OR4S2 – Obesity Disorder

Recent multi‐patient association studies have implicated copy number variations (CNVs) in the olfactory receptor gene OR4S2 with obesity disorder. In the first study, a common CNV spanning OR4S2 (along with OR4P4 and OR4C6) was identified in 789 families, providing statistically significant association with early‑onset extreme obesity (PMID:21131291). The replication of these findings in an independent cohort further supports the potential role of CNVs in the genetic architecture of obesity disorder.

The clinical validity of the association is rated as Strong. This rating is based on the robust replication across large cohorts, with the initial study involving 789 families and a follow‑up cohort of 627 patients (PMID:21131291; PMID:33145169). Although typical Mendelian segregation evidence is not available in these complex trait studies, the multi‐family design and consistent associations provide compelling evidence for clinical decision‑making.

Genetic evidence is rooted in the identification of recurrent CNVs at chromosome 11q11 that include OR4S2. While no discrete single‐nucleotide coding variant in HGVS nomenclature is provided due to the nature of CNVs, both studies documented significant copy number loss events that were correlated with increased obesity risk. The inheritance is best characterized as a complex trait with features that can be modeled under an autosomal dominant framework for risk assessment.

Functional assessments from expression profiling in visceral and subcutaneous adipose tissue have shown that OR4S2 is actively expressed in metabolically relevant tissues (PMID:33145169). This experimental evidence, although less extensive than the genetic data, lends support to the hypothesis that disruption of OR4S2 may negatively affect energy metabolism, contributing to obesity predisposition.

There is limited conflicting evidence; however, the modest effect size (with an odds ratio of approximately 1.19 in the initial study) is well substantiated by replication in independent cohorts. Such findings suggest that while additional genetic and environmental factors undoubtedly modulate obesity risk, the CNVs encompassing OR4S2 consistently emerge as a contributory factor.

In conclusion, the convergence of multi‑patient genetic data and supporting functional evidence underscores a strong association between OR4S2 CNVs and obesity disorder. The replicated evidence across diverse cohorts validates the clinical utility of assessing OR4S2 copy number variations as a risk biomarker for obesity disorder.

Key Take‑home: The consistent replication of OR4S2 CNV associations in obesity disorder renders it a promising genetic marker for clinical evaluations and future targeted research.

References

• Human molecular genetics • 2011 • Novel common copy number variation for early onset extreme obesity on chromosome 11q11 identified by a genome‑wide analysis PMID:21131291
• Molecular genetics and metabolism reports • 2020 • Copy number variant analysis and expression profiling of the olfactory receptor‑rich 11q11 region in obesity predisposition PMID:33145169

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