. 2022 Jun 29;14(1):70.

doi: 10.1186/s13073-022-01074-2.

Development and validation of a trans-ancestry polygenic risk score for type 2 diabetes in diverse populations

Tian Ge^{1

2

3

4}, Marguerite R Irvin⁵, Amit Patki⁶, Vinodh Srinivasasainagendra⁶, Yen-Feng Lin^{7

8

9}, Hemant K Tiwari⁶, Nicole D Armstrong⁵, Barbara Benoit¹⁰, Chia-Yen Chen¹¹, Karmel W Choi^{12

13

14}, James J Cimino¹⁵, Brittney H Davis¹⁶, Ozan Dikilitas^{17

18}, Bethany Etheridge¹⁶, Yen-Chen Anne Feng^{12

19}, Vivian Gainer¹⁰, Hailiang Huang^{20

21

22}, Gail P Jarvik²³, Christopher Kachulis²⁰, Eimear E Kenny²⁴, Atlas Khan²⁵, Krzysztof Kiryluk²⁵, Leah Kottyan²⁶, Iftikhar J Kullo¹⁷, Christoph Lange²⁷, Niall Lennon²⁰, Aaron Leong^{20

28

29}, Edyta Malolepsza²⁰, Ayme D Miles¹⁵, Shawn Murphy³⁰, Bahram Namjou²⁶, Renuka Narayan¹⁶, Mark J O'Connor³¹, Jennifer A Pacheco³², Emma Perez^{33

34}, Laura J Rasmussen-Torvik³⁵, Elisabeth A Rosenthal²³, Daniel Schaid³⁶, Maria Stamou³⁷, Miriam S Udler^{12

20

21}, Wei-Qi Wei³⁸, Scott T Weiss³⁹, Maggie C Y Ng⁴⁰, Jordan W Smoller^{12

13

14

20}, Matthew S Lebo^{20

34

41}, James B Meigs^{20

21

28}, Nita A Limdi¹⁶, Elizabeth W Karlson^{33

34}

Affiliations

¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. tge1@mgh.harvard.edu.
² Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA. tge1@mgh.harvard.edu.
³ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. tge1@mgh.harvard.edu.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA. tge1@mgh.harvard.edu.
⁵ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
⁶ Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
⁷ Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan.
⁸ Department of Public Health & Medical Humanities, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁹ Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
¹⁰ Mass General Brigham Research Information Science & Computing, Boston, MA, USA.
¹¹ Translational Biology, Biogen Inc., Cambridge, MA, USA.
¹² Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹³ Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Informatics Institute, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁶ Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁷ Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
¹⁸ Department of Internal Medicine, Mayo Clinician-Investigator Training Program, Mayo Clinic, Rochester, MN, USA.
¹⁹ Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.
²⁰ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²¹ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
²² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
²³ Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁴ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁵ Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, USA.
²⁶ Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
²⁷ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²⁸ Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.
²⁹ Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
³⁰ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
³¹ UMass Memorial Health Care, Worcester, MA, USA.
³² Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
³³ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³⁴ Mass General Brigham Personalized Medicine, Boston, MA, USA.
³⁵ Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
³⁶ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
³⁷ Division of Endocrinology, Massachusetts General Hospital, Boston, MA, USA.
³⁸ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
³⁹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴⁰ Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴¹ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.

PMID: 35765100
PMCID: PMC9241245
DOI: 10.1186/s13073-022-01074-2

Development and validation of a trans-ancestry polygenic risk score for type 2 diabetes in diverse populations

Tian Ge et al. Genome Med. 2022.

. 2022 Jun 29;14(1):70.

doi: 10.1186/s13073-022-01074-2.

Authors

Affiliations

¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. tge1@mgh.harvard.edu.
² Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA. tge1@mgh.harvard.edu.
³ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. tge1@mgh.harvard.edu.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA. tge1@mgh.harvard.edu.
⁵ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
⁶ Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
⁷ Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan.
⁸ Department of Public Health & Medical Humanities, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁹ Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
¹⁰ Mass General Brigham Research Information Science & Computing, Boston, MA, USA.
¹¹ Translational Biology, Biogen Inc., Cambridge, MA, USA.
¹² Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹³ Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Informatics Institute, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁶ Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁷ Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
¹⁸ Department of Internal Medicine, Mayo Clinician-Investigator Training Program, Mayo Clinic, Rochester, MN, USA.
¹⁹ Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.
²⁰ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²¹ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
²² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
²³ Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁴ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁵ Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, USA.
²⁶ Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
²⁷ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²⁸ Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.
²⁹ Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
³⁰ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
³¹ UMass Memorial Health Care, Worcester, MA, USA.
³² Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
³³ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³⁴ Mass General Brigham Personalized Medicine, Boston, MA, USA.
³⁵ Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
³⁶ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
³⁷ Division of Endocrinology, Massachusetts General Hospital, Boston, MA, USA.
³⁸ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
³⁹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴⁰ Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴¹ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.

PMID: 35765100
PMCID: PMC9241245
DOI: 10.1186/s13073-022-01074-2

Abstract

Background: Type 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent. Comprehensive assessment of T2D PRS in non-European populations is critical for equitable deployment of PRS to clinical practice that benefits global populations.

Methods: We integrated T2D GWAS in European, African, and East Asian populations to construct a trans-ancestry T2D PRS using a newly developed Bayesian polygenic modeling method, and assessed the prediction accuracy of the PRS in the multi-ethnic Electronic Medical Records and Genomics (eMERGE) study (11,945 cases; 57,694 controls), four Black cohorts (5137 cases; 9657 controls), and the Taiwan Biobank (4570 cases; 84,996 controls). We additionally evaluated a post hoc ancestry adjustment method that can express the polygenic risk on the same scale across ancestrally diverse individuals and facilitate the clinical implementation of the PRS in prospective cohorts.

Results: The trans-ancestry PRS was significantly associated with T2D status across the ancestral groups examined. The top 2% of the PRS distribution can identify individuals with an approximately 2.5-4.5-fold of increase in T2D risk, which corresponds to the increased risk of T2D for first-degree relatives. The post hoc ancestry adjustment method eliminated major distributional differences in the PRS across ancestries without compromising its predictive performance.

Conclusions: By integrating T2D GWAS from multiple populations, we developed and validated a trans-ancestry PRS, and demonstrated its potential as a meaningful index of risk among diverse patients in clinical settings. Our efforts represent the first step towards the implementation of the T2D PRS into routine healthcare.

Keywords: Clinical implementation; Diverse populations; Polygenic risk score; Type 2 diabetes.

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Conflict of interest statement

CYC is an employee of Biogen, Inc. and holds Biogen stock. KWC is involved in the Genetics and Neuroscience Special Interest Group and the Anxiety & Depression Association of America. JJC serves on the Board of Directors of the American Medical Informatics Association. EEK is a paid consultant of Encompass Bio and Galatea Bio, received honoraria from Illumina, Regeneron and 23&Me, and is a member of the Board of Directors of the American Society of Human Genetics and a member of the International Expert Committee, H3Africa. KK serves on the Scientific Advisory Board for Gilead Sciences and Goldfinch Bio. STW has received compensation from UpToDate. JWS is a member of the Leon Levy Foundation Neuroscience Advisory Board, participates on the Data and Safety Monitoring Board (DSMB) for the Implementing Genomics in Practice (IGNITE II) program, and received an honorarium for an internal seminar at Biogen, Inc. JBM is an Academic Associate with Quest Diagnostics R&D. EP is a paid consultant for Allelica. The remaining authors declare that they have no competing interests.

Figures

**Fig. 1**
Workflow of the construction and evaluation of the trans-ancestry T2D PRS

**Fig. 2**
Comparison of the predictive performance of PRS-CSx with three alternative PRS construction methods in the African and Hispanic/Latino samples of the eMERGE dataset. Alternative PRS methods include (i) a European-specific score derived by applying PRS-CS-auto to the European T2D GWAS summary statistics (PRS-CS EUR); (ii) a trans-ancestry score derived by applying PRS-CS-auto to the meta-analysis of the European, MEDIA and BBJ T2D GWAS (PRS-CS Meta); and (iii) a trans-ancestry score derived by applying LDpred2-auto to the T2D meta-GWAS (LDpred2 Meta)

**Fig. 3**
Tail discrimination of the PRS-CSx-derived trans-ancestry T2D PRS at various percentage cutoffs in the European, African (by meta-analyzing the eMERGE African dataset with the four UAB Black cohorts) and East Asian (by meta-analyzing the three TWB batches) populations. POP, population; EUR, European; AFR, African; EAS, East Asian; PPV, prevalence-adjusted positive predictive value; NPV, prevalence-adjusted negative predictive value

See this image and copyright information in PMC

References

1. Dietrich S, Jacobs S, Zheng J-S, Meidtner K, Schwingshackl L, Schulze MB. Gene-lifestyle interaction on risk of type 2 diabetes: A systematic review. Obes Rev. John Wiley & Sons, Ltd. 2019;20(11):1557–1571. - PMC - PubMed
1. Wang L, Li X, Wang Z, Bancks MP, Carnethon MR, Greenland P, et al. Trends in prevalence of diabetes and control of risk factors in diabetes among US adults, 1999-2018. JAMA. 2021;326(8):704–716. - PMC - PubMed
1. Gregg EW, Boyle JP, Thompson TJ, Barker LE, Albright AL, Williamson DF. Modeling the impact of prevention policies on future diabetes prevalence in the United States: 2010-2030. Popul Health Metr. 2013;11(1):18. - PMC - PubMed
1. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988-2012. JAMA. 2015;314(10):1021–1029. - PubMed
1. Centers for Disease Control and Prevention . National Diabetes Statistics Report. 2020.

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Development and validation of a trans-ancestry polygenic risk score for type 2 diabetes in diverse populations

Affiliations

Development and validation of a trans-ancestry polygenic risk score for type 2 diabetes in diverse populations

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical