the formation of;

Reproductive Organ Development: Laying the Foundation

Female fertility begins with the proper development of the reproductive organs during embryogenesis. Genes such as WNT4 and PROX1 play critical roles in this foundational step.

1. WNT4, located at 1p36.12, is vital for the formation of the uterus and ovaries.
2. PROX1 (1q32.2) is a transcription factor involved in guiding organogenesis.

Disruption in either gene can lead to malformations or underdevelopment of the reproductive tract, impairing fertility from the earliest stages.

Hormonal Signaling Regulation: The Endocrine Symphony

Once the reproductive organs are formed, their function is orchestrated by precise hormonal signaling. Specifically, genes like GREB1, ESR1, TRHR, and ZEB2 ensure the correct response to sex hormones.

1. GREB1 (2p25.1) and ESR1 (6q25.1) are integral to the estrogen response pathway, which governs reproductive cycles and ovulation.
2. TRHR (8q23.1) connects the hypothalamus to ovarian activity via the thyroid axis.
3. ZEB2 (2q22.3) helps regulate hormone signaling cascades at the transcriptional level.

Alterations in these genes can distort hormone balance and feedback loops, disturbing ovulatory cycles and hormone responsiveness.

Ovulation and Follicle Regulation: Ensuring Egg Release

A successful ovulation process is essential for fertility.

1. INHBB (2q14.2) encodes the inhibin β B subunit, which regulates FSH—a hormone that controls follicle development.
2. DENND1A (9q33.3) influences the risk for Polycystic Ovary Syndrome (PCOS), a major cause of anovulation.

Malfunctions in these genes can lead to irregular cycles, failure of egg release, or hormonal imbalances characteristic of PCOS, all of which are significant contributors to infertility.

Oocyte Quality and Maturation: Preserving Egg Health

As follicles mature, several genes ensure the egg cell remains viable and structurally sound.

1. AZIN1 (8q22.3) supports egg cell growth, while
2. SYNE1 (6q25.2) and AKAP12 (6q24.2) help maintain cellular architecture and coordinate signaling pathways.
3. FBXO48 (17q12) and TTC28 (22q12.3) manage protein turnover and cell division during egg maturation.
4. CHEK2 (22q12.1) acts as a DNA checkpoint kinase that repairs DNA damage in oocytes.

Disruptions in these processes can lower egg quality, reduce fertilization potential, and contribute to age-related or idiopathic infertility.

Immune Tolerance and Implantation: Preparing for Embryo Reception

Following fertilization, a receptive uterine environment is crucial for embryo implantation and pregnancy progression.

1. PKHD1L1 (8q22.1) and EBAG9 (8q21.13) are involved in immune modulation, allowing the maternal immune system to tolerate the embryo.
2. TNFSF12 (17p13.1) fine-tunes cytokine signaling to support implantation, while
3. TMEM26 (4q32.1) is a novel marker under study for its potential role in endometrial receptivity.

Faults in these genes may lead to implantation failure or recurrent pregnancy loss, impeding the establishment of a successful pregnancy.

Metabolic and Medication Response: Influencing Treatment Outcomes

For women with metabolic disorders like PCOS, treatment response can vary depending on genetic makeup.

1. SLC47A2 (17q24.3) encodes a drug transporter that affects how patients respond to medications such as metformin.

Variability in this gene can alter treatment efficacy, making personalized medicine an important consideration in reproductive healthcare.

Additional Contributors: Underexplored but Impactful

Other genes also contribute to fertility in less direct but meaningful ways:

1. UBE2K (4q21.1) and BCOR (Xq26.1) regulate protein degradation and gene expression necessary for proper ovarian function.
2. GPC2 (7q22.1) is linked to hormone signaling, and although rare, it may contribute to unexplained infertility.

These emerging markers highlight the intricate genetic web influencing female fertility, many of which are still under investigation.

