Endocrine Abstracts

Background: Male genital development is driven by fetal androgen exposure, yet the genetic determinants underlying interindividual variation in adult penile volume remain largely unexplored, particularly due to sample size constraints and potential cohort and measurement biases. Defining the genetic architecture of penile volume through large-scale, population-based genomic analysis is therefore vital for understanding male genital ontogeny and disorders of sex development (DSD).

Methods: We leveraged magnetic resonance imaging (MRI) data from a population-based cohort of ~30,000 adult men of European ancestry. Total erectile tissue volume (comprising bulb, crura, corpora and glans) was quantified under resting (flaccid) conditions using automated deep learning-based segmentation. Genome-wide association analysis (GWAS) was performed using Regenie (adjusting for age, age², genotyping batch and first 10 PCs). SNP-based heritability and genetic correlations were estimated via linkage disequilibrium score regression (LDSC). Bivariate MiXeR analysis quantified polygenic overlap with hypospadias as a proxy for androgen-dependent congenital malformations.

Results: Mean (SD) total penile volume was 117.8 ± 27.0 mL. We identified 20 independent genetic loci associated with penile volume at genome-wide significance (P < 5×10⁻⁸). SNP-based heritability (h²) was estimated at ~30% (SE 2%), indicating a substantial polygenic component. Several loci were located near genes involved in androgen signaling and local steroid metabolism, including SRD5A2, CYP21A2 and members of the AKR1 family, consistent with the established role of androgen conversion and tissue-level androgen activity in male genital development. Additional loci highlighted pathways involved in somatic growth and developmental size regulation. Genetic correlation analyses revealed strong overlap with lean mass and height (r_g ≈0.30-0.40), while correlations with adult circulating testosterone were modest (r_g ≈ 0.09) and no correlation was observed with SHBG. Bivariate MiXeR estimated that ~80% (SE 16%) of hypospadias’ inferred causal component was shared with penile volume but represented only ~6% (SE 1.4%) of the latter’s polygenic signal.

Conclusion: Penile volume is a substantially heritable, polygenic trait whose genetic architecture is shaped by androgen metabolism and somatic growth pathways – reflecting both local endocrine exposure and tissue responsiveness. Our findings provide a population-level genomic framework for understanding variation in male genital development, highlighting potential genetic contributors to DSD.