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

A Wang; J Shen; A A Rodriguez; E J Saunders; F Chen; R Janivara; B F Darst; X Sheng; Y Xu; A J Chou; S Benlloch; T Dadaev; M N Brook; A Plym; A Sahimi; T J Hoffman; A Takahashi; K Matsuda; Y Momozawa; M Fujita; T Laisk; J Figuerêdo; K Muir; S Ito; X Liu; Biobank Japan Project; Y Uchio; M Kubo; Y Kamatani; A Lophatananon; P Wan; C Andrews; A Lori; P P Choudhury; J Schleutker; TLJ Tammela; C Sipeky; A Auvinen; G G Giles; M C Southey; R J MacInnis; C Cybulski; D Wokolorczyk; J Lubinski; C T Rentsch; K Cho; B H Mcmahon; D E Neal; J L Donovan; F C Hamdy; R M Martin; B G Nordestgaard; S F Nielsen; M Weischer; S E Bojesen; A Røder; H V Stroomberg; J Batra; S Chambers; L Horvath; J A Clements; W Tilly; G P Risbridger; H Gronberg; M Aly; R Szulkin; M Eklund; T Nordstrom; N Pashayan; A M Dunning; M Ghoussaini; R C Travis; T J Key; E Riboli; J Y Park; T A Sellers; H-Y Lin; D Albanes; S Weinstein; M B Cook; L A Mucci; E Giovannucci; S Lindstrom; P Kraft; D J Hunter; K L Penney; C Turman; C M Tangen; P J Goodman; I M Thompson; R J Hamilton; N E Fleshner; A Finelli; M-É Parent; J L Stanford; E A Ostrander; S Koutros; L E Beane Freeman; M Stampfer; A Wolk; N Håkansson; G L Andriole; R N Hoover; M J Machiela; K D Sørensen; M Borre; W J Blot; W Zheng; E D Yeboah; J E Mensah; Y-J Lu; H-W Zhang; N Feng; X Mao; Y Wu; S-C Zhao; Z Sun; S N Thibodeau; S K McDonnell; D J Schaid; CML West; G Barnett; C Maier; T Schnoeller; M Luedeke; A S Kibel; B F Drake; O Cussenot; G Cancel-Tassin; F Menegaux; T Truong; Y A Koudou; E M John; E M Grindedal; L Maehle; K-T Khaw; S A Ingles; M C Stern; A Vega; A Gómez-Caamaño; L Fachal; B S Rosenstein; S L Kerns; H Ostrer; M R Teixeira; P Paulo; A Brandão; S Watya; A Lubwama; J T Bensen; E N Butler; J L Mohler; J A Taylor; M Kogevinas; T Dierssen-Sotos; G Castaño-Vinyals; L Cannon-Albright; C C Teerlink; C D Huff; P Pilie; Y Yu; R J Bohlender; J Gu; S S Strom; L Multigner; P Blanchet; L Brureau; R Kaneva; C Slavov; V Mitev; R J Leach; H Brenner; X Chen; B Holleczek; B Schöttker; E A Klein; A W Hsing; R A Kittles; A B Murphy; C J Logothetis; J Kim; S L Neuhausen; L Steele; Y C Ding; W B Isaacs; B Nemesure; AJM Hennis; J Carpten; H Pandha; Agnieszka Michael; K De Ruyck; G De Meerleer; P Ost; J Xu; A Razack; J Lim; S-H Teo; L F Newcomb; D W Lin; J H Fowke; C M Neslund-Dudas; B A Rybicki; M Gamulin; D Lessel; T Kulis; N Usmani; A Abraham; S Singhal; M Parliament; F Claessens; S Joniau; T Van den Broeck; M Gago-Dominguez; J E Castelao; M E Martinez; S Larkin; P A Townsend; C Aukim-Hastie; W S Bush; M C Aldrich; D C Crawford; S Srivastava; J Cullen; G Petrovics; G Casey; Y Wang; Y Tettey; J Lachance; W Tang; R B Biritwum; A A Adjei; E Tay; A Truelove; S Niwa; K Yamoah; K Govindasami; A P Chokkalingam; J M Keaton; J N Hellwege; P E Clark; M Jalloh; S M Gueye; L Niang; O Ogunbiyi; O Shittu; O Amodu; A O Adebiyi; O I Aisuodionoe-Shadrach; H O Ajibola; M A Jamda; O P Oluwole; M Nwegbu; B Adusei; S Mante; A Darkwa-Abrahams; H Diop; S M Gundell; M J Roobol; G Jenster; RHN van Schaik; J J Hu; M Sanderson; L Kachuri; R Varma; R McKean-Cowdin; M Torres; M H Preuss; RJF Loos; M Zawistowski; S Zöllner; Z Lu; S K Van Den Eeden; D F Easton; S Ambs; T L Edwards; R Mägi; T R Rebbeck; L Fritsche; S J Chanock; S I Berndt; F Wiklund; H Nakagawa; J S Witte; J M Gaziano; A C Justice; N Mancuso; C Terao; R A Eeles; Z Kote-Jarai; R K Madduri; D V Conti; C A Haiman

doi:10.1038/s41588-023-01534-4

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

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

A Wang, J Shen, A A Rodriguez, E J Saunders, F Chen, R Janivara, B F Darst, X Sheng, Y Xu, A J Chou, …

Nature genetics, Vol.55, pp.2065-2074

15/09/2023

DOI: https://doi.org/10.1038/s41588-023-01534-4

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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Title: Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants
Creators: A Wang
J Shen
A A Rodriguez
E J Saunders
F Chen
R Janivara
B F Darst
X Sheng
Y Xu
A J Chou
S Benlloch
T Dadaev
M N Brook
A Plym
A Sahimi
T J Hoffman
A Takahashi
K Matsuda
Y Momozawa
M Fujita
T Laisk
J Figuerêdo
K Muir
S Ito
X Liu
Biobank Japan Project
Y Uchio
M Kubo
Y Kamatani
A Lophatananon
P Wan
C Andrews
A Lori
P P Choudhury
J Schleutker
TLJ Tammela
C Sipeky
A Auvinen
G G Giles
M C Southey
R J MacInnis
C Cybulski
D Wokolorczyk
J Lubinski
C T Rentsch
K Cho
B H Mcmahon
D E Neal
J L Donovan
F C Hamdy
R M Martin
B G Nordestgaard
S F Nielsen
M Weischer
S E Bojesen
A Røder
H V Stroomberg
J Batra
S Chambers
L Horvath
J A Clements
W Tilly
G P Risbridger
H Gronberg
M Aly
R Szulkin
M Eklund
T Nordstrom
N Pashayan
A M Dunning
M Ghoussaini
R C Travis
T J Key
E Riboli
J Y Park
T A Sellers
H-Y Lin
D Albanes
S Weinstein
M B Cook
L A Mucci
E Giovannucci
S Lindstrom
P Kraft
D J Hunter
K L Penney
C Turman
C M Tangen
P J Goodman
I M Thompson
R J Hamilton
N E Fleshner
A Finelli
M-É Parent
J L Stanford
E A Ostrander
S Koutros
L E Beane Freeman
M Stampfer
A Wolk
N Håkansson
G L Andriole
R N Hoover
M J Machiela
K D Sørensen
M Borre
W J Blot
W Zheng
E D Yeboah
J E Mensah
Y-J Lu
H-W Zhang
N Feng
X Mao
Y Wu
S-C Zhao
Z Sun
S N Thibodeau
S K McDonnell
D J Schaid
CML West
G Barnett
C Maier
T Schnoeller
M Luedeke
A S Kibel
B F Drake
O Cussenot
G Cancel-Tassin
F Menegaux
T Truong
Y A Koudou
E M John
E M Grindedal
L Maehle
K-T Khaw
S A Ingles
M C Stern
A Vega
A Gómez-Caamaño
L Fachal
B S Rosenstein
S L Kerns
H Ostrer
M R Teixeira
P Paulo
A Brandão
S Watya
A Lubwama
J T Bensen
E N Butler
J L Mohler
J A Taylor
M Kogevinas
T Dierssen-Sotos
G Castaño-Vinyals
L Cannon-Albright
C C Teerlink
C D Huff
P Pilie
Y Yu
R J Bohlender
J Gu
S S Strom
L Multigner
P Blanchet
L Brureau
R Kaneva
C Slavov
V Mitev
R J Leach
H Brenner
X Chen
B Holleczek
B Schöttker
E A Klein
A W Hsing
R A Kittles
A B Murphy
C J Logothetis
J Kim
S L Neuhausen
L Steele
Y C Ding
W B Isaacs
B Nemesure
AJM Hennis
J Carpten
H Pandha - University of Surrey, School of Biosciences
Agnieszka Michael (Author) - University of Surrey, School of Biosciences
K De Ruyck
G De Meerleer
P Ost
J Xu
A Razack
J Lim
S-H Teo
L F Newcomb
D W Lin
J H Fowke
C M Neslund-Dudas
B A Rybicki
M Gamulin
D Lessel
T Kulis
N Usmani
A Abraham
S Singhal
M Parliament
F Claessens
S Joniau
T Van den Broeck
M Gago-Dominguez
J E Castelao
M E Martinez
S Larkin
P A Townsend (Author) - University of Surrey, School of Biosciences
C Aukim-Hastie
W S Bush
M C Aldrich
D C Crawford
S Srivastava
J Cullen
G Petrovics
G Casey
Y Wang
Y Tettey
J Lachance
W Tang
R B Biritwum
A A Adjei
E Tay
A Truelove
S Niwa
K Yamoah
K Govindasami
A P Chokkalingam
J M Keaton
J N Hellwege
P E Clark
M Jalloh
S M Gueye
L Niang
O Ogunbiyi
O Shittu
O Amodu
A O Adebiyi
O I Aisuodionoe-Shadrach
H O Ajibola
M A Jamda
O P Oluwole
M Nwegbu
B Adusei
S Mante
A Darkwa-Abrahams
H Diop
S M Gundell
M J Roobol
G Jenster
RHN van Schaik
J J Hu
M Sanderson
L Kachuri
R Varma
R McKean-Cowdin
M Torres
M H Preuss
RJF Loos
M Zawistowski
S Zöllner
Z Lu
S K Van Den Eeden
D F Easton
S Ambs
T L Edwards
R Mägi
T R Rebbeck
L Fritsche
S J Chanock
S I Berndt
F Wiklund
H Nakagawa
J S Witte
J M Gaziano
A C Justice
N Mancuso
C Terao
R A Eeles
Z Kote-Jarai
R K Madduri
D V Conti
C A Haiman
Publication Details: Nature genetics, Vol.55, pp.2065-2074
Publisher: Nature Research
Date published: 15/09/2023
Grant note: 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).
Identifiers: 99853161202346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article
Data Access Statement: 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/). Supplementary Information Supplementary Figs. 1–7 and additional acknowledgements. Reporting Summary Peer Review File Supplementary Tables 1–19 Supplementary Tables 1–19. 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).

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

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