OR27-04 Unraveling the Genetic Architecture of Male Fertility: A Population-Based GWAS of Testicular Volume Using Machine Learning-Based Segmentation

Abstract Disclosure: P. Beeken: None. J. Ernsting: None. L. Ogoniak: None. J. Kockwelp: None. T. Hahn: None. B. Risse: None. A.S. Busch: None. Background: The genetic factors influencing male fertility remain elusive. While testicular volume closely mirrors quantitative spermatogenesis, testicular size serves as a reliable proxy for male reproductive capacity. Previous approaches have faced limitations, as large-scale assessment has been hindered by traditional invasive measurement techniques, resulting in biased samples and restricted applicability. Despite its significance, the genetic basis of testicular volume remains largely unexplored. Methods: We applied machine learning to evaluate bi-testicular volume in 22,499 male participants from the UK Biobank using abdominal DIXON MRI scans. A U-Net model, trained on manual segmentations performed by medical experts, generated automated segmentations for the dataset. Following quality control, excluded incomplete segmentations and participants with conditions affecting segmentation, e.g. undescended testis, 18,998 participants were included. A genome-wide association study (GWAS) on bi-testicular volume was conducted using PLINK adjusting for age and the first ten principal components. Results: The U-Net model for MRI segmentation achieved Dice score of 0.87 (median), enabling precise measurement of testicular volume. The mean (SD) bi-testicular volume was 52 (16) mL. The GWAS identified 14 genome-wide significant loci (p<5×10⁻⁸), offering new insights into the genetic determinants of testicular volume. The most significant association was at rs12271187 within the FSHB locus on chromosome 11 (p = 1.33×10⁻⁴¹), with additional findings at the FSHR locus on chromosome 2, emphasizing the role of follicle-stimulating hormone and its receptor in male reproductive health. Conclusion: Circumventing previous challenges in assessing testicular volume, our study offers a large-scale approach, effectively addressing the limitations of traditional methods. By identifying genetic loci associated with testicular volume, we provide a foundation for further research into the genetic determinants of male fertility and reproductive health. Presentation: Monday, July 14, 2025