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. 2024 Dec 29;26(1):189.
doi: 10.1186/s13058-024-01947-x.

Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction

Kristia Yiangou  1 , Nasim Mavaddat  2 , Joe Dennis  2 , Maria Zanti  1 , Qin Wang  2 , Manjeet K Bolla  2 , Mustapha Abubakar  3 , Thomas U Ahearn  3 , Irene L Andrulis  4   5 , Hoda Anton-Culver  6 , Natalia N Antonenkova  7 , Volker Arndt  8 , Kristan J Aronson  9 , Annelie Augustinsson  10 , Adinda Baten  11 , Sabine Behrens  12 , Marina Bermisheva  13   14 , Amy Berrington de Gonzalez  15 , Katarzyna Białkowska  16 , Nicholas Boddicker  17 , Clara Bodelon  18 , Natalia V Bogdanova  7   19   20 , Stig E Bojesen  21   22   23 , Kristen D Brantley  24 , Hiltrud Brauch  25   26   27 , Hermann Brenner  8   28 , Nicola J Camp  29 , Federico Canzian  30 , Jose E Castelao  31 , Melissa H Cessna  32   33 , Jenny Chang-Claude  12   34 , Georgia Chenevix-Trench  35 , Wendy K Chung  36 ; NBCS Collaborators; Sarah V Colonna  29 , Fergus J Couch  37 , Angela Cox  38 , Simon S Cross  39 , Kamila Czene  40 , Mary B Daly  41 , Peter Devilee  42   43 , Thilo Dörk  20 , Alison M Dunning  44 , Diana M Eccles  45 , A Heather Eliassen  24   46   47 , Christoph Engel  48   49 , Mikael Eriksson  40 , D Gareth Evans  50   51 , Peter A Fasching  52 , Olivia Fletcher  53 , Henrik Flyger  54 , Lin Fritschi  55 , Manuela Gago-Dominguez  56 , Aleksandra Gentry-Maharaj  57   58 , Anna González-Neira  59   60 , Pascal Guénel  61 , Eric Hahnen  62   63 , Christopher A Haiman  64 , Ute Hamann  65 , Jaana M Hartikainen  66   67 , Vikki Ho  68 , James Hodge  18 , Antoinette Hollestelle  69 , Ellen Honisch  70 , Maartje J Hooning  69 , Reiner Hoppe  25   71 , John L Hopper  72 , Sacha Howell  73   74   75 , Anthony Howell  76 ; ABCTB Investigators; kConFab Investigators; Simona Jakovchevska  77 , Anna Jakubowska  16   78 , Helena Jernström  10 , Nichola Johnson  53 , Rudolf Kaaks  12 , Elza K Khusnutdinova  13   79 , Cari M Kitahara  80 , Stella Koutros  3 , Vessela N Kristensen  81   82 , James V Lacey  83   84 , Diether Lambrechts  85   86 , Flavio Lejbkowicz  87 , Annika Lindblom  88   89 , Michael Lush  2 , Arto Mannermaa  67   90   91 , Dimitrios Mavroudis  92 , Usha Menon  57 , Rachel A Murphy  93   94 , Heli Nevanlinna  95 , Nadia Obi  96   97 , Kenneth Offit  98   99 , Tjoung-Won Park-Simon  20 , Alpa V Patel  18 , Cheng Peng  46 , Paolo Peterlongo  100 , Guillermo Pita  59 , Dijana Plaseska-Karanfilska  77 , Katri Pylkäs  101   102 , Paolo Radice  103 , Muhammad U Rashid  65   104 , Gad Rennert  105 , Eleanor Roberts  73 , Juan Rodriguez  40 , Atocha Romero  106 , Efraim H Rosenberg  107 , Emmanouil Saloustros  108 , Dale P Sandler  109 , Elinor J Sawyer  110 , Rita K Schmutzler  62   63   111 , Christopher G Scott  17 , Xiao-Ou Shu  112 , Melissa C Southey  113   114   115 , Jennifer Stone  72   116 , Jack A Taylor  109   117 , Lauren R Teras  18 , Irma van de Beek  118 , Walter Willett  24   46   47 , Robert Winqvist  101   102 , Wei Zheng  112 , Celine M Vachon  119 , Marjanka K Schmidt  120   121   122 , Per Hall  40   123 , Robert J MacInnis  72   115 , Roger L Milne  72   113   115 , Paul D P Pharoah  124 , Jacques Simard  125 , Antonis C Antoniou  2 , Douglas F Easton  2   44 , Kyriaki Michailidou  126   127
Affiliations

Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction

Kristia Yiangou et al. Breast Cancer Res. .

Abstract

Background: The 313-variant polygenic risk score (PRS313) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed.

Methods: We explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank. The mean PRS was calculated by country in the BCAC dataset and by country of birth in the UK Biobank. We explored different approaches to reduce the observed heterogeneity in the mean PRS across the countries, and investigated the implications of the distribution variability in risk prediction.

Results: The mean PRS313 differed markedly across European countries, being highest in individuals from Greece and Italy and lowest in individuals from Ireland. Using the overall European PRS313 distribution to define risk categories, leads to overestimation and underestimation of risk in some individuals from these countries. Adjustment for principal components explained most of the observed heterogeneity in the mean PRS. The mean estimates derived when using an empirical Bayes approach were similar to the predicted means after principal component adjustment.

Conclusions: Our results demonstrate that PRS distribution differs even within European ancestry populations leading to underestimation or overestimation of risk in specific European countries, which could potentially influence clinical management of some individuals if is not appropriately accounted for. Population-specific PRS distributions may be used in breast cancer risk estimation to ensure predicted risks are correctly calibrated across risk categories.

Keywords: Breast cancer; Polygenic risk scores; Risk calibration; Risk prediction.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: All study participants gave written informed consent, and all the Breast Cancer Association Consortium studies were approved by the relevant ethics committees. The Breast Cancer Association Consortium data have been used under the application with access number 712. The use of the UK Biobank has been approved under application ID102655. Consent for publication: Not applicable. Competing interests: The following authors declare conflicts not directly relevant to this work as stated below: U.M. has a patent (no: EP10178345.4) for Breast Cancer Diagnostics and held personal shares in Abcodia Ltd between 2011 and 2021. She has research collaborations with Mercy Bioanalytics, iLOF, RNA Guardian and Micronoma in the field of early detection of cancer. P.A.F. conducts research funded by Amgen, Novartis and Pfizer. He received Honoraria from Roche, Novartis and Pfizer. R.A.M. is a Consultant for Pharmavite.

Figures

Fig. 1
Fig. 1
Standardized PRS313 distribution across countries for overall, ER-positive and ER-negative breast cancer in BCAC. The squares represent the mean PRS by country, and the error bars represent the corresponding 95% confidence intervals. ER, Oestrogen receptor; FE Model, Fixed-effects Model; PRS, Polygenic risk score
Fig. 2
Fig. 2
PRS distribution across countries for overall breast cancer in the UK Biobank. Distribution of the mean PRS306 and “standard” PRS for breast cancer, as defined in the UK Biobank, across countries of origin for participating white females. The squares represent the mean PRS by country, and the error bars represent the corresponding 95% confidence intervals. FE Model, Fixed-effects Model; PRS, Polygenic risk score
Fig. 3
Fig. 3
PRS313 distribution by percentiles in the pooled BCAC dataset, Greece, Ireland and Italy. The dashed line corresponds to the 95th percentile of the PRS313 distribution in controls of the pooled BCAC dataset
See this image and copyright information in PMC

Update of

  • Differences in polygenic score distributions in European ancestry populations: implications for breast cancer risk prediction.
    Yiangou K, Mavaddat N, Dennis J, Zanti M, Wang Q, Bolla MK, Abubakar M, Ahearn TU, Andrulis IL, Anton-Culver H, Antonenkova NN, Arndt V, Aronson KJ, Augustinsson A, Baten A, Behrens S, Bermisheva M, de Gonzalez AB, Białkowska K, Boddicker N, Bodelon C, Bogdanova NV, Bojesen SE, Brantley KD, Brauch H, Brenner H, Camp NJ, Canzian F, Castelao JE, Cessna MH, Chang-Claude J, Chenevix-Trench G, Chung WK; NBCS Collaborators; Colonna SV, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Dörk T, Dunning AM, Eccles DM, Eliassen AH, Engel C, Eriksson M, Evans DG, Fasching PA, Fletcher O, Flyger H, Fritschi L, Gago-Dominguez M, Gentry-Maharaj A, González-Neira A, Guénel P, Hahnen E, Haiman CA, Hamann U, Hartikainen JM, Ho V, Hodge J, Hollestelle A, Honisch E, Hooning MJ, Hoppe R, Hopper JL, Howell S, Howell A; ABCTB Investigators; kConFab Investigators; Jakovchevska S, Jakubowska A, Jernström H, Johnson N, Kaaks R, Khusnutdinova EK, Kitahara CM, Koutros S, Kristensen VN, Lacey JV, Lambrechts D, Lejbkowicz F, Lindblom A, Lush M, Mannermaa A, Mavroudis D, Menon U, Murphy RA, Nevanlinna H, Obi N, Offit K, Park-Simon TW, Patel AV, Peng C, Peterlongo P, Pita G, Plaseska-Karanfilska D, Pylkäs… See abstract for full author list ➔ Yiangou K, et al. medRxiv [Preprint]. 2024 Feb 13:2024.02.12.24302043. doi: 10.1101/2024.02.12.24302043. medRxiv. 2024. Update in: Breast Cancer Res. 2024 Dec 29;26(1):189. doi: 10.1186/s13058-024-01947-x. PMID: 38410445 Free PMC article. Updated. Preprint.

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