Population-Based Study of Rare Coding Variants in NR5A1/SF-1

Area of Science:

• Genetics
• Endocrinology
• Reproductive Biology

Background:

• Steroidogenic Factor 1/Nuclear Receptor Subfamily 5 Group A Member 1 (SF-1/NR5A1) is crucial for reproductive organ development and function.
• While rare SF-1/NR5A1 variants are linked to differences in sex development (DSD), their population-level impact is unknown.

Purpose of the Study:

• To investigate the impact of rare, predicted deleterious SF-1/NR5A1 variants on age at menopause and other traits in a large population.
• To assess the association between SF-1/NR5A1 variants and adult obesity risk.

Main Methods:

• Analysis of health records and exome sequencing data from up to 420,162 UK Biobank participants.
• Assessment of rare (frequency < 0.1%) predicted deleterious SF-1/NR5A1 variants.

Main Results:

• Rare missense SF-1/NR5A1 variants in the DNA binding (DBD) and ligand binding (LBD) domains are associated with an earlier age at menopause (beta = -2.36 years/allele).
• Carriers of these variants have an increased risk of adult obesity, especially women (OR = 1.095).
• No protein-truncating variants were identified.

Conclusions:

• Deleterious missense variants in the SF-1/NR5A1 DBD and LBD disrupt its function, impacting menopause timing and obesity risk.
• The relevance of SF-1/NR5A1 variants extends beyond rare DSDs, necessitating broader phenotyping and monitoring.