Novel strategy for disease risk prediction incorporating predicted gene expression and DNA methylation data: a multi-phased study of prostate cancer.
integrative models
polygenic risk scores
predicted DNA methylation
predicted gene expression
prostate cancer
risk prediction
Journal
Cancer communications (London, England)
ISSN: 2523-3548
Titre abrégé: Cancer Commun (Lond)
Pays: United States
ID NLM: 101723675
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
revised:
10
06
2021
received:
03
03
2021
accepted:
26
07
2021
pubmed:
15
9
2021
medline:
2
2
2022
entrez:
14
9
2021
Statut:
ppublish
Résumé
DNA methylation and gene expression are known to play important roles in the etiology of human diseases such as prostate cancer (PCa). However, it has not yet been possible to incorporate information of DNA methylation and gene expression into polygenic risk scores (PRSs). Here, we aimed to develop and validate an improved PRS for PCa risk by incorporating genetically predicted gene expression and DNA methylation, and other genomic information using an integrative method. Using data from the PRACTICAL consortium, we derived multiple sets of genetic scores, including those based on available single-nucleotide polymorphisms through widely used methods of pruning and thresholding, LDpred, LDpred-funt, AnnoPred, and EBPRS, as well as PRS constructed using the genetically predicted gene expression and DNA methylation through a revised pruning and thresholding strategy. In the tuning step, using the UK Biobank data (1458 prevalent cases and 1467 controls), we selected PRSs with the best performance. Using an independent set of data from the UK Biobank, we developed an integrative PRS combining information from individual scores. Furthermore, in the testing step, we tested the performance of the integrative PRS in another independent set of UK Biobank data of incident cases and controls. Our constructed PRS had improved performance (C statistics: 76.1%) over PRSs constructed by individual benchmark methods (from 69.6% to 74.7%). Furthermore, our new PRS had much higher risk assessment power than family history. The overall net reclassification improvement was 69.0% by adding PRS to the baseline model compared with 12.5% by adding family history. We developed and validated a new PRS which may improve the utility in predicting the risk of developing PCa. Our innovative method can also be applied to other human diseases to improve risk prediction across multiple outcomes.
Sections du résumé
BACKGROUND
DNA methylation and gene expression are known to play important roles in the etiology of human diseases such as prostate cancer (PCa). However, it has not yet been possible to incorporate information of DNA methylation and gene expression into polygenic risk scores (PRSs). Here, we aimed to develop and validate an improved PRS for PCa risk by incorporating genetically predicted gene expression and DNA methylation, and other genomic information using an integrative method.
METHODS
Using data from the PRACTICAL consortium, we derived multiple sets of genetic scores, including those based on available single-nucleotide polymorphisms through widely used methods of pruning and thresholding, LDpred, LDpred-funt, AnnoPred, and EBPRS, as well as PRS constructed using the genetically predicted gene expression and DNA methylation through a revised pruning and thresholding strategy. In the tuning step, using the UK Biobank data (1458 prevalent cases and 1467 controls), we selected PRSs with the best performance. Using an independent set of data from the UK Biobank, we developed an integrative PRS combining information from individual scores. Furthermore, in the testing step, we tested the performance of the integrative PRS in another independent set of UK Biobank data of incident cases and controls.
RESULTS
Our constructed PRS had improved performance (C statistics: 76.1%) over PRSs constructed by individual benchmark methods (from 69.6% to 74.7%). Furthermore, our new PRS had much higher risk assessment power than family history. The overall net reclassification improvement was 69.0% by adding PRS to the baseline model compared with 12.5% by adding family history.
CONCLUSIONS
We developed and validated a new PRS which may improve the utility in predicting the risk of developing PCa. Our innovative method can also be applied to other human diseases to improve risk prediction across multiple outcomes.