Conclusion: A Continuous Genetic Symphony

Based on these steps, it becomes clear that female infertility is not caused by a single gene or step, but rather by a cascade of interconnected biological processes—each controlled by specific genes. For instance, disruptions can occur at various stages: such as from organ formation (WNT4, PROX1) and hormonal signaling (ESR1, GREB1, ZEB2) to ovulation (INHBB, DENND1A), egg quality (SYNE1, AZIN1, CHEK2), implantation (PKHD1L1, TNFSF12), and immune tolerance (EBAG9). At any of these stages, disruption can derail fertility. Thus, understanding this continuous chain helps clinicians move toward more effective, personalized fertility treatments, ultimately offering hope for women struggling with infertility.

Below we present 21 of the most important female-associated infertility loci, grouped by function and significance (Table 1).

Genetic Variants Linked to Female Infertility

Table 1: Table: Genetic Variants Linked to Female Infertility
Gene/Locus	Chromosomal Location	Gene Product	Primary Function	Impact on Fertility
WNT4	1p36.12	Wnt signaling protein	Essential for uterus & ovary development	Disruption may reduce uterine/ovarian formation
GREB1	2p25.1	Estrogen-regulated protein	Modulates estrogen response	Dysregulation may impair fertility hormone balance
INHBB	2q14.2	Inhibin β B subunit	Regulates follicle-stimulating hormone (FSH)	Alters ovulation; may lead to irregular cycles
ZEB2	2q22.3	Zinc-finger transcription factor	Key in hormone signaling cascades	Can disrupt hormone communication pathways
PKHD1L1 / EBAG9	8q22.1 / 8q21.13	Cilia-related / estrogen-binding	Influences immune tolerance in early pregnancy	Dysfunction may contribute to recurrent loss
TRHR	8q23.1	Thyrotropin-releasing hormone rec.	Links hypothalamus to ovarian activity	Variants may precipitate early menopause
AZIN1	8q22.3	Antizyme inhibitor	Supports egg cell growth	Impairment may affect egg maturation
ESR1	6q25.1	Estrogen receptor α	Central to estrogen response pathways	Mutation linked to hormone resistance
AKAP12	6q24.2	A-kinase anchoring protein 12	Coordinates signaling pathways	Disruption may weaken hormonal signal quality
SYNE1	6q25.2	Nuclear envelope support protein	Maintains nuclear integrity in gametes	Variants may lower egg health
PROX1	1q32.2	Transcription factor	Guides organ development	May affect uterus formation
FBXO48	17q12	Ubiquitin ligase	Involved in protein turnover	Alters oocyte regulation
TTC28	22q12.3	Cell cycle protein	Manages cell division	May impair egg maturation
TNFSF12	17p13.1	Cytokine ligand	Modulates uterine immune environment	May alter implantation dynamics
UBE2K	4q21.1	Ubiquitin-conjugating enzyme	Reproductive protein breakdown	May affect protein turnover in ovaries
BCOR	Xq26.1	Transcriptional corepressor	Regulates female gonadal genes	May influence ovarian development
SLC47A2	17q24.3	Drug transporter	Affects medication response (e.g., metformin)	Impacts PCOS treatment efficacy
TMEM26	4q32.1	Unknown transmembrane protein	Unknown	Emerging infertility marker; under study
GPC2 (rare)	7q22.1	Proteoglycan	Hormone signaling	Linked to unexplained infertility
CHEK2	22q12.1	DNA checkpoint kinase	Repairs DNA damage	Reduced egg quality when variation is present
DENND1A	9q33.3	DENN domain protein	Elevates polycystic ovary syndrome (PCOS) risk	PCOS contributes heavily to infertility

Key Genetic Infertility Loci in Men

Understanding Genetic Influences on Male Infertility: A Continuous Molecular Pathway

Male fertility depends on the precise regulation of spermatogenesis, hormonal communication, and sperm function. A disruption at any stage—from testicular development to sperm motility—can compromise fertility. Recent studies have identified key genes such as ENO4, UMODL1, and NCKAP5, which are involved in critical stages of this reproductive process. Such as;

Stage 1: Hormonal Communication – The Brain-Testes Axis

At the top of the male reproductive hierarchy lies the brain–testes axis, a neuroendocrine loop that governs testicular function through hormonal signals.

