rs13405728 — LHCGR

LHCGR rs13405728 — The PCOS Susceptibility Variant at the LH Receptor Locus

The luteinizing hormone/choriogonadotropin receptor (LHCGR) is the primary gateway through which the pituitary communicates its ovulatory signal to the ovary. When the pituitary releases a surge of LH, it binds LHCGR on theca cells and mature granulosa cells, triggering steroidogenesis, follicle rupture, and corpus luteum formation. In males, the same receptor on Leydig cells drives testosterone production. rs13405728 is an intronic variant deep within LHCGR¹¹ intronic variant deep within LHCGR
Located at c.161+4491, meaning 4,491 nucleotides into the first intron of the coding sequence; its exact regulatory effect is still being characterized that was identified as one of the strongest PCOS susceptibility signals in the first genome-wide association study of PCOS — and remains one of the most replicated PCOS loci in Asian populations.

The Mechanism

The A allele at rs13405728 is enriched in PCOS cases and tracks with a hormonal phenotype characterized by elevated androgens, higher LH/FSH ratios, and metabolic dysregulation. Carriers of the AA genotype showed significantly elevated total testosterone, triglycerides, and LDL cholesterol compared to those with the AG or GG genotype²² Carriers of the AA genotype showed significantly elevated total testosterone, triglycerides, and LDL cholesterol compared to those with the AG or GG genotype
Pairwise comparisons in 151 PCOS cases and 99 controls from the Hui Chinese cohort. The protective G allele is present in roughly 7% of Europeans, 27% of East Asians, and 28% of Africans, making this one of the most population-stratified PCOS loci known — a difference that likely explains why PCOS prevalence and phenotype show significant ethnic variation.

The molecular mechanism is not yet established at the protein level, as this is an intronic variant with no direct amino acid consequence. A 2021 three-dimensional genome mapping study identified STON1 and FSHR — not LHCGR itself — as the most likely functional targets of this locus³³ A 2021 three-dimensional genome mapping study identified STON1 and FSHR — not LHCGR itself — as the most likely functional targets of this locus
Hi-C chromatin interaction data showed rs13405728 in spatial contact with STON1 promoter elements and the FSHR regulatory region; LHCGR expression was not differentially expressed in PCOS ovarian tissue despite proximity. STON1 is implicated in adipocyte metabolism; FSHR modulates follicle immune signaling. This finding reframes the locus as a regulatory hub for the broader gonadotropin signaling neighborhood rather than a simple LHCGR coding effect.

The Evidence

The original GWAS by Chen et al.⁴⁴ The original GWAS by Chen et al.
Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nature Genetics, 2011 analyzed three cohorts totalling 4,082 PCOS cases and 6,687 controls from Han Chinese women. rs13405728 emerged as the top hit at the 2p16.3 locus with a combined OR of 0.71 (meaning the G allele is protective) and P=7.55×10⁻²¹ — one of the strongest GWAS signals ever observed for a PCOS locus.

A 2018 meta-analysis pooling 14 case-control studies (11,738 PCOS cases, 35,329 controls)⁵⁵ A 2018 meta-analysis pooling 14 case-control studies (11,738 PCOS cases, 35,329 controls)
Association of luteinizing hormone/choriogonadotropin receptor gene polymorphisms with polycystic ovary syndrome risk. Gynecological Endocrinology, 2018 confirmed the association in Asian populations across multiple genetic models (G vs A: OR=0.735, 95% CI=0.699–0.773; GG vs AA+AG: OR=0.578, P<.001). Importantly, rs13405728 was not significantly associated with PCOS in Caucasian populations — a finding consistent with the low minor allele frequency (~7%) in Europeans, which limits statistical power for detection.

A study of Hui Chinese women found the AA genotype (homozygous risk) present in 65.5% of PCOS cases vs 49.5% of controls⁶⁶ found the AA genotype (homozygous risk) present in 65.5% of PCOS cases vs 49.5% of controls
Association Study between Polycystic Ovarian Syndrome and the Susceptibility Genes Polymorphisms in Hui Chinese Women. PLOS ONE, 2015, with the A allele carrying an OR of 1.729 (95% CI 1.149–2.603) for PCOS diagnosis. The AA genotype specifically showed elevations in total testosterone (69.5 vs 62.2 ng/dL, P=0.014), triglycerides (1.46 vs 1.38 mmol/L, P=0.038), and LDL cholesterol (2.71 vs 2.38 mmol/L, P=0.023).