Identifiants
pubmed: 34520132
doi: 10.1002/cac2.12205
pmc: PMC8696216
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1387-1397Subventions
Organisme : The National Health and Medical Research Council, Australia
ID : 251533
Organisme : NCI NIH HHS
ID : U01 CA188392
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA261339
Pays : United States
Organisme : NIA NIH HHS
ID : R03 AG070669
Pays : United States
Organisme : CIHR
Pays : Canada
Organisme : NCI NIH HHS
ID : U19 CA148537
Pays : United States
Organisme : Prostate cancer SuscEptibility (ELLIPSE)
ID : X01HG007492
Organisme : NCI NIH HHS
ID : R01 CA128813
Pays : United States
Organisme : European Community's Seventh Framework Programme
ID : 223175
Organisme : Swedish Cancer Foundation
ID : 12-823
Organisme : The National Health and Medical Research Council, Australia
ID : 940394
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : Swedish Research Council, Swedish Research Council
ID : 2014-2269
Organisme : NIH HHS
ID : R03 AG070669
Pays : United States
Organisme : Canadian Institutes of Health Research, European Commission's Seventh Framework Programme grant agreement
ID : HEALTH-F2-2009-223175
Organisme : The National Health and Medical Research Council, Australia
ID : 126402
Organisme : Swedish Cancer Foundation
ID : 11-484
Organisme : U.S. National Institutes of Health, National Cancer Institute
ID : U01-CA98758
Organisme : The National Health and Medical Research Council, Australia
ID : 396414
Organisme : Swedish Research Council, Swedish Research Council
ID : K2010-70X-20430-04-3
Organisme : Cancer Research UK
ID : C5047/A10692
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : U01 CA098216
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201200008C
Pays : United States
Organisme : Cancer Research UK
ID : C5047/A7357
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA128978
Pays : United States
Organisme : U.S. National Institutes of Health, National Cancer Institute
ID : U01-CA98710
Organisme : Cancer Research UK
ID : C1287/A10118
Pays : United Kingdom
Organisme : The National Institute of Health (NIH) Cancer Post-Cancer GWAS
ID : 1 U19 CA 148537-01
Organisme : The National Health and Medical Research Council, Australia
ID : 504700
Organisme : The National Health and Medical Research Council, Australia
ID : 504702
Organisme : NCI NIH HHS
ID : U01 CA098233
Pays : United States
Organisme : U.S. National Institutes of Health, National Cancer Institute
ID : U01-CA98233
Organisme : Cancer Research UK
ID : C16913/A6135
Pays : United Kingdom
Organisme : The National Health and Medical Research Council, Australia
ID : 504715
Organisme : Swedish Cancer Foundation
ID : 09-0677
Organisme : Post-Cancer GWAS initiative
ID : 1U19 CA148112
Organisme : NCI NIH HHS
ID : U19 CA148112
Pays : United States
Organisme : U.S. National Institutes of Health, National Cancer Institute
ID : U01-CA98216
Organisme : NCI NIH HHS
ID : U01 CA098758
Pays : United States
Organisme : US National Institutes of Health (NIH)
ID : U19 CA 148537
Organisme : The National Health and Medical Research Council, Australia
ID : 623204
Organisme : NCI NIH HHS
ID : U19 CA148065
Pays : United States
Organisme : Cancer Research UK
ID : C5047/A3354
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : HHSN268201200008I
Pays : United States
Organisme : The National Health and Medical Research Council, Australia
ID : 614296
Organisme : NCI NIH HHS
ID : P30 CA071789
Pays : United States
Organisme : Cancer Research UK
ID : C1287/A16563
Pays : United Kingdom
Organisme : Post-Cancer GWAS initiative
ID : 1U19 CA148065
Organisme : Wellcome Trust
ID : 209057
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : U01 CA098710
Pays : United States
Organisme : The National Health and Medical Research Council, Australia
ID : 450104
Organisme : Post-Cancer GWAS initiative
ID : 1U19 CA148537
Informations de copyright
© 2021 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.
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