Multi-ethnic transcriptome-wide association study of prostate cancer

Abstract

<jats:title>Abstract</jats:title><jats:p>The genetic risk for prostate cancer has been governed by a few rare variants with high penetrance and over 150 commonly occurring variants with lower impact on risk; however, most of these variants have been identified in studies containing exclusively European individuals. People of non-European ancestries make up less than 15% of prostate cancer GWAS subjects. Across the globe, incidence of prostate cancer varies with population due to environmental and genetic factors. The discrepancy between disease incidence and representation in genetics highlights the need for more studies of the genetic risk for prostate cancer across diverse populations. To better understand the genetic risk for prostate cancer across diverse populations, we performed PrediXcan and GWAS in a cohort of 4,769 self-identified African American (2,463 cases and 2,306 controls), 2,199 Japanese American (1,106 cases and 1,093 controls), and 2,147 Latin American (1,081 cases and 1,066 controls) individuals from the Multiethnic Genome-wide Scan of Prostate Cancer. We used prediction models from 46 tissues in GTEx version 8 and five models from monocyte transcriptomes in the Multi-Ethnic Study of Artherosclerosis. Across the three populations, we predicted 19 gene-tissue pairs, including five unique genes, to be significantly (<jats:italic>lfsr</jats:italic> &lt; 0.05) associated with prostate cancer. One of these genes, <jats:italic>NKX3-1</jats:italic>, replicated in a larger European cohort. At the SNP level, 110 SNPs met genome-wide significance in the African American cohort while 123 SNPs met significance in the Japanese American cohort. Fine mapping revealed three significant independent loci in the African American cohort and two significant independent loci in the Japanese American cohort. These identified loci confirm findings from previous GWAS of prostate cancer in diverse cohorts while PrediXcan-identified genes suggest potential new directions for prostate cancer research in populations across the globe.</jats:p>

Multi-ancestry fine-mapping improves precision to identify causal genes in transcriptome-wide association studies

“…On the other hand, recent trans-ancestry design of GWAS have highlighted the benefits of taking an integrative, multi-ancestry approach to studying complex disease biology, both by leveraging genetic heterogeneity across human groups to aid in finemapping, and by enabling the discovery of ancestry-specific disease etiologies 20,21,[25][26][27] . As with GWAS, we expect the integration of genetically diverse datasets into TWAS methodologies will improve our understanding of trait architectures that are both shared and unique to particular genetic ancestries 28,30,32 .…”

Vitamin D receptor cistrome-transcriptome analyses establishes quantitatively distinct receptor genomic interactions in African American prostate cancer regulated by BAZ1A

“…PCa in AA men is more aggressive and occurs at a younger age than in European American (EA) counterparts [1]. Current understanding of the drivers of PCa health disparities leverages genetic [2][3][4] and epigenetic [5][6][7][8][9][10] factors, combined with a range of biopsychosocial processes. The combined interactions of these intrinsic and extrinsic factors appear to drive uniquely aggressive disease in AA men.…”