TY - JOUR
T1 - Development and validation of a trans-ancestry polygenic risk score for type 2 diabetes in diverse populations
AU - Ge, Tian
AU - Irvin, Marguerite R.
AU - Patki, Amit
AU - Srinivasasainagendra, Vinodh
AU - Lin, Yen Feng
AU - Tiwari, Hemant K.
AU - Armstrong, Nicole D.
AU - Benoit, Barbara
AU - Chen, Chia Yen
AU - Choi, Karmel W.
AU - Cimino, James J.
AU - Davis, Brittney H.
AU - Dikilitas, Ozan
AU - Etheridge, Bethany
AU - Feng, Yen Chen Anne
AU - Gainer, Vivian
AU - Huang, Hailiang
AU - Jarvik, Gail P.
AU - Kachulis, Christopher
AU - Kenny, Eimear E.
AU - Khan, Atlas
AU - Kiryluk, Krzysztof
AU - Kottyan, Leah
AU - Kullo, Iftikhar J.
AU - Lange, Christoph
AU - Lennon, Niall
AU - Leong, Aaron
AU - Malolepsza, Edyta
AU - Miles, Ayme D.
AU - Murphy, Shawn
AU - Namjou, Bahram
AU - Narayan, Renuka
AU - O’Connor, Mark J.
AU - Pacheco, Jennifer A.
AU - Perez, Emma
AU - Rasmussen-Torvik, Laura J.
AU - Rosenthal, Elisabeth A.
AU - Schaid, Daniel
AU - Stamou, Maria
AU - Udler, Miriam S.
AU - Wei, Wei Qi
AU - Weiss, Scott T.
AU - Ng, Maggie C.Y.
AU - Smoller, Jordan W.
AU - Lebo, Matthew S.
AU - Meigs, James B.
AU - Limdi, Nita A.
AU - Karlson, Elizabeth W.
N1 - Funding Information:
The eMERGE Network was initiated and funded by National Human Genome Research Institute (NHGRI) through the following grants: U01HG006828 (Cincinnati Children's Hospital Medical Center and Boston Children’s Hospital); U01HG006830 (Children’s Hospital of Philadelphia); U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation, and Pennsylvania State University); U01HG006382 (Geisinger Clinic); U01HG006375 (Group Health Cooperative and the University of Washington); U01HG006379 (Mayo Clinic); U01HG006380 (Icahn School of Medicine at Mount Sinai); U01HG006388 (Northwestern University); U01HG006378 (Vanderbilt University Medical Center); and U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center). The eMERGE IV Mass General Brigham site was funded by the NHGRI through U01HG008685, the Columbia University site was funded through U01HG008680, and the University of Alabama at Birmingham site was funded through U01HG011167. The REGARDS genetics (R01HL136666), HyperGEN (R01HL055673), GenHAT (R01HL123782) and WPC (R01HL092173, K24HL133373) studies were all supported by the National Heart, Lung, and Blood Institute (NHLBI). The parent REGARDS study was funded by the National Institute of Neurological Disorders and Stroke (NINDS) through U01NS041588. This work was additionally supported by grant 2020096 from the Doris Duke Charitable Foundation (A.L.) and by the following NIH grants: UL1TR001873, OT2OD026553, OT2HL161841, P30AR070253, P30AR069625, U01HG011723, U01DK105556 (M.C.Y.N), R01DK066358 (M.C.Y.N), R01DK078616 (J.B.M.), R01HL151855 (J.B.M.), R01HL092173 (N.A.L.), R01AR063759 (E.W.K.), R21AR078339 (E.W.K), R00AG054573 (T.G.), K25DK128563 (A.K.), K23DK114551 (M.S.U).
Funding Information:
All patient/participant consent of the eMERGE Network has been obtained and the appropriate institutional forms have been archived. The use of eMERGE data in the present work was approved by the Institutional Review Board (IRB) at Mass General Brigham (Protocol 2020P000575). Participants in the four Black cohorts from the University of Alabama at Birmingham (UAB) provided consent for genetic research related to cardiovascular diseases. Generation of the GWAS data was funded through the National Heart, Lung, and Blood Institute (NHLBI). The use of the data for PRS validation was approved by the UAB IRB (REGARDS IRB: 161228001; GenHAT IRB: 160415008; HyperGEN IRB: 160331004; WPC IRB: 131122001). Collection of the Taiwan Biobank (TWB) data was approved by the Ethics and Governance Council (EGC) of TWB and the Department of Health and Welfare, Taiwan (Wei-Shu-I-Tzu NO.1010267471). TWB obtained informed consent from all participants for research use of collected data. The access to and the use of TWB data in the present work was approved by the EGC of TWB (Approval Number: TWBR10907-05) and the Institutional Review Board (IRB) of National Health Research Institutes, Taiwan (Approval Number: EC1090402-E). This study was conducted in accordance with the Declaration of Helsinki.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - Clinical implementation
KW - Diverse populations
KW - Polygenic risk score
KW - Type 2 diabetes
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U2 - 10.1186/s13073-022-01074-2
DO - 10.1186/s13073-022-01074-2
M3 - Article
C2 - 35765100
AN - SCOPUS:85133024033
SN - 1756-994X
VL - 14
JO - Genome Medicine
JF - Genome Medicine
IS - 1
M1 - 70
ER -