In IVF outcomes, a 2019 case-control study of PCOS patients undergoing IVF-ET⁷⁷ a 2019 case-control study of PCOS patients undergoing IVF-ET
Association of Rs13405728, Rs12478601, and Rs2479106 SNPs and in vitro fertilization and embryo transfer efficacy in patients with polycystic ovarian syndrome. Medicine, 2019 found that the TT genotype (equivalent to AA on the plus strand) was associated with poor treatment outcomes, including lower clinical gestation rates compared to CT/CC carriers.

The rs13405728 locus also extends beyond reproductive conditions. A study of Han Chinese women⁸⁸ A study of Han Chinese women
Variants in DENND1A and LHCGR are associated with endometrioid adenocarcinoma. Gynecologic Oncology, 2012 found that allele A conferred risk for endometrioid adenocarcinoma (endometrial cancer), connecting the PCOS androgen-signaling pathway to endometrial cancer susceptibility — a link consistent with the established epidemiological association between PCOS and endometrial cancer risk.

Practical Implications

For women carrying the AA genotype, the actionable considerations center on early clinical evaluation for PCOS features, monitoring of androgens and metabolic markers, and awareness of IVF implications. The A allele is the ancestral common allele in all populations — the AA genotype represents the absence of the protective G allele rather than a rare mutation. This contextualizes the risk appropriately: this genotype does not guarantee PCOS, but confers a meaningful increase in susceptibility, especially in East Asian and South Asian individuals where the G allele is substantially more common (27%) than in Europeans (7%).

For individuals of East Asian ancestry, where the G allele frequency (~27%) means the AG genotype is relatively common, heterozygosity provides partial protection worth knowing about. In European individuals, the AG genotype is uncommon enough (~13%) that finding it represents a genuinely meaningful deviation from the background risk.

Interactions

DENND1A rs2479106: The most clinically important compound interaction with this SNP. DENND1A encodes a regulator of androgen biosynthesis in theca cells, and rs2479106 is the other major PCOS GWAS locus. Both were identified in the same original GWAS⁹⁹ Both were identified in the same original GWAS
Chen et al. 2011, Nature Genetics and the same IVF study found that both the AA genotype at rs13405728 AND the AG/GG genotype at rs2479106 independently predicted poor IVF-ET outcomes. When both risk genotypes are present, two distinct PCOS-promoting pathways converge: DENND1A rs2479106 drives abnormal androgen production in theca cells via the DENND1A-CYP17A1 axis, while the rs13405728 locus affects gonadotropin receptor signaling and LH sensitivity. A person carrying both risk genotypes faces a dual-pathway androgen excess phenotype — one from dysregulated biosynthesis, one from altered receptor signaling — which may produce a more severe or treatment-resistant PCOS presentation than either variant alone. The recommended approach for this combination would integrate both biosynthetic pathway support (inositol supplementation targeting DENND1A-linked insulin-androgen coupling) and gonadotropin monitoring (LH/FSH ratio tracking relevant to the LHCGR locus).

LHCGR rs2293275 (N312S): This coding-variant in the same gene (LHCGR Asn312Ser) has documented effects on IVF outcomes and ovarian stimulation response. Carrying both an intronic susceptibility variant (rs13405728) and the coding N312S variant may compound LH receptor signaling alterations, though direct interaction studies between these two specific LHCGR variants are not yet published.

FSHR rs6166 (N680S): The FSH receptor N680S variant governs ovarian response to FSH stimulation and is on the same chromosome (2p) near the LHCGR locus. Both LHCGR and FSHR variants operate in the same gonadotropin signaling neighborhood; combined receptor sensitivity profiles from both genes may define distinct IVF pharmacogenetic subgroups.