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Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants

Abstract

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

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Fig. 1: Manhattan plot of results from the multi-ancestry prostate cancer meta-analysis.
Fig. 2: Comparison of the ancestry-specific results of the 451 risk variants for prostate cancer.
Fig. 3: Percentage of cases in the lowest and highest GRS quintiles based on GRS100, GRS181, GRS269 and GRS451 in the multi-ancestry sample.
Fig. 4: The associations of GRS and prostate cancer risk in GWAS discovery and replication samples.
Fig. 5: Cumulative absolute risk by age.

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Data availability

The full summary statistics resulting from this investigation are available in the GWAS Catalog (https://www.ebi.ac.uk/gwas/) under accession codes as follows: cross-ancestry (GCST90274713), European (GCST90274714), African (GCST90274715), Asian (GCST90274716) and Hispanic (GCST90274717). Genotype and covariate data used in this study are deposited in dbGaP under accession codes phs001391.v1.p1, phs000306.v4.p1, phs001120.v2.p2phs001221.v1.p1, phs000812.v1.p1 and phs000838.v1.p1. The variants and weights for the GRS269 and GRS451 are available on the PGS Catalog under accession codes PGP000122 and PGP000488, respectively (https://www.pgscatalog.org/). Publicly available data described in this manuscript can be found from the following websites: 1000 Genomes Project (http://ftp.1000genomes.ebi.ac.uk/vol1/ftp/phase3/); Human Genome Diversity Project (https://www.internationalgenome.org/data-portal/data-collection/hgdp); SEER (https://seer.cancer.gov/); National Center for Health Statistics, CDC (https://www.cdc.gov/nchs/index.htm); Cistrome Data Browser (http://cistrome.org/db/); RefZ (https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000985.v1.p1); GTEx (https://gtexportal.org/home/datasets); TCGA (https://portal.gdc.cancer.gov); CancerSplicingQTL database (http://www.cancersplicingqtl-hust.com/); and EnTEx/ENCODE (http://entex.encodeproject.org/).

Code availability

Imputation was performed using IMPUTE2, MACH 1.0, Beagle 4.1, Beagle 5.1, EAGLE v2.4, Minimac3 and Minimac4. Association testing was performed using PLINK 1.07 and 2.0, SNPtest v2.5.2, SAIGE v.0.20 and R v3.6.3. Meta-analyses were conducted using METAL v2011-03-25 and fine-mapping with mJAM (https://github.com/USCbiostats/hJAM/). Genome-wide PRS was derived from PRS-CSx v1.0.0 (https://github.com/getian107/PRScsx). Variant annotation was performed with wANNOVAR (https://wannovar.wglab.org/, accessed 20 May 2022) and R package rtracklayer v1.42.2. TWAS was performed with FUSION (https://github.com/gusevlab/fusion_twas, accessed 20 May 2022; TWAS weights: GTEx v8 and TCGA: http://gusevlab.org/projects/fusion/, RefZ: https://www.mancusolab.com/prostate-twas/, INTERVAL: https://www.mancusolab.com/pwas/) and GCTA v1.94.0beta. Data visualization was performed using ggplot2 v3.4.2 and gwasforest v1.0.0 packages in R software (v3.6.3).

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Acknowledgements

This project was supported by the US National Institutes of Health (NIH) grants R01CA257328 (C.A.H.), U19CA214253 (C.A.H.), U01CA261339 (D.V.C.), P01CA196569 (D.V.C.) and R00CA246063 (B.F. Darst), and the Prostate Cancer Foundation grants 20CHAS03 (CAH) and 21YOUN11 (B.F. Darst). We acknowledge support from The National Institute of Health Research to The Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, the DJ Fielding Medical Trust and the Joseph Fraser Trust via The Royal Marsden Cancer Charity. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This research has been conducted using the UK Biobank Resource under application number 42195. This research is based on data from the Million Veteran Program, Office of Research and Development, and the Veterans Health Administration. This publication does not represent the views of the Department of Veteran Affairs or the US Government. A full description of funding and acknowledgements for each of the contributing studies can be found in the Supplementary Note.

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