Women in Pakistan who carried one particular variant in the follicle-stimulating hormone receptor gene had more than seven times the odds of having polycystic ovary syndrome compared with women carrying the commoner version of that gene, according to a new hospital-based case-control study published in the Egyptian Journal of Medical Human Genetics. The researchers stress that the findings are exploratory and come from a modest sample of 115 women recruited in Lahore, so the effect sizes need confirmation in much larger and more diverse cohorts before any clinical use.
Polycystic ovary syndrome is the most common endocrine disorder affecting women of reproductive age, with an estimated global prevalence ranging from 5 to 15 percent. It is defined by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology, and it frequently travels with metabolic problems including obesity, insulin resistance, dyslipidaemia, impaired glucose tolerance and raised lifetime risks of type 2 diabetes and cardiovascular disease. Familial clustering and twin studies estimate its heritability at 60 to 70 percent, pointing to a substantial genetic contribution, yet genome-wide association studies have so far explained only a small fraction of that heritability. That gap has kept candidate-gene approaches alive, particularly in populations that remain under-represented in large genetic databases.
The two variants chosen for this study sit in complementary biological pathways. FSHR rs6165 is a non-synonymous polymorphism in the follicle-stimulating hormone receptor gene on chromosome 2p16.3, which encodes a G protein-coupled receptor expressed on granulosa cells. Binding of follicle-stimulating hormone activates intracellular cAMP signalling, promoting cell proliferation, aromatase expression, follicular growth and estradiol synthesis. The rs6165 change, known as Thr307Ala, substitutes an amino acid in the extracellular receptor domain and may influence receptor folding, ligand affinity, membrane trafficking and downstream signalling efficiency. ADIPOQ rs2241766, by contrast, lies in exon 2 of the adiponectin gene on chromosome 3q27, within the signal peptide region of the adiponectin protein, and produces a threonine-to-glycine substitution at codon 15. Adiponectin is an adipocyte-derived hormone that regulates insulin sensitivity, glucose homeostasis, lipid metabolism and systemic inflammation, and circulating adiponectin concentrations are consistently reduced in women with PCOS.
The study recruited 55 women diagnosed with PCOS according to the Rotterdam 2003 criteria and 60 healthy controls from Lady Willingdon Hospital, Jinnah Hospital and private infertility clinics in Lahore. PCOS diagnosis required at least two of oligo/anovulation, clinical or biochemical hyperandrogenism, and ultrasound-confirmed polycystic ovarian morphology. Women with congenital adrenal hyperplasia, androgen-secreting tumours, Cushing’s syndrome, thyroid disorders, hyperprolactinaemia, premature ovarian insufficiency or recent hormonal medication were excluded, and controls had regular menstrual cycles, normal ovarian morphology and no evidence of endocrine or metabolic disease. Both groups underwent the same pelvic ultrasonographic evaluation and clinical assessment for hyperandrogenism using Ferriman-Gallwey scoring and acne assessment. Participants were predominantly of Punjabi ancestry, though ethnicity was self-reported, and written informed consent was obtained under approval from the Institutional Ethics Committee of the University of the Punjab.
Genotyping was carried out with different laboratory techniques for the two variants: ADIPOQ rs2241766 was typed using polymerase chain reaction restriction fragment length polymorphism, while FSHR rs6165 was typed using allele-specific PCR. Genotyping succeeded for all 115 samples at the ADIPOQ locus and for 114 of 115 samples at the FSHR locus, with one control sample failing amplification. Duplicate restriction digestion of 10 percent of randomly selected ADIPOQ samples showed 100 percent concordance, and genotype distributions among controls conformed to Hardy-Weinberg equilibrium for both polymorphisms, which the authors interpret as showing no evidence of significant genotyping error or sampling bias. All genetic association analyses used logistic regression adjusted for age and body mass index, because the PCOS group was significantly older and heavier than the controls, with mean BMI of 28.43 versus 21.71 kilograms per square metre.
The headline result concerns FSHR rs6165. The heterozygous AG genotype appeared in 80 percent of the PCOS patients but only 37.7 percent of controls, and after adjustment for age and BMI it was associated with an odds ratio of 7.56, with a 95 percent confidence interval of 3.10 to 18.43 and a p value below 0.001. The minor G allele was also significantly more common among patients, at 43.6 percent versus 20.5 percent, giving an adjusted odds ratio of 2.32 with a confidence interval of 1.52 to 3.56. The overall codominant model was statistically significant, but the GG genotype estimate, although elevated at an odds ratio of 8.01, rests on only three carriers across the entire study and carries a very wide confidence interval of 0.63 to 101.2. The authors themselves caution that candidate-gene studies of common polymorphisms typically report odds ratios between 1.2 and 2.5, and that small studies are susceptible to effect-size inflation through sparse genotype counts, sampling variation and limited geographic recruitment.
