rs13164856 — IRF1

The 5q31 PCOS Locus — Immune Signaling, Androgens, and Polycystic Ovary Risk

On chromosome 5, within a gene-dense region at 5q31.1, lies rs13164856 — a regulatory variant in the vicinity of two notable genes: [IRF1 | Interferon Regulatory Factor 1, a transcription factor that modulates immune signaling and gene expression] and [RAD50 | A DNA double-strand break repair protein that is part of the MRN complex critical for genome integrity]. This variant was identified in one of the first large-scale genome-wide association studies of polycystic ovary syndrome (PCOS) in women of European ancestry, and has been distinguished from other PCOS loci by its specific association with circulating testosterone levels.

The Mechanism

rs13164856 is a non-coding tag SNP — it does not change a protein sequence but instead tags a haplotype block that likely affects the regulation of one or more nearby genes. The 5q31 region contains a cluster of immunologically active genes (IL4, IL13, IL5, IRF1, RAD50), and colocalization analyses using single-cell [eQTL | expression quantitative trait locus — a variant that influences how much a nearby gene is expressed] data have identified IRF1 as the most plausible candidate causal gene at this locus.

IRF1 is a transcription factor with broad roles in innate immunity and cellular stress responses. It has also been identified as a regulator of androgen receptor (AR) expression through the IL-6/TLR4 signalling axis, providing a plausible molecular link between immune activation and androgen excess — a hallmark of PCOS. RAD50, as part of the MRN (MRE11-RAD50-NBS1) complex, participates in DNA double-strand break repair, a process that is critical for oocyte viability and primordial follicle maintenance throughout a woman's reproductive lifespan.

The T allele at rs13164856 is the common allele (approximately 71% in Europeans) and is the risk-associated allele, meaning the majority of women carry at least one copy. The effect is additive: each additional T allele modestly increases PCOS risk. Among the confirmed PCOS susceptibility loci, the IRF1/RAD50 locus stands out for its association specifically with testosterone levels rather than LH/FSH ratios, ovarian morphology, or other PCOS endophenotypes.

The Evidence

Day et al. 2015¹¹ Day et al. 2015
Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nature Communications 6:8464 conducted a GWAS of PCOS in up to 5,184 self-reported European-ancestry cases and 82,759 controls, followed by replication in approximately 2,000 clinically validated cases and 100,000 controls. The study identified six genome-wide significant loci including the RAD50/IRF1 5q31 locus (P=3.5×10⁻⁹). Mendelian randomisation analyses in the same paper confirmed causal roles for elevated BMI, insulin resistance, and reduced SHBG in PCOS aetiology.

A 2018 large-scale meta-analysis²² A 2018 large-scale meta-analysis
Day et al. Large-scale GWAS meta-analysis of PCOS in 10,074 cases and 103,164 controls. PLOS Genetics, 2018 confirmed rs13164856 at genome-wide significance (P=1.45×10⁻¹⁰) with an odds ratio of 1.13 (95% CI 1.09–1.18). Crucially, in phenotypic analyses of PCOS endophenotypes, the IRF1/RAD50 locus was the only confirmed PCOS locus uniquely associated with testosterone levels, distinguishing it from loci that primarily affect gonadotropin ratios, ovulatory function, or ovarian morphology.

Replication in Han Chinese³³ Replication in Han Chinese
Peng et al. ERBB4 confers risk for PCOS in Han Chinese. Scientific Reports 2017 found that allele frequencies of rs13164856 were not significantly different between PCOS cases and controls in 1,500 Han Chinese cases and 1,220 controls, suggesting the association is European-ancestry specific or that the effect size is considerably smaller in East Asian populations.

The variant has no entry in ClinVar and is not listed in OMIM as pathogenic — it represents a common susceptibility allele with a modest but replicated effect in the expected direction.

Practical Implications

The T allele's association with testosterone levels positions this variant as relevant to both PCOS diagnosis workup and reproductive decision-making. Women who carry one or two copies of the T allele — the majority of European-ancestry women — may have a modestly elevated androgen set-point compared to CC carriers. In practice, this means that borderline elevated testosterone or free androgen index measurements may, in part, reflect genetic background rather than a pathological process.

From a monitoring perspective, women with the TT genotype who have irregular cycles, unwanted hair growth, or fertility difficulties should consider having total and free testosterone measured alongside anti-Müllerian hormone (AMH), as this genotype is specifically linked to the androgen-excess dimension of PCOS. The CC genotype (approximately 8% of European-ancestry women) does not provide protection from PCOS through other pathways, but does suggest that androgen excess specifically driven by this locus is less likely.

For offspring analysis, males who carry the T allele do not express the ovarian PCOS phenotype, but may pass the allele to daughters. The T allele does not have documented effects in males in the published GWAS literature.

Interactions

FSHB rs10553397: The FSHB locus (11p14.1) is another of the six Day et al. 2015 PCOS loci and is strongly associated with elevated LH and a high LH/FSH ratio — the hallmark neuroendocrine PCOS phenotype. A woman carrying both the rs13164856 T allele (elevated testosterone via the IRF1/RAD50 pathway) and a FSHB risk variant (elevated LH, suppressed FSH via pituitary dysregulation) would carry susceptibility through two distinct biological mechanisms: androgen-excess and gonadotropin imbalance. These represent the two most clinically prominent PCOS dimensions, and their combination may identify women with a more complete PCOS phenotype requiring both anti-androgen and gonadotropin-normalizing considerations in management.

FSHR rs6166 (hormones-sleep category): Although rs13164856 is not an FSHR variant (it is on chromosome 5 near IRF1/RAD50, while FSHR is on chromosome 2), women with this variant who also carry the FSHR rs6166 GG (Ser/Ser) genotype face a compound challenge: elevated androgen levels (from rs13164856) combined with reduced FSH receptor sensitivity (from rs6166 GG). In an IVF context, this combination may predict both PCOS-like ovarian phenotype and a relatively poor response to standard gonadotropin stimulation, warranting a tailored approach that addresses both dimensions.