PD16-11: Trans-ethnic genome-wide association study reveals new therapeutic targets for benign prostatic hyperplasia.

Michael Ng, Oxford, United Kingdom, Koichi Matsuda, Chizu Tanikawa, Tokyo, Japan, Chikashi Terao, Yokohama, Japan, Yoichiro Kamatani, Tokyo, Japan, Wei Wang, Adam Auton, * 23andme Research Team, Sunnyvale, CA, Benjamin Turney, Richard Bryant*, Dominic Furniss, Oxford, United Kingdom

Introduction: Benign prostatic hyperplasia (BPH) is a common condition affecting men in and beyond middle age, causing significant morbidity. Medical treatments comprise a small number of pharmacological agents, and patients often progress to require surgery. There is an unmet clinical need to identify genomic drivers of BPH progression requiring surgery, and to identify novel targets for pharmacological intervention.

Methods: We performed a large genome-wide association study of BPH in 126,082 subjects from UK Biobank, with replication in 44,093 subjects from the RIKEN Japanese biobank, and 756,878 subjects from 23andMe (total 110,916 BPH cases and 816,137 controls). We investigated candidate genes using differential expression between single cell subtypes in samples from BPH versus normal prostate. A genetic risk score for BPH was constructed to assess its use for prognostication. Therapeutic targets were identified from the Open Targets platform.

Results: We identified 17 BPH-associated loci. Two loci were only associated with this condition in men of Western European or Japanese origin, and represent ethnicity-specific risk alleles. We demonstrated differential expression of associated genes in cells derived from BPH compared to normal prostate. For example, we provide evidence that the homeobox gene NKX3.1 specifically plays a role in BPH in basal epithelial cells. Patients with BPH managed with surgery had a higher genetic risk score than those managed conservatively or with non-surgical treatment. Several genes implicated in our genetic analysis are tractable to therapeutic targeting or drug repurposing, and represent attractive targets for new therapeutic development.

Conclusions: These results point to important genes driving the pathophysiology of BPH, and reveal promising candidates for future therapeutic development. Our proof-of-principle that the genetic risk score correlates with the severity of BPH, and the need for surgery, provides a first step towards personalised medicine in the management of this common condition.

Source of Funding: This work was co-funded by co-funded by the John Black Foundation and the Rosetrees Trust, with funding administered by The Urology Foundation. The BioBank Japan project was supported by the Ministry of Education, Culture, Sports, Sciences and Technology Japan and the Japan Agency for Medical Research and Development. The funders had no role in the design of the study, the collection, analysis or interpretation of data, the writing of the manuscript, or the decision to publish the results. We would like to thank the research participants and employees of 23andMe for making this work possible.