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. 2023 Jul 6;110(7):1200-1206.
doi: 10.1016/j.ajhg.2023.05.010. Epub 2023 Jun 12.

Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry

Burcu F Darst  1 Jiayi Shen  2 Ravi K Madduri  3 Alexis A Rodriguez  3 Yukai Xiao  3 Xin Sheng  2 Edward J Saunders  4 Tokhir Dadaev  4 Mark N Brook  4 Thomas J Hoffmann  5 Kenneth Muir  6 Peggy Wan  2 Loic Le Marchand  7 Lynne Wilkens  7 Ying Wang  8 Johanna Schleutker  9 Robert J MacInnis  10 Cezary Cybulski  11 David E Neal  12 Børge G Nordestgaard  13 Sune F Nielsen  13 Jyotsna Batra  14 Judith A Clements  14 Australian Prostate Cancer BioResource  15 Henrik Grönberg  16 Nora Pashayan  17 Ruth C Travis  18 Jong Y Park  19 Demetrius Albanes  20 Stephanie Weinstein  20 Lorelei A Mucci  21 David J Hunter  22 Kathryn L Penney  23 Catherine M Tangen  24 Robert J Hamilton  25 Marie-Élise Parent  26 Janet L Stanford  27 Stella Koutros  20 Alicja Wolk  28 Karina D Sørensen  29 William J Blot  30 Edward D Yeboah  31 James E Mensah  31 Yong-Jie Lu  32 Daniel J Schaid  33 Stephen N Thibodeau  34 Catharine M West  35 Christiane Maier  36 Adam S Kibel  37 Géraldine Cancel-Tassin  38 Florence Menegaux  39 Esther M John  40 Eli Marie Grindedal  41 Kay-Tee Khaw  42 Sue A Ingles  43 Ana Vega  44 Barry S Rosenstein  45 Manuel R Teixeira  46 NC-LA PCaP Investigators  47 Manolis Kogevinas  48 Lisa Cannon-Albright  49 Chad Huff  50 Luc Multigner  51 Radka Kaneva  52 Robin J Leach  53 Hermann Brenner  54 Ann W Hsing  55 Rick A Kittles  56 Adam B Murphy  57 Christopher J Logothetis  58 Susan L Neuhausen  59 William B Isaacs  60 Barbara Nemesure  61 Anselm J Hennis  62 John Carpten  63 Hardev Pandha  64 Kim De Ruyck  65 Jianfeng Xu  66 Azad Razack  67 Soo-Hwang Teo  68 Canary PASS Investigators  69 Lisa F Newcomb  69 Jay H Fowke  70 Christine Neslund-Dudas  71 Benjamin A Rybicki  71 Marija Gamulin  72 Nawaid Usmani  73 Frank Claessens  74 Manuela Gago-Dominguez  75 Jose Esteban Castelao  76 Paul A Townsend  77 Dana C Crawford  78 Gyorgy Petrovics  79 Graham Casey  80 Monique J Roobol  81 Jennifer F Hu  82 Sonja I Berndt  20 Stephen K Van Den Eeden  83 Douglas F Easton  84 Stephen J Chanock  20 Michael B Cook  20 Fredrik Wiklund  16 John S Witte  85 Rosalind A Eeles  86 Zsofia Kote-Jarai  87 Stephen Watya  88 John M Gaziano  89 Amy C Justice  90 David V Conti  2 Christopher A Haiman  2
Affiliations

Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry

Burcu F Darst et al. Am J Hum Genet. .

Abstract

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.

Keywords: African ancestry; genetics; genome-wide polygenic risk score; health disparities; polygenic risk score; prostate cancer; risk modeling.

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Conflict of interest statement

Declaration of interests The authors have no conflicts of interest to disclose.

Figures

Figure 1
Figure 1
Comparison of PRS performance in the CA UG Study and the UK Biobank testing data (A–D) PRS performance is evaluated using area under the curve (AUC) estimated in men of (A) African and (C) European ancestry and OR of prostate cancer for each SD increase in PRS in men of (B) African and (D) European ancestry. Note that differences in base model performances between populations most likely reflect differences in participant recruitment procedures rather than true differences between populations.
Figure 2
Figure 2
Comparison of PRS performance in the MVP validation data (A–D) PRS performance is evaluated using area under the curve (AUC) estimated in men of (A) African and (C) European ancestry and OR of prostate cancer for each SD increase in PRS in men of (B) African and (D) European ancestry.

Update of

  • Evaluating Approaches for Constructing Polygenic Risk Scores for Prostate Cancer in Men of African and European Ancestry.
    Darst BF, Shen J, Madduri RK, Rodriguez AA, Xiao Y, Sheng X, Saunders EJ, Dadaev T, Brook MN, Hoffmann TJ, Muir K, Wan P, Le Marchand L, Wilkens L, Wang Y, Schleutker J, MacInnis RJ, Cybulski C, Neal DE, Nordestgaard BG, Nielsen SF, Batra J, Clements JA; Australian Prostate Cancer BioResource; Grönberg H, Pashayan N, Travis RC, Park JY, Albanes D, Weinstein S, Mucci LA, Hunter DJ, Penney KL, Tangen CM, Hamilton RJ, Parent MÉ, Stanford JL, Koutros S, Wolk A, Sørensen KD, Blot WJ, Yeboah ED, Mensah JE, Lu YJ, Schaid DJ, Thibodeau SN, West CM, Maier C, Kibel AS, Cancel-Tassin G, Menegaux F, John EM, Grindedal EM, Khaw KT, Ingles SA, Vega A, Rosenstein BS, Teixeira MR; NC-LA PCaP Investigators; Kogevinas M, Cannon-Albright L, Huff C, Multigner L, Kaneva R, Leach RJ, Brenner H, Hsing AW, Kittles RA, Murphy AB, Logothetis CJ, Neuhausen SL, Isaacs WB, Nemesure B, Hennis AJ, Carpten J, Pandha H, De Ruyck K, Xu J, Razack A, Teo SH; Canary PASS Investigators; Newcomb LF, Fowke JH, Neslund-Dudas C, Rybicki BA, Gamulin M, Usmani N, Claessens F, GagoDominguez M, Castelao JE, Townsend PA, Crawford DC, Petrovics G, Casey G, Roobol MJ, Hu JF, Berndt SI, Van Den Eeden SK, Easton DF, Chanock SJ, Co… See abstract for full author list ➔ Darst BF, et al. medRxiv [Preprint]. 2023 May 15:2023.05.12.23289860. doi: 10.1101/2023.05.12.23289860. medRxiv. 2023. Update in: Am J Hum Genet. 2023 Jul 6;110(7):1200-1206. doi: 10.1016/j.ajhg.2023.05.010. PMID: 37292833 Free PMC article. Updated. Preprint.

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