Abstract Prostate cancer (PCa) incidence is highest in African Americans and lowest in Asians. These long-standing racial/ethnic differences have yet to be explained. Genome-wide association studies of PCa have provided support for common and population-specific genetic effects for PCa and for a genetic basis of the underlying population differences in risk. To further progress in understanding the genetic basis of PCa across populations, we propose to substantially augment the size of genetic association studies in men of European, African, Asian and Latino ancestry to create the largest genetic database of PCa ever assembled in these populations, with substantially greater statistical power for novel discovery of risk alleles for PCa as well as aggressive disease. More specifically, we will expand studies in men of African ancestry from 10,368 cases and 10,986 controls to 34,000 cases and 74,000 controls, in men of Asian ancestry from 8,610 cases and 18,809 controls to 20,000 cases and 40,000 controls, in men of Latino ancestry from 2,714 cases and 5,239 controls to 10,000 cases and 20,000 controls, and in men of European ancestry from 82,000 cases and 61,000 controls to 117,000 cases and 517,000 controls, with all studies imputed to a multiethnic whole-genome sequence reference panel (e.g. TOPMed). In Aim 1, we will search for novel common risk alleles for overall and aggressive PCa in ethnic-specific and multiethnic analyses. Within known and newly discovered risk regions, we will conduct multiethnic fine- mapping using novel Bayesian statistical approaches that incorporate functional annotations and biology with statistical evidence to identify independent markers of risk as well as the most promising functional candidates. In Aim 2, we will create the first multiethnic genome-wide SNP-eQTL prostate reference panel for men of European, African, Asian and Latino ancestry using whole-transcriptome RNA sequencing of ~1,000 histologically normal, fresh-frozen prostate tissue specimens. We will characterize eQTLs in the sample and impute gene expression in men of European, African, Asian, and Latino ancestry to perform a multiethnic transcriptome-wide association scan (TWAS). In Aim 3, we will construct and evaluate a polygenic risk score (PRS) across populations, using known and novel risk variants from Aim 1 and TWAS loci from Aim 2. PRS validation testing will be conducted in three independent multiethnic cohorts (>38,000 PCa cases from ATLAS, All of Us and CCPM). We expect findings from this study will make a major contribution to our understanding of genetic susceptibility to PCa and lead to better risk models that more accurately predict a man's risk of developing PCa and are efficacious across racial/ethnic populations.

Project Narrative In this project, we will conduct genome-wide discovery efforts to identify variants and genes that contribute to risk of prostate cancer and aggressive disease in men of European, African, Asian and Latino ancestry. We expect findings from this study will make a major contribution to our understanding of genetic susceptibility to prostate cancer and will have widespread applicability and significance, leading to better risk models to more accurately predict a man's risk of developing prostate cancer.