1. UMODL1, located at 21q22.11, encodes a uromodulin-like protein believed to facilitate communication between the brain and the testes.
2. This gene’s product may help regulate hormonal cues essential for initiating and sustaining spermatogenesis—the process of sperm production.
3. Disruptions in UMODL1 may lead to distorted hormonal signaling, thereby inhibiting proper sperm development, which is a foundational step in male fertility.

Stage 2: Testicular Cellular Support – Structural and Neural Dynamics

Once hormonal signals reach the testes, they must be correctly interpreted by the testicular microenvironment.

1. NCKAP5, found at 2q32.1, encodes a cytoskeletal regulator involved in maintaining structural integrity within cells, potentially including testicular neurons and supporting cells.
2. Although the role of NCKAP5 in reproduction is still being elucidated, early evidence suggests it may support testicular nerve and gamma-tubulin dynamics, which are essential for spermatogenesis and sperm structure.
3. Aberrations in this gene could disturb the internal cellular framework necessary for effective sperm formation and motility.

Stage 3: Sperm Maturation and Motility – Fueling Fertilization

The final and most directly observable aspect of male fertility is sperm motility, critical for successful fertilization.

1. ENO4, located at 10q23.31, encodes enolase 4, an enzyme that functions in the glycolysis pathway, which provides the energy required for sperm movement.
2. Impairment in ENO4 expression results in reduced ATP generation, compromising the sperm’s ability to swim efficiently toward the egg.
3. Consequently, poor motility due to ENO4 dysfunction severely reduces the likelihood of successful fertilization,even if sperm are otherwise healthy.

Conclusion: From Brain to Flagellum – A Genetic Cascade in Male Fertility

These three genes—UMODL1, NCKAP5, andENO4—represent a continuum of processes necessary for male fertility (Table 2):

1. Hormonal communication from the brain to the testes (UMODL1). UMODL1’s expression in reproductive tissues suggests mechanistic links to hormone signaling.
2. Cytoskeletal organization and cellular support during spermatogenesis (NCKAP5). NCKAP5 is perhaps a novel discovery in male fertility, highlighting neural and structural aspects of sperm development.
3. Energy-dependent sperm motility required for fertilization (ENO4). ENO4 is directly connected to sperm-specific energy metabolism, making it a clear candidate for poor motility.

Disruption in any part of this coordinated genetic system can cause male infertility. While ENO4’s role is directly linked to sperm function, UMODL1 and NCKAP5 highlight how less obvious processes, such as hormonal relay and cellular architecture, are equally critical. Understanding these molecular contributors opens new doors for diagnosing and treating male infertility on a genetic level.

Genetics plays a vital role in male fertility, influencing factors like sperm count, motility, and morphology. Mutations in genes such as DAZ, AZF, and CFTR have been closely associated with infertility. To explore this topic in more depth, especially rare and often-overlooked genetic contributors, read our comprehensive article on “Male Infertility: 4 Hidden Causes and the Genetic Link“

Table 2: Genetic Variants Linked to Male Infertility
Gene/Locus	Chromosomal Location	Gene Product	Function	Reproductive Role
ENO4	10q23.31	Enolase 4	Sperm motility (glycolysis pathway)	Poor movement reduces fertilization
UMODL1	21q22.11	Uromodulin-like protein	Brain–testes hormonal communication	May disrupt spermatogenesis
NCKAP5	2q32.1	Cytoskeletal regulator	Supports testicular nerve/gamma dynamics	New link—requires further study

Methodology: How Genetic Infertility Loci Were Identified

The GWAS study followed rigorous methodology such as;

1. Large Cohort Analysis: Over 1.5 million individuals, including case-control groups (infertility) and general population controls.
2. High-Density SNP Arrays: Millions of single nucleotide polymorphisms (SNPs) were tested for fertility associations.
3. Multiple Cohorts & Ethnicities: Findings validated across diverse ancestral groups (European, East Asian, African).
4. Statistical Significance Threshold: Strong control for false positives (p-values < 5×10⁻⁸).
5. Gene Mapping & Functional Analysis: Used expression data to link SNPs to functional genes; some enriched in reproductive tissues.
6. Pathway Enrichment: Confirmed overrepresentation in biological categories like hormone regulation and immune response.

These robust methods minimize chance findings and support clinical translation.

Clinical Applications of Genetic Infertility Loci

1. Diagnostics & Risk Prediction
   • Genetic testing panels for fertility clinics might soon include these 25 loci.
   • Identifying variants may offer answers in “unexplained infertility” cases.
2. Personalized Treatment Plans
   • Estrogen receptor (ESR1) or FSH pathway (INHBB) variants could inform hormone therapy customization.
   • SLC47A2 variants may affect metformin dosing in PCOS, enabling more effective medication strategies.
3. Preconception Counseling & Family Planning
   • Couples with known risk variants can receive tailored counseling—such as timing of conception, donor gamete options, or pre-implantation genetic testing (PGT).
4. Drug Discovery & Therapeutics
   • Hormone-pathway genes (like WNT4 or TRHR) represent potential drug targets for novel fertility-enhancing treatments.
5. Risk Screening & Population Health
   • Variants like CHEK2 can inform on chromosomal integrity, potentially anticipating risks for miscarriage or chromosomal abnormalities.

Ethical, Social & Accessibility Considerations

Genetic fertility insights carry weighty responsibilities:

1. Genetic Counseling: Interpretation only by trained professionals to avoid misunderstandings.
2. Privacy & Discrimination Risks: Safeguards needed to prevent genetic data misuse by insurers or employers.
3. Health Equity: Broad access across global populations—including low-income and minority groups—is essential.

Psychological Support: Results can create emotional and mental health stress; support resources are critical.

Why Do These Infertility Genes Still Exist?

Although these loci may hinder fertility, many also serve protective or advantageous roles—leading to an evolutionary trade-off:

1. WNT4, PROX1, or hormone regulators support essential organ development.
2. Cancer/immune-related genes (e.g., CHEK2, TNFSF12) help prevent malignancy or infections.
3. ENO4’s role in sperm energy metabolism offers critical reproductive advantages in otherwise healthy individuals.

Over generations, benefits like survival and disease resistance outweighed fertility drawbacks—allowing these variants to persist.

Future Directions & Research Horizons

1. Functional Studies – Lab research to confirm causality and uncover molecular mechanisms.
2. Expanded Male Infertility Research – Deeper exploration of sperm-specific pathways.
3. Diverse Population Validations – Ensuring relevance across global ancestries.
4. Polygenic Risk Scores (PRS) – Integrating multiple loci to predict infertility risk.
5. Gene–Environment Studies – Exploring how lifestyle, toxins, or diet interact with these loci.
6. Regulatory Impact – Evaluate how variants modulate gene expression in ovarian/testicular tissues.

Final Thoughts

The identification of 25 genetic infertility loci through a massive 2025 GWAS marks a turning point in reproductive biology and medicine. These loci unlock biological mysteries in areas like egg quality, hormone signaling, immune tolerance, and sperm function. Here’s why it matters:

1. Individuals gain explanations for previously unexplained infertility.
2. Clinicians can personalize treatments and embrace genomic fertility medicine.
3. Researchers and companies now have targets for novel therapies.
4. Society confronts boundless ethical and accessibility questions—but also opportunity for better reproductive equity.

Fertility is profoundly personal. Yet science is illuminating the path forward—sequencing by sequencing, gene by gene—so that everyone gets the chance to conceive with knowledge and compassion.

References & Suggested Reading

1. Venkatesh, S.S., Wittemans, L.B.L., Palmer, D.S. et al. Genome-wide analyses identify 25 infertility loci and relationships with reproductive traits across the allele frequency spectrum. Nat Genet 57, 1107–1118 (2025). https://doi.org/10.1038/s41588-025-02156-8
2. Qing Sang et al. Understanding the genetics of human infertility. Science380,158-163(2023).DOI:10.1126/science.adf7760
3. Grande G. Human Infertility and Reproductive Endocrinology. Life. 2024; 14(12):1550. https://doi.org/10.3390/life14121550
4. World Health Organization: WHO 2024 Infertility. World Health Organization: WHO, 22 May. Available at https://www.who.int/news-room/fact-sheets/detail/infertility [Last accessed 13 June 2025].

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