Population-Based Study of Rare Coding Variants in /SF-1.

BACKGROUND

Steroidogenic Factor 1/Nuclear Receptor Subfamily 5 Group A Member 1 (SF-1/) is critical for the development and function of sex organs, influencing steroidogenesis and reproduction. While rare deleterious /SF-1 variants have been identified in individuals with various differences of sex development (DSD), primary ovarian insufficiency, and infertility, their impact on the general population remains unclear.

METHODS

We analyzed health records and exome sequencing data from up to 420 162 individuals (227 858 women) from the UK Biobank study to assess the impact of rare (frequency < 0.1%) predicted deleterious /SF-1 variants on age at menopause and 26 other traits.

RESULTS

No carriers of rare protein truncating variants in /SF-1 were identified. We found that the previously reported association of rare deleterious missense /SF-1 variants with earlier age at menopause is driven by variants in the DNA binding domain (DBD) and ligand binding domain (LBD) (combined test: beta = -2.36 years/allele, [95% CI: 3.21, -1.51], N = 107 carriers, = 4.6 × 10). Carriers also had a higher risk of adult obesity (OR = 1.061, [95% CI: 1.003, 1.104], N = 344, = .015), particularly among women (OR = 1.095 [95% CI: 1.034, 1.163, = 3.87 × 10], N = 176), but not men (OR = 1.019, [95% CI: 0.955, 1.088], = .57, N = 168).

CONCLUSION

Deleterious missense variants in the DBD and LBD likely disrupt /SF-1 function. This study broadens the relevance of deleterious /SF-1 variants beyond rare DSDs, suggesting the need for extended phenotyping and monitoring of affected individuals.