KRR1 – Polycystic Ovary Syndrome

This summary reviews the association between KRR1 (HGNC:5176) and polycystic ovary syndrome (MONDO_0008487) based on several large-scale genetic studies and supporting experimental data. Multiple genome‑wide association studies (GWAS) in diverse populations have implicated risk loci near KRR1 in PCOS susceptibility. Although these studies have employed large cohorts with thousands of cases (PMID:28195137, PMID:26416764, PMID:28068351), the strength of the association is moderated by some inconsistencies in replication across cohorts.

The initial case‑control study in Han Chinese encompassing approximately 1,500 PCOS cases and 1,220 controls identified several loci, including signals near KRR1, although the risk variant rs1275468 did not reach significance upon replication (PMID:28195137). Subsequent investigations in European cohorts have bolstered the overall genetic evidence by including KRR1 among six susceptibility signals, with analyses drawn from more than 5,000 cases and over 80,000 controls. These large sample sizes enhance confidence in the reported associations, even if detailed variant‐level data for KRR1 remain sparse.

In parallel, additional studies using deep phenotyping and expression quantitative trait locus (eQTL) analyses have demonstrated that risk alleles at several PCOS loci, including KRR1, may influence metabolic and reproductive features. Although these investigations describe multiple potential disease subtypes and implicate diverse pathways, the specific contribution of KRR1 is derived from statistical signals rather than direct clinical segregation data. Notably, the absence of clear familial segregation evidence further suggests that KRR1 acts as one component among many in a complex trait model.

Functional evidence for KRR1 is primarily derived from experimental studies using yeast as a model. A landmark study demonstrated that yeast Krr1p is essential for 40S ribosome biogenesis through its physical and functional interaction with Kri1p (PMID:11027267). While these findings confirm that KRR1 homologues play key roles in fundamental cellular processes, no direct functional assays have yet recapitulated PCOS‐specific phenotypes. Thus, the experimental data provide biological plausibility but remain indirectly related to the human disease condition.

Integrating the genetic and experimental evidence, the overall association between KRR1 and PCOS is best characterized as moderate. Multiple independent GWAS support the presence of risk signals near KRR1, and functional studies in yeast underscore its importance in cellular biology. However, inconsistencies in replication and the absence of direct in vivo models for PCOS temper the strength of the conclusion. Further experimental work is needed to elucidate how defects in KRR1 might contribute to the metabolic and reproductive dysregulation seen in PCOS.

Key take‑home sentence: Although current evidence supports a moderate association between KRR1 and polycystic ovary syndrome, further studies are warranted to establish its direct role in disease pathogenesis and clinical stratification.

References

• Scientific reports • 2017 • ERBB4 Confers Risk for Polycystic Ovary Syndrome in Han Chinese PMID:28195137
• Nature communications • 2015 • Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome PMID:26416764
• PloS one • 2017 • Phenotype and Tissue Expression as a Function of Genetic Risk in Polycystic Ovary Syndrome PMID:28068351
• Molecular and cellular biology • 2000 • Yeast Krr1p physically and functionally interacts with a novel essential Kri1p, and both proteins are required for 40S ribosome biogenesis in the nucleolus PMID:11027267

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