The adiponectin variant told a quieter story. The minor G allele was present in 21.8 percent of cases versus 13.3 percent of controls, and after adjustment it showed a non-significant trend toward increased risk, with an odds ratio of 1.78, a confidence interval of 0.88 to 3.58 and a p value of 0.09. Women carrying the TG genotype showed a similarly non-significant elevation compared with TT homozygotes, and the GG genotype was too uncommon in both groups to yield precise estimates. The authors note that a post hoc power calculation indicated the observed effect size for this variant was detected with only about 55 percent power, so the study may simply have been underpowered to detect a modest genetic effect. Previous association studies of rs2241766 have produced inconsistent findings across populations, and meta-analyses suggest any contribution is likely to be modest and dependent on ethnicity, obesity and insulin resistance.
When the two variants were combined into a weighted genetic risk score ranging from 0 to 4 risk alleles, the mean score was significantly higher among women with PCOS, at 1.34 versus 0.72. After adjustment for age and BMI, women in the highest tertile had an odds ratio of 3.80 for PCOS compared with the lowest tertile, with a confidence interval of 1.80 to 8.02, and those in the intermediate tertile also showed significantly increased odds of 2.45. Receiver operating characteristic analysis gave an area under the curve of 0.71, with a confidence interval of 0.63 to 0.79, which the authors describe as only moderate discriminatory performance. Because the score incorporates just two candidate variants, captures only a very small proportion of PCOS genetic architecture, and used weighting coefficients estimated within the same dataset, the researchers explicitly warn that it is an exploratory measure rather than a clinically applicable prediction model, and that overfitting is a real risk.
The study also explored relationships between FSHR genotype and hormone levels among the PCOS cases. Mean serum follicle-stimulating hormone concentrations showed a nominal difference among genotype groups, with AA carriers showing higher levels than AG and GG carriers, but this comparison was not corrected for multiple testing across five hormones, and applying a conservative Bonferroni correction would render it non-significant, so the authors label it hypothesis-generating rather than confirmatory. No significant associations were found between genotype and testosterone, prolactin or thyroid-stimulating hormone, and a trend toward higher luteinizing hormone among G-allele carriers did not reach significance. Subgroup comparisons involving the rare GG genotype, held by only two participants, should be interpreted with particular caution.
The authors frame the work as one of relatively few genetic susceptibility investigations in Pakistani women, a population in which some studies have reported PCOS prevalence approaching 18 percent among reproductive-aged women, although that estimate still requires confirmation through population-based surveys using standardized criteria. They list strengths including internationally accepted diagnostic criteria, high genotyping success rates, Hardy-Weinberg equilibrium in controls and adjustment for age and BMI. Limitations include the modest sample size, recruitment from a single geographic catchment around Lahore, the absence of ancestry-informative markers to formally assess population stratification, the lack of circulating adiponectin measurements and insulin resistance indices, and no duplicate sequencing confirmation of genotypes. The team calls for multicentre replication across diverse Pakistani ethnic groups, integration of additional susceptibility loci identified through recent genome-wide studies, detailed metabolic phenotyping, and functional studies of how these variants affect receptor signalling, granulosa cell function and adiponectin expression before any of these findings move toward clinical application.
Subject of Research: Genetic variants associated with polycystic ovary syndrome susceptibility in Pakistani women
Article Title: Association of FSHR rs6165 and ADIPOQ rs2241766 variants with polycystic ovary syndrome (PCOS) in Pakistani women: a two-locus genetic risk analysis
Article References: Sajjad, K., Tahira, T., Saeed, Z., & Shabana, N. (2026). Association of FSHR rs6165 and ADIPOQ rs2241766 variants with polycystic ovary syndrome (PCOS) in Pakistani women: a two-locus genetic risk analysis. Egyptian Journal of Medical Human Genetics, 27(1), Article 87. https://doi.org/10.1186/s43042-026-00917-6
Image Credits: AI Generated
DOI: 10.1186/s43042-026-00917-6
Keywords: PCOS, FSHR rs6165, ADIPOQ rs2241766, genetic risk score, case-control study, Pakistani women, polymorphism, adiponectin, follicle-stimulating hormone receptor, Rotterdam criteria, candidate genes, South Asian genetics
News Source: Juliet Wilcox. (October 28, 2026). Two Gene Variants Linked to PCOS Risk in Pakistani Women in Case-Control Study. Scienmag.
