Fertility & Ovarian Function

Missense variant in PRRC2A (HLA-B associated transcript) linked to age at natural menopause through immune-mediated oocyte depletion; the A allele may be associated with earlier menopause onset

Intergenic PCOS susceptibility locus downstream of PLGRKT (plasminogen receptor); the C allele is the risk allele associated with increased PCOS susceptibility, reduced fibrinolytic capacity, and prothrombotic physiology in affected women

A 3' UTR variant in PIWIL1 that alters miRNA binding to the transcript and modifies PIWIL1 expression; the T allele is associated with decreased epithelial ovarian cancer susceptibility in southern Chinese women, consistent with PIWIL1's role in piRNA-mediated genome stability in ovarian follicular cells

Promoter variant reducing FSH beta-subunit transcription by ~50%, lowering serum FSH levels and impairing folliculogenesis in females and spermatogenesis in males

Synonymous variant in PIWIL1 associated with increased epithelial ovarian cancer risk in southern Chinese women; the AA genotype confers a roughly 5.7-fold elevated risk in case-control data.

Distal enhancer variant ~26 kb upstream of FSHB associated with FSH levels, dizygotic twinning, PCOS susceptibility, age at menopause, and male reproductive parameters

Intronic variant in BRSK1 (BR serine/threonine kinase 1) on chromosome 19q13.4, associated with earlier age at natural menopause and reduced ovarian reserve; T allele carriers have lower AMH levels and accelerated follicle depletion.

Missense variant in the LH/hCG receptor producing a gain-of-function increase in receptor sensitivity, influencing ovarian stimulation response, IVF outcomes, and gonadotropin-dependent signaling

Intronic variant in THADA (thyroid adenoma associated) on chromosome 2p21; the C allele is a PCOS risk allele at the THADA locus (companion tag SNP to rs13429458, the original Han Chinese GWAS lead), tagging a haplotype that reduces THADA-mediated SERCA uncoupling, impairing ER calcium homeostasis in pancreatic beta cells and predisposing to PCOS and insulin secretion defects

Intronic variant in the LH/choriogonadotropin receptor gene associated with PCOS susceptibility and elevated androgen levels, predominantly in Asian and East African populations

Missense variant in the MCM8 DNA repair helicase associated with ovarian reserve and age at natural menopause; the A allele is linked to higher AMH levels and later menopause onset.

An intronic variant in the ZBTB16 (PLZF) locus on chromosome 11q23.2; the T allele is associated with PCOS susceptibility (genome-wide significant in a 2018 meta-analysis of 10,074 cases) and with polycystic ovarian morphology, likely through disrupted retinoic acid–responsive transcriptional regulation of follicular development

Intronic SYCP2L variant in a U12-type minor intron; the A allele splices more efficiently in oocytes, raising SYCP2L expression and supporting primordial follicle survival — the G allele reduces expression and associates with lower anti-Müllerian hormone levels and earlier natural menopause

An intronic variant in ERBB4 on chromosome 2q34; the A allele tags reduced ERBB4/HER4 signalling in granulosa cells, impairing intercellular junctions required for normal folliculogenesis and increasing PCOS susceptibility in European women

Intronic variant in the FSHR gene associated with PCOS susceptibility and FSH level modulation; the C allele tags a GWAS-identified risk haplotype that elevates basal FSH and increases PCOS risk, while the T allele is protective and associated with normal FSH levels

Intronic variant in the FSH receptor gene; identified in a genome-wide association study as associated with post-radiotherapy erectile dysfunction risk in African-American men; located in close proximity to rs2268361 and serves as an FSHR haplotype tag with potential relevance to gonadotropin signaling

A splice-region variant at the ERBB3/RAB5B locus on chromosome 12q13.2, a replicated PCOS susceptibility region; the A allele tags coordinated dysregulation of EGF receptor signalling, vesicular trafficking, and androgen co-repression in ovarian theca cells, increasing PCOS susceptibility with additive metabolic risk

Affects LH/hCG receptor sensitivity near a glycosylation site, influencing ovarian response to LH stimulation, PCOS risk, ovarian aging, and IVF outcomes

Intronic variant in FNDC4 (fibronectin type III domain containing 4) on chromosome 2; the T allele is associated with earlier age at natural menopause and increased risk of primary ovarian insufficiency through disruption of follicular granulosa cell signaling.

Intronic variant in the androgen-regulating DENND1A gene associated with polycystic ovary syndrome (PCOS) risk; the G allele is linked to increased PCOS susceptibility and elevated post-load insulin levels, primarily in East Asian and Han Chinese populations

A regulatory variant upstream of PIWIL1 on chromosome 12, in a CpG region of the gene's promoter; the A allele is associated with earlier age at natural menopause via a recessive mechanism, linking piRNA-pathway genome surveillance in oocytes to ovarian reserve and reproductive lifespan

Intronic variant in LIN28B associated with puberty timing — the C allele may be linked to earlier menarche in females and earlier puberty milestones in males, with implications for reproductive window length and cumulative estrogen exposure

Regulatory variant 2 kb upstream of EIF4EBP1 (encoding 4E-BP1, a direct mTOR effector); the C allele is associated with later age at menopause (beta +0.376 years per allele) and higher circulating AMH, consistent with slower primordial follicle activation through attenuated mTOR signalling

Intronic PCOS susceptibility variant near TOX3; the G allele is associated with increased PCOS risk, insulin resistance, and altered metabolic features in affected women

An intergenic tag SNP ~50 kb downstream of PRSS23 (serine protease 23) on chromosome 11q14.2; the G allele is associated with higher serum FSH levels in a dose-responsive pattern (AA 9.0, AG 9.5, GG 10.7 IU/L) and with PCOS susceptibility, reflecting PRSS23's role in granulosa cell survival and follicular atresia

Missense variant in the extracellular domain of the FSH receptor that removes an O-linked glycosylation site, altering FSH binding affinity; nearly completely co-inherited with rs6166 (Asn680Ser) and associated with poor ovarian response in IVF and PCOS susceptibility

Regulatory variant near LIN28B associated with puberty timing — the T allele is linked to earlier menarche in females and earlier puberty in males, with implications for reproductive window length and age-at-onset of fertility

An intronic variant in the DENND1A locus on chromosome 9q33.3, a robustly replicated PCOS susceptibility region; the A allele tags regulatory variation that drives DENND1A overexpression in theca cells, elevating androgen biosynthesis

Intergenic variant at the GATA4/NEIL2 locus on chromosome 8p23.1 associated with polycystic ovary syndrome susceptibility; the T allele tags regulatory variation linked to elevated androstenedione and PCOS risk (OR ~1.14), with the strongest effect in NIH-diagnosed PCOS

Regulatory variant 2 kb upstream of SYCP2L; each copy of the minor C allele associates with approximately 0.26 additional years before natural menopause, reflecting altered expression of a meiotic chromosome-pairing protein in oocytes

Intronic variant in SYCP2L on chromosome 6p24.2; the G allele associates with earlier natural menopause (approximately 0.17 years per allele copy) by influencing expression of a meiosis-specific centromere protein essential for primordial follicle survival