2025 Sequencing Strategies for Population and Cancer Epidemiology Studies (SeqSPACE) : Submission #6

Abstract Summary Prostate cancer (PCa) is the 2nd most common cancer in men, with African American (AFR) men experiencing the highest disease incidence. Metabolomic dysregulation likely contributes to pathogenesis, however epidemiological evidence is heterogenous and limited in diverse populations. Herein, we conducted a two-sample Mendelian Randomization (MR) analyses, facilitated by imputation to dense sequencing resources, to assess causal relationships between serum metabolites and PCa risk in AFR, European (EUR) and Hispanic (HIS) populations.MR was performed using GWAS summary statistics (imputed to TOPMed) from the Atherosclerosis Risk in Communities (ARIC) cohort (NMetabolites=250, NEUR=1,498, NAFR=1,740) and the Hispanic Community Health Study/ Study of Latinos (HCHS/SOL) cohort (NMetabolites=711, NHIS=3,166). Metabolites were quantified by untargeted mass spectroscopy (Metabolon). PCa GWAS summary statistics (imputed to 1KGP) were obtained from PRACTICAL (AFR=10,368/10,986, EUR=85,554/91, HIS=3,931/26,405 cases/controls). Genome-wide significant (P<5x10-8) and independent (R2<0.2 in TopLD) SNPs were included in instruments. MR results were meta-analyzed across populations. The strength of MR evidence was evaluated utilizing newly developed criteria for metabolites with a false discovery rate (FDR) < 0.10. Fifty metabolites significantly associated with PCa risk in population-specific or cross-population analyses. Based on our criteria, fourteen metabolites had strong MR evidence, and were followed up in additional analyses. We found that 10 of these metabolites were novel associations, three were drug-modifiable and six were dietary modifiable. The fatty acid hexadecanedioate was the only metabolite associated with PCa risk in AFR (OR=1.10, 95% CI=1.05-1.16, Padj=0.02) and exhibited evidence of colocalization for rs28864441. Hexadecanedioate was not associated with PCa risk in EURs or HISs. This large-scale MR study provides evidence of causal associations between serum metabolites and PCa within and across populations and highlights the role lipids, nucleotides and amino acids in PCa development. Underlining biological mechanisms and the clinical utility of identified metabolites as PCa biomarkers should be evaluated in diverse populations.