. 2023 Jun;13(6):e1291.

doi: 10.1002/ctm2.1291.

Trans-ethnic polygenic risk scores for body mass index: An international hundred K+ cohorts consortium study

Hui-Qi Qu¹, John J Connolly¹, Peter Kraft², Jirong Long³, Alexandre Pereira^{2

4}, Christopher Flatley⁵, Constance Turman², Bram Prins⁶, Frank Mentch¹, Paulo A Lotufo^{7

8}, Per Magnus^{9

10}, Meir J Stampfer^{2

11

12}, Rulla Tamimi², A Heather Eliassen², Wei Zheng³, Gun Peggy Stromstad Knudsen⁵, Oyvind Helgeland⁵, Adam S Butterworth^{6

13

14

15}, Hakon Hakonarson^{1

16

17

18

19}, Patrick M Sleiman^{1

16

17}; IHCC consortium

Affiliations

¹ The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
³ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁴ Department of Population Health Sciences, Weill Cornell Medicine, New York, New York, USA.
⁵ Division of Health Data and Digitalization, Department of Genetics and Bioinformatics, Norwegian Institute of Public Health, Oslo, Norway.
⁶ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁷ Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
⁸ Centro de Pesquisas Clínicas e Epidemiológicas, Hospital Universitário, Universidade de São Paulo, São Paulo, Brazil.
⁹ University of Oslo, Oslo, Norway.
¹⁰ Center for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
¹¹ Department of Nutrition, Harvard T.H., Chan School of Public Health, Boston, Massachusetts, USA.
¹² Channing Division of Network Medicine, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
¹³ The National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁴ British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
¹⁵ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
¹⁶ Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁷ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹⁸ Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹⁹ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

PMID: 37337639
PMCID: PMC10280047
DOI: 10.1002/ctm2.1291

Trans-ethnic polygenic risk scores for body mass index: An international hundred K+ cohorts consortium study

Hui-Qi Qu et al. Clin Transl Med. 2023 Jun.

. 2023 Jun;13(6):e1291.

doi: 10.1002/ctm2.1291.

Authors

Affiliations

¹ The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
³ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁴ Department of Population Health Sciences, Weill Cornell Medicine, New York, New York, USA.
⁵ Division of Health Data and Digitalization, Department of Genetics and Bioinformatics, Norwegian Institute of Public Health, Oslo, Norway.
⁶ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁷ Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
⁸ Centro de Pesquisas Clínicas e Epidemiológicas, Hospital Universitário, Universidade de São Paulo, São Paulo, Brazil.
⁹ University of Oslo, Oslo, Norway.
¹⁰ Center for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
¹¹ Department of Nutrition, Harvard T.H., Chan School of Public Health, Boston, Massachusetts, USA.
¹² Channing Division of Network Medicine, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
¹³ The National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁴ British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
¹⁵ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
¹⁶ Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁷ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹⁸ Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹⁹ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

PMID: 37337639
PMCID: PMC10280047
DOI: 10.1002/ctm2.1291

Abstract

Background: While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non-European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans-ethnic PRS for body mass index (BMI) through this relatively new international effort.

Methods: The polygenic risk score (PRS) model was developed, trained and tested at the Center for Applied Genomics (CAG) of The Children's Hospital of Philadelphia (CHOP) based on a BMI meta-analysis from the GIANT consortium. The validated PRS models were subsequently disseminated to the participating sites. Scores were generated by each site locally on their cohorts and summary statistics returned to CAG for final analysis.

Results: We show that in the absence of a well powered trans-ethnic GWAS from which to derive marker SNPs and effect estimates for PRS, trans-ethnic scores can be generated from European ancestry GWAS using Bayesian approaches such as LDpred, by adjusting the summary statistics using trans-ethnic linkage disequilibrium reference panels. The ported trans-ethnic scores outperform population specific-PRS across all non-European ancestry populations investigated including East Asians and three-way admixed Brazilian cohort.

Conclusions: Here we show that for a truly polygenic trait such as BMI adjusting the summary statistics of a well powered European ancestry study using trans-ethnic LD reference results in a score that is predictive across a range of ancestries including East Asians and three-way admixed Brazilians.

Keywords: body mass index; obesity; polygenic risk score; population admixture; trans-ethnic.

PubMed Disclaimer

Conflict of interest statement

A.S.B declares grants outside of this work from AstraZeneca, Bayer, Biogen, BioMarin, Merck and Sanofi. All other authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

**FIGURE 1**
Development of a trans‐ethnic polygenic risk score for body mass index.

**FIGURE 2**
AUC values following the initial validation of PRS models in‐house. 57 613 randomly selected individuals with genotypes and BMI data from the the Center for Applied Genomics biobank at the Children's Hospital of Philadelphia were used for the validation.

See this image and copyright information in PMC

Update of

Trans-ethnic Polygenic Risk Scores for Body Mass Index: An International Hundred K+ Cohorts Consortium Study.
Qu H, Connolly JJ, Kraft P, Long J, Pereira A, Flatley C, Turman C, Prins B, Mentch F, Lotufo PA, Magnus P, Stampfer MJ, Tamimi R, Eliassen AH, Zheng W, Knudsen GPS, Helgeland O, Butterworth AS, Hakonarson H, Sleiman PM. Qu H, et al. medRxiv [Preprint]. 2023 Jan 18:2023.01.17.23284675. doi: 10.1101/2023.01.17.23284675. medRxiv. 2023. Update in: Clin Transl Med. 2023 Jun;13(6):e1291. doi: 10.1002/ctm2.1291. PMID: 36712066 Free PMC article. Updated. Preprint.

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Trans-ethnic polygenic risk scores for body mass index: An international hundred K+ cohorts consortium study

Affiliations

Trans-ethnic polygenic risk scores for body mass index: An international hundred K+ cohorts consortium